Levetiracetam shows promise for treatment of feline audiogenic reflex seizures

A group of UK-based investigators from Davies Veterinary Group and the UCL School of Pharmacy, who recently engaged the veterinary world with an article defining the previously undocumented syndrome of feline audiogenic reflex seizures (FARS), have published follow-up findings about the treatment of the condition. Their paper, ‘Levetiracetam in the management of feline audiogenic reflex seizures: a randomised, controlled, open label study’, appears in the Journal of Feline Medicine and Surgery.

FARS is a problem of older cats, which typically exhibit myoclonic seizures (brief, shock-like jerks of a muscle or a group of muscles) in response to certain high-pitched sounds. Both non-pedigree and pedigree cats (in particular, Birmans) may be affected. A range of sound stimuli has been reported, including the crinkling of tin foil and a metal spoon dropping into a ceramic feeding bowl, through to firewood spitting and even texting on a phone. It was this bizarre collection of triggers that captured the imagination of media around the world, which dubbed the condition ‘Tom and Jerry syndrome’, and spread the story far and wide.

While avoiding the triggering sounds can reduce the incidence of seizures, this is not always practical and so this latest research potentially spells good news for owners of affected cats.

The study compared the efficacy of two antiepileptic drugs, levetiracetam (a relatively novel medication that has proven effective in studies of people with generalised epilepsies that experience myoclonic seizures) and the much older first generation drug phenobarbital, in 57 cats diagnosed with FARS. Cats were treated with one or other drug over a 12 week period; and owners were asked to record the date, number and type of seizures, any signs of illness, side effects and changes in activity or attitude, as well as whether they thought their cat’s quality of life had improved, remained the same or deteriorated since starting the medication.

All cats receiving levetiracetam showed a reduction in the number of days that they experienced myoclonic seizures by at least half. In comparison, only 3% of cats showed the same reduction when treated with phenobarbital. The majority of reported side effects, such as lethargy and inappetence, were mild to moderate in both groups and these resolved after about 2 weeks in the cats treated with levetiracetam; in the phenobarbital group, however, side effects were relatively persistent. Owners of cats treated with phenobarbital perceived no benefit from using the medication; in contrast, all of the owners of cats treated with levetiracetam commented that their cat appeared brighter and more responsive after the first couple of weeks of treatment. Moreover, five cats treated with phenobarbital were switched to levetiracetam after the study, as their owners desired improved seizure control.

Having established that levetiracetam is an effective and well-tolerated treatment for cats with hallmark myoclonic seizures, the next step is to identify whether levetiracetam will also prevent so-called generalised tonic-clonic seizures. This is another seizure type seen in cats with FARS, and is what most people think of as a ‘seizure’, with the cat losing consciousness and its body stiffening and jerking, often for several minutes.

Lead author on the paper, Mark Lowrie, says, ‘It is great to find a medication that works so well at controlling these seizures. Levetiracetam is not licensed in cats but it has proven to be a very safe drug. For affected cats to benefit, it is important that vets recognise the signs as this newly defined syndrome of FARS and that this medication is used in preference to other, less efficacious, anti-epileptic drugs.’  Science Daily  Original web page at Science Daily


* Pharmacists’ study helps prevent antibiotic-induced kidney failure

When associate professor of pharmacy practice Tadd Hellwig of South Dakota State University and three pharmacy colleagues at the Sanford USD Medical Center noticed that some hospital patients given two common antibiotics developed kidney failure, they decided to take a closer look.

What they discovered led to closer monitoring of patients receiving vancomycin and piperacillin-tazobactam due to an increased risk of kidney damage. Vancomycin is used to treat patients with staph bacteria that are resistant to antibiotics, Hellwig explained. Piperacillin-tazobactam is a broad-spectrum antibiotic combination. “Both are very common within the hospital setting,” he said, noting that they are given intravenously.

“People associate vancomycin with nephrotoxicity,” said Sanford collaborator pharmacist Rhonda Hammerquist. She recalled that the question about whether the combination of vancomycin and piperacillin-tazobactam increased that risk came up during a weekly residency program meeting. Others involved in the study were Sanford pharmacists Beth Loecker and Jamie Shields.

The antibiotics can be used for several types of infections, including skin and soft tissue infections, as well as pneumonia, Hammerquist explained. “Based on our population, we see this combination quite frequently.”

The researchers identified 735 Sanford USD Medical Center adult patients who received vancomycin, piperacillin-tazobactam or both during two 3-month periods, one in 2009 and another in 2010. From 2009 to 2010, the procedure for administering piperacillin-tazobactam changed from a 30-minute to a 4-hour infusion time.

More than 20 percent of the 109 patients who received both antibiotics in the shorter infusion time developed acute kidney failure, according Hellwig. Among the 101 who received the drug combination infusion over the longer period, the incidence of kidney failure was 16.8 percent.

This is significantly higher than the overall 10.5 percent rate of acute kidney failure for all the patients in the study, he noted. When only piperacillin-tazobactam was administered, the kidney failure rates decreased to 13.5 percent for the shorter infusion time and 8.4 percent for patients who received the antibiotic over the 4-hour period.

“Piperacillin-tazobactam results in more acute renal failure than vancomycin,” Hellwig pointed out. With vancomycin alone, the kidney failure rate dropped to 4.9 percent.

“We were among the first groups to look at and present the data,” Hammerquist said. That then led to educating the Sanford staff about what they had learned. “This is one of the first big research projects that I’ve done,” Hellwig said. “It showed me that even without grant funding, I can still look at problems, do research and get results that can improve patient care.”

Tyler Turek, pharmacy clinical manager at Sanford USD Medical Center, said, “Overall, this study heightened our awareness of the need to consider alternative therapies whenever clinically appropriate.”

Hellwig and his colleagues presented their results at the February 2012 Society of Critical Care Medicine annual meeting. Their work was one of two studies subsequently highlighted in the June 2012 Pharmacy Practice News.

“It opened the doors for lots of others to look at it further,” he said. Researchers from the University of Florida-Jacksonville, Duke University and Campbell University in North Carolina and the University of Maryland published similar studies in a 2014 issue of Pharmacotherapy.

“This work continues to highlight the role that our pharmacists have as experts who can identify opportunities for improvement in medication-related care,” Turek said.

Hellwig agreed. “Within a hospital setting, we are able to identify these types of problems, then do the research to clarify what the results actually are and how to use those results in daily monitoring of patients in the hospital.”  Science Daily  Original web page at Science Daily


Endangered foxes on Catalina Island get promising treatment to reduce ear tumors

A team of scientists led by UC Davis found alarming rates of ear mites and ear canal tumors in the endangered foxes. Ear mite treatments they initiated have since dramatically reduced the problem, their studies show.

Until recently, endangered foxes on California’s Catalina Island were suffering from one of the highest prevalences of tumors ever documented in a wildlife population, UC Davis scientists have found. But treatment of ear mites appears to be helping the wild animals recover. Roughly half of adult foxes examined between 2001 and 2008 had tumors in their ears, with about two-thirds of those malignant, according to a UC Davis study published this month in the journal PLOS ONE.

More than 98 percent of the foxes were also infected with ear mites. These mites appear to be a predisposing factor for ear tumors in the Santa Catalina Island fox. “We established a high prevalence of both tumors and ear mites, and hypothesized that there was something we could potentially do about it, which now appears to be significantly helping this population,” said Winston Vickers, lead author of the prevalence study and an associate veterinarian with the UC Davis Wildlife Health Center at the UC Davis School of Veterinary Medicine.

Working closely with researchers from the Institute for Wildlife Studies and Catalina Island Conservancy, the scientists conducted one of the few studies to estimate disease prevalence in an entire free-living wildlife population.

A complementary study, also led by UC Davis and published in PLOS ONE today, found that treatments with acaracide, a chemical agent used to kill ear mites in dogs and cats, reduced the prevalence of ear mite infection dramatically, from 98 percent to 10 percent among treated foxes at the end of the six-month trial. Ear canal inflammation and other signs of developing ear tumors also dropped.

“It’s rare to have a success story,” said the ear mite study’s lead author, Megan Moriarty, a student with the UC Davis School of Veterinary Medicine when the study began and currently a staff research associate at the UC Davis Wildlife Health Center. “It was interesting to see such striking results over a relatively short time period.”

Santa Catalina Island foxes are intensively managed by the Catalina Island Conservancy. In 2009, when the mite treatment study began, the Conservancy added acaracide to the variety of preventative treatments they administer to the foxes each year.

The Conservancy confirms that, in the years since, the overall prevalence of ear mites has dramatically declined in the areas they normally catch and treat foxes, as have the rates of tissue masses in the ear canals, suggesting reduced tumor presence.

“The annual prophylactic acaracide treatment has greatly improved the overall condition of the foxes’ ear canals,” said Julie King, the Conservancy’s director of Conservation and Wildlife Management and co-author of both studies. “Within just a few months post treatment, the presence of wax, infection, inflammation, and pigmentation virtually disappear. We have also noted an apparent reduction in the number of tumors observed, despite the fact that the absence of wax and other obstructions has made them easier to detect.

Conservancy biologists have also documented a cascade effect on the foxes’ offspring, since most young foxes get the ear mites from their parents. “Prior to treatment in 2009, approximately 90 percent of all pups handled had ear mites, whereas by 2015, mites were detected in only 15 percent of new pups.” King said.

The studies pose new questions. For instance, the mite treatment certainly reduces the prevalence and severity of mite infection, as well as risk factors for tumor development, but what effect will it have on overall tumor and cancer rates for these foxes in the long term?

Also, ear mites infect other Channel Island foxes, but those foxes don’t develop ear canal tumors. So why are Santa Catalina Island foxes predisposed to these tumors and not other Channel Island foxes? Vickers and colleagues are preparing to research possible genetic reasons for this.

“Catalina foxes have an over-exuberant tissue reaction to the same stimuli–the mites–and that appears to lead to the tumors,” Vickers said. “That’s why we gravitate toward genetics in addition to other factors.” The Santa Catalina Island fox is one of six subspecies native to the Channel Islands off the coast of Southern California. Its population declined dramatically in 1999 when a distemper epidemic decimated up to 90 percent of the population, prompting the federal endangered species listing for the roughly 150 foxes remaining. The population has since rebounded to an estimated 1,717 foxes.   Science Daily  Original web page at Science Daily


US government approves transgenic chicken

Transgenic chickens are the latest animals engineered to produce ‘farmaceutical’ drugs.

The US Food and Drug Administration (FDA) has approved a chicken that has been genetically engineered to produce a drug in its eggs. The drug, Kanuma (sebelipase alfa), is a recombinant human enzyme marketed by Alexion Pharmaceuticals. It replaces a faulty enzyme in people with a rare, inherited condition that prevents the body from breaking down fatty molecules in cells.

Following its approval by the FDA on 8 December, Kanuma joins a small group of ‘farmaceuticals’ on the US market. In 2009, the agency approved genetically modified goats that produce an anticoagulant called ATryn (antithrombin) in their milk. And last year, the FDA authorized a drug for treating hereditary angioedema that is produced by transgenic rabbits.

The FDA’s latest decision “shows that the ATryn goats weren’t just a one-off”, says Jay Cormier, a lawyer at Hyman, Phelps and McNamara in Washington DC and a former scientific reviewer for the FDA. “The process can function for more than just one particular unique case.”

The agency moved quickly to consider Kanuma, giving it a priority review, orphan-drug status and a breakthrough-therapy designation. The disease that it is designed to treat, lysosomal acid lipase deficiency, causes fat to accumulate in the liver, spleen and vasculature. A form of the disease that strikes infants is quickly fatal. A second form that affects older patients causes liver enlargement, fibrosis and cirrhosis, as well as cardiovascular disease.

“Before we had this drug, we didn’t have any treatment for the patients that really addressed the underlying biochemical defect in the disorder,” says Barbara Burton, a paediatrician with the Northwestern University Feinberg School of Medicine in Chicago, Illinois. Clinicians could only provide nutrition and supportive care to infants, says Burton, who worked with Alexion to conduct the clinical trials. Older patients are treated with statins — which do not address the fatty build-up in the liver.

Unlike the genetically engineered AquAdvantage salmon that was approved by the FDA last month, the transgenic chickens that produce Kanuma are not intended to enter the food supply. But just as with the AquAdvantage salmon, the FDA considers the chicken’s genetic modifications to be an ‘animal drug’.

Because every cell in the modified chicken contains altered DNA, the FDA “asserts its jurisdiction over the entire chicken”, says Cormier. Under its process for considering animal drugs, the FDA examined whether altering the chickens’ DNA would harm them, and whether the modified DNA was stable as it passed to new generations of chickens. The FDA says that the chickens are not likely to accidentally enter the food supply or adversely affect the environment because they are raised in indoor facilities.

William Muir, a geneticist at Purdue University in West Lafayette, Indiana, praised the FDA’s decision to approve the transgenic chickens. “The floodgates are opening,” he says, “and I can’t wait to see what comes next.”

Nature doi:10.1038/nature.2015.18985  Nature  Original web page at Nature


Wild toads saved from killer fungal disease

After a six-year effort, biologists say they have for the first time managed to rid a wild toad species of a lethal fungal disease that threatens amphibians around the world.

Midwife toads on the Spanish island of Mallorca are now free of the chytrid fungus Batrachochytrium dendrobatidis, says Jaime Bosch, an evolutionary biologist at Spain’s National Museum of Natural History in Madrid. His team reported their success in the journal Biology Letters on 18 November. But the successful treatment — which involved treating tadpoles with an antifungal drug and chemically cleansing their ponds — may not be widely applicable to the habitats of other amphibian species that are threatened by chytrid, the researchers and others say.

The fungal disease is one of the greatest threats amphibians face across the globe: chytrid has already wiped out hundreds of species of frogs. Bosch and his colleagues in Spain and the United Kingdom first set out to save isolated populations of vulnerable midwife toads on Mallorca in 2009. The fungus was spreading on the toads’ skin, stifling their ability to breathe and manage their water balance, and ultimately killing them.

The researchers removed all the toads’ tadpoles and treated them in the laboratory with the antifungal drug itraconazole, while also draining and drying out their ponds in the hope of eliminating the pathogen. But after they were returned home – via helicopter – the first batch of successfully treated tadpoles was soon infected with the fungus again.

In 2012, the researchers tried again: this time, they drained and treated one set of ponds with Virkon S, an agricultural disinfectant made by DuPont. Tadpoles that were returned to those ponds a year later remained healthy, whereas those returned to ponds that were drained but not treated fell ill. After disinfecting the rest of the ponds, the researchers found no evidence of fungal infection two years on.

It is still unclear exactly where and how the fungus lingered in the untreated drained ponds, though Bosch and his team suspect that tadpoles were being reinfected by adult toads that remained tucked out of sight. The team sprayed disinfectant into nooks and crannies, so may have managed to reach the hidden adults.

“It’s pretty exciting that they were able to eliminate chytrid fungus in multiple sites across the island,” says Karen Lips, a conservation biologist at the University of Maryland, College Park. But Lips thinks that the treatment may only work in specific habitats. Mallorca is dry, with granite-carved ponds that flood seasonally, and few other species live there that could reintroduce the fungus. “Not many other places are geared to this approach,” Lips says. Exceptions include other isolated environments such as captive breeding programmes, zoos, laboratories and other kinds of islands — for example, urban islands and mountaintops. Still, she says, in places where species are endangered and costs are not a barrier, “I think this shows there are certain things you can do.”

To rid many amphibians of their fungal infection, it will be necessary to find another way, Bosch agrees. But the study shows that it may be worth trying the aggressive chemical intervention in some circumstances, he says. One of Bosch’s co-authors, Trent Garner of the Zoological Society of London, would like to see more mitigation efforts. “We spray for fungal infections in our crops every year,” he says. “Are there other things that we could use that could be applied environmentally and at a large scale?”

Doug Woodhams, an amphibian disease ecologist at the University of Massachusetts, Boston, hopes that interventions that don’t involve extensive spraying of antifungal chemicals might also work. In his laboratory he is trying probiotic therapy, which introduces beneficial microbes to fight fungal infection — but he has yet to prove that it works in the wild.

Meanwhile, in southeast continental Spain, which has a similar geographical landscape to Mallorca, Bosch and his colleagues are using their method to try to protect populations of the Betic midwife toad. Endemic to the region for millions of years, the toads now inhabit a landscape where humans have shifted water into artificial ponds meant for cattle. The toads now make these plastic-lined pools their home — a perfect setting in which to knock out the chytrid fungus.

Artificial cattle ponds in southeast Spain, where fungal-infected Betic midwife toads now reside, will also be cleansed.

Nature doi:10.1038/nature.2015.18814  Nature  Original web page at Nature


Diabetes drug could be used to combat fatty liver disease, research shows

New research published in The Lancet has shown that a drug, currently used in the treatment of Type II diabetes, can be effective in clearing fatty liver disease from some patients. The researchers from the University of Birmingham believe that the findings present the possibility of new therapies for patients with non-alcoholic fatty liver disease, for which there is no current licensed treatment

The trial was the first of its type to look into the action of liraglutide in the treatment of non-alcoholic steatohepatitis. The trial demonstrated that 48 weeks of treatment with liraglutide resulted in 4 out of 10 patients clearing evidence of NASH from their livers. This was much higher than the effect seen in patients receiving placebo (1 in 10) and met the pre-specified primary end-point. Additionally, patients in the active treatment group showed a higher level of weight loss (over 5 kg) whilst receiving medication.

Liraglutide is manufactured and licenced by Novo Nordisk and is currently licenced for the treatment of Type II diabetes. It is administered in the form of an injection which the patient self-injects, which means the treatment could be administered at home.

Non-alcoholic fatty liver disease (NAFLD) describes a wide range of conditions caused by a build-up of fat within the liver cells, usually seen in people who are overweight or obese. It is the most common liver disorder in developed countries — affecting approximately 20% of the United States population and 25-30% of people in the UK.

Non-alcoholic steatohepatitis (NASH) is the more serious form of NAFLD and can ultimately increase the risk of total liver failure which means a transplant is required, but if one is not found, it will lead to death. It is often considered to be something of a ‘silent killer’ because most people feel well, unaware that they have a liver problem, until the disease is at an advanced stage.

The trial was led by the National Institute for Health Research (NIHR) Birmingham Liver Biomedical Research Unit (BRU) in conjunction with the Wellcome Trust and Novo Nordisk and other sites at universities in Nottingham, Hull and Leeds. Professor Philip Newsome, the lead investigator from the University of Birmingham, explained, “Because there are no licensed treatments available for non-alcoholic fatty liver disease, there is a large unmet clinical need. It is becoming ever more important that we find a treatment as the occurrence of fatty liver disease continues to grow — hand in hand with the problem of obesity. This study provides confidence in the further exploration of this class of drugs in NASH.” Science Daily  Original web page at Science Daily


Data scientists create world’s first therapeutic venom database

What doesn’t kill you could cure you. A growing interest in the therapeutic value of animal venom has led a pair of Columbia University data scientists to create the first catalog of known animal toxins and their physiological effects on humans.

VenomKB, short for Venom Knowledge Base, summarizes the results of 5,117 studies in the medical literature describing the use of venom toxins as painkillers and as treatments for diseases like cancer, diabetes, obesity, and heart failure. Drawn from an automated analysis of the literature, VenomKB documents nearly 42,723 effects on the body. Though modern medicine makes use of only a small fraction of the toxins documented thus far, the researchers hope that the catalog will spur the discovery of new compounds and medical treatments.

“With this list we can take stock of what we know about venoms and their therapeutic effects” said Nicholas Tatonetti, an assistant professor of biomedical informatics at Columbia University Medical Center and a member of the Data Science Institute. “The questions now is: How can we use this information with other databases to discover new compounds and therapies?”

Tatonetti and Joseph Romano, a graduate student, searched on the term “venoms/therapeutic use” in a database of 22 million medical research papers. This produced a list of 5,117 venom-related studies whose results they summarized using a pair of computer algorithms. After cross-referencing toxins and drugs listed under multiple names and correcting other irregularities in the data, they found 42,723 unique mentions of venoms having a specific effect on the body. Their results are published in a companion study to Venom KB in the journal Scientific Data.

Venom’s capacity to heal is paradoxically linked to its fast-acting, lethal effects in the wild. Found in more than 173,000 species, venoms evolved over millions of years to target molecules that are often involved in disease. The toxic proteins and amino acids known as peptides that make up venom act on cell receptors and ion channels, controlling how cells behave.

By mimicking or altering how these toxins act on specific human cells, researchers can develop drugs that inhibit pain or treat diseases, often with fewer side effects than those of drugs already on the market.

About a dozen major drugs have emerged from this strategy so far, National Geographic magazine reported in 2013. One of the first, an anticoagulant called Arvin, gained favor in the late 1960s after a doctor discovered that ancrod, a protein found in the venom of the Malayan pit viper, could treat blood clots in the legs.

The widely used type 2 diabetes drug Byetta, is made from the toxin exenatide, found in the saliva of the venomous Gila monster, a lizard native to the United States and Mexico.

Another drug, bombesin, uses a toxin found in the skin of the venomous European fire-bellied toad to treat gastrointestinal disorders. Bombesin’s ability to bind to neuronal tumors has led to interest in developing a florescent version that could guide surgeons around the edges of a tumor.

Five compounds produced by the venomous cone snail have made it to clinical trials, including ziconotide, the generic term for an analgesic similar to morphine.

The Malayan pit viper, Gila monster, European fire-bellied toad, and cone snail account for about 18 percent of the 5,117 venom-related studies now catalogued in Venom KB. Yet there are 10 million or more venomous species that have yet to be studied. Zoltan Takacs, a toxinologist who earned his PhD in evolutionary studies at Columbia, estimates there are 20 million venom toxins waiting to be screened.

Venom KB got its start after Romano approached Tatonetti, his thesis adviser, about studying medicinal uses of venom. Tatonetti suggested that Romano start looking through the venom database. To their surprise there was neither a database nor a list. Still modest in size, VenomKB is expected to grow more useful as researchers contribute more data. “With a large enough library we can screen for more effective, safer compounds,” said Romano.

Databases of compounds and their biological effects have been used in recent years to discover and develop new drugs as well as uncover problems with drugs already in use. Tatonetti and his colleagues mined a federal database of documented drug side effects, the FDA Adverse Event Reporting System (FAERS), and discovered that the interaction of the anti-depressant paroxetine, sold under the brand name Paxil, and the statin pravastatin, sold as Pravachol, could raise blood glucose levels in diabetic patients.

With VenomKB up and running, Tatonetti and Romano plan to contribute data of their own. Starting with samples of dried venom from the black mamba, they will perform experiments and explore new treatments for chronic pain, diabetes and heart disease.   Science Daily  Original web page at Science Daily


* Experimental drug targeting Alzheimer’s disease shows anti-aging effects

Salk Institute researchers have found that an experimental drug candidate aimed at combating Alzheimer’s disease has a host of unexpected anti-aging effects in animals. The Salk team expanded upon their previous development of a drug candidate, called J147, which takes a different tack by targeting Alzheimer’s major risk factor–old age. In the new work, the team showed that the drug candidate worked well in a mouse model of aging not typically used in Alzheimer’s research. When these mice were treated with J147, they had better memory and cognition, healthier blood vessels in the brain and other improved physiological features, as detailed November 12, 2015 in the journal Aging.

“Initially, the impetus was to test this drug in a novel animal model that was more similar to 99 percent of Alzheimer’s cases,” says Antonio Currais, the lead author and a member of Professor David Schubert’s Cellular Neurobiology Laboratory at Salk. “We did not predict we’d see this sort of anti-aging effect, but J147 made old mice look like they were young, based upon a number of physiological parameters.”

Alzheimer’s disease is a progressive brain disorder, recently ranked as the third leading cause of death in the United States and affecting more than five million Americans. It is also the most common cause of dementia in older adults, according to the National Institutes of Health. “While most drugs developed in the past 20 years target the amyloid plaque deposits in the brain (which are a hallmark of the disease), none have proven effective in the clinic,” says Schubert, senior author of the study.

Several years ago, Schubert and his colleagues began to approach the treatment of the disease from a new angle. Rather than target amyloid, the lab decided to zero in on the major risk factor for the disease–old age. Using cell-based screens against old age-associated brain toxicities, they synthesized J147.

Previously, the team found that J147 could prevent and even reverse memory loss and Alzheimer’s pathology in mice that have a version of the inherited form of Alzheimer’s, the most commonly used mouse model. However, this form of the disease comprises only about 1 percent of Alzheimer’s cases. For everyone else, old age is the primary risk factor, says Schubert. The team wanted to explore the effects of the drug candidate on a breed of mice that age rapidly and experience a version of dementia that more closely resembles the age-related human disorder.

In this latest work, the researchers used a comprehensive set of assays to measure the expression of all genes in the brain, as well as over 500 small molecules involved with metabolism in the brains and blood of three groups of the rapidly aging mice. The three groups of rapidly aging mice included one set that was young, one set that was old and one set that was old but fed J147 as they aged.

The old mice that received J147 performed better on memory and other tests for cognition and also displayed more robust motor movements. The mice treated with J147 also had fewer pathological signs of Alzheimer’s in their brains. Importantly, because of the large amount of data collected on the three groups of mice, it was possible to demonstrate that many aspects of gene expression and metabolism in the old mice fed J147 were very similar to those of the young animals. These included markers for increased energy metabolism, reduced brain inflammation and reduced levels of oxidized fatty acids in the brain.

Another notable effect was that J147 prevented the leakage of blood from the microvessels in the brains of old mice. “Damaged blood vessels are a common feature of aging in general, and in Alzheimer’s, it is frequently much worse,” says Currais. Currais and Schubert note that while these studies represent a new and exciting approach to Alzheimer’s drug discovery and animal testing in the context of aging, the only way to demonstrate the clinical relevance of the work is to move J147 into human clinical trials for Alzheimer’s disease. “If proven safe and effective for Alzheimer’s, the apparent anti-aging effect of J147 would be a welcome benefit,” adds Schubert. The team aims to begin human trials next year.

This study was supported by the Salk Institute Pioneer Fund Postdoctoral Scholar Award and the Salk Nomis Fellowship Award, fellowships from the Hewitt Foundation and Bundy Foundation, and grants from the Burns Foundation and NIH  Science Daily  Original web page at Science Daily


* Exploring vulnerabilities of the Cryptosporidium parasite

Cryptosporidium parvum is a gastrointestinal parasite that can cause moderate to severe diarrhea in children and adults, and deadly opportunistic infection in AIDS patients. Because C. parvum is resistant to chlorine disinfectant treatment, it frequently causes water-borne outbreaks around the world. A study published on Nov. 12th in PLOS Pathogens provides a detailed analysis of a C. parvum protein that is central to glycolysis — the only pathway by which the parasite can generate energy — and identifies it as a potential drug target.

Guan Zhu and colleagues, from Texas A&M University in College Station, USA, study the parasite’s metabolism during its complicated life-cycle. C. parvum exists both in free stages (where parasites are in the environment or in the host’s digestive tract) and intracellular stages following host cell invasion, during which the parasite occupies a specialized compartment — the parasitophorous vacuole — which is delineated by a host-cell derived border called the parasitophorous vacuole membrane (PVM).

For this study, the researchers focused on lactate dehydrogenase (LDH), an enzyme central to glycolysis. Glycolysis is the only metabolic process by which organisms like C. parvum universal biological energy storage molecule. They found that the C. parvum LDH (CpLDH) protein is found inside the parasite’s cells during the free stages, but is then transferred to the PVM during intracellular development, indicating involvement of the PVM in parasite energy  — that lack functional mitochondria to derive energy from oxygen — can generate ATP, the metabolism, and specifically, in lactate fermentation. They also demonstrate that two known LDH inhibitors, gossypol and FX11, can inhibit both CpLDH activity and parasite growth.

The researchers summarize that their observations “not only reveal a new function for the poorly understood PVM structure in hosting the intracellular development of C. parvum, but also suggest LDH as a potential target for developing therapeutics against this opportunistic pathogen, for which fully effective treatments are not yet available.” Acknowledging that the ultimate validation of CpLDH as a drug target requires tools for knockout or knockdown of genes of interest in Cryptosporidium, they say recent advances towards this goal raise hope that such validation will be possible in the near future.

Overall, they conclude that “the present data, together with the fact that C. parvum relies on glycolysis for producing ATP, support the notion that CpLDH is worth exploring as a potential target for the development of anti-cryptosporidial therapeutics.”  Science Daily  Original web page at Science Daily


Blocking enzymes in hair follicles promotes hair growth

Two FDA-approved drugs reawaken dormant hair follicles. Inhibiting a family of enzymes inside hair follicles that are suspended in a resting state restores hair growth, a new study from researchers at Columbia University Medical Center has found. The research was published today in the online edition of Science Advances. In experiments with mouse and human hair follicles, Angela M. Christiano, PhD, and colleagues found that drugs that inhibit the Janus kinase (JAK) family of enzymes promote rapid and robust hair growth when directly applied to the skin.

The study raises the possibility that drugs known as JAK inhibitors could be used to restore hair growth in multiple forms of hair loss such as that induced by male pattern baldness, and additional types that occur when hair follicles are trapped in a resting state. Two JAK inhibitors have been approved by the U.S. Food and Drug Administration. One is approved for treatment of blood diseases (ruxolitinib) and the other for rheumatoid arthritis (tofacitinib). Both are being tested in clinical trials for the treatment of plaque psoriasis and alopecia areata, an autoimmune disease that causes hair loss.

“What we’ve found is promising, though we haven’t yet shown it is effective for male pattern baldness,” said Dr. Christiano. “More work needs to be done to test formulations of JAK inhibitors specially made for the scalp to determine whether they can induce hair growth in humans.

Christiano and her colleagues serendipitously discovered the effect of JAK inhibitors on hair follicles when they were studying a type of hair loss known as alopecia areata, caused by an autoimmune attack on the hair follicles. Christiano and colleagues reported last year that JAK inhibitors shut off the signal that provokes the autoimmune attack, and that oral forms of the drug restore hair growth in some people with the disorder.

In the course those experiments, Dr. Christiano noticed that mice grew more hair when the drug was applied topically to the skin than when given internally. This suggested JAK inhibitors might have a direct effect on the hair follicles in addition to inhibiting the immune attack.

When the researchers looked more closely at normal mouse hair follicles, they found that JAK inhibitors rapidly awakened resting follicles out of dormancy. Hair follicles do not produce hair constantly but rather by cycling between resting and growing phases.

JAK inhibitors trigger the follicles’ normal reawakening process, the researchers found. Mice treated for five days with one of two JAK inhibitors sprouted new hair within 10 days, greatly accelerating the hair follicle growth phase. No hair grew on untreated control mice in the same time period.

“There are very few compounds that can push hair follicles into their growth cycle so quickly,” said Dr. Christiano. “Some topical agents induce tufts of hair here and there after a few weeks, but very few have such a potent and rapid-acting effect.” The drugs also produce longer hair from human hair follicles grown in culture and on skin grafted onto mice.

It’s likely that the drugs that are so effective in enhancing hair growth in the mice could affect the same pathways in human follicles, suggesting they could induce new hair growth and extend the growth of existing hairs in humans.

It remains to be seen if JAK inhibitors can reawaken hair follicles that have been suspended in a resting state because of androgenetic alopecia (which causes male and female pattern baldness) or other forms of hair loss. So far, all the experiments have been conducted in normal mice and human follicles. Experiments to address hair follicles affected by hair loss disorders are under way. The title of the paper is: Pharmacologic inhibition of JAK-STAT signaling promotes hair growth.  Science Daily  Original web page at Science Daily


Intestine-specific delivery of insulin demonstrates promise with new oral formulation

An intestinal patch device containing insulin that can be swallowed in the form of a capsule, in development by researchers at University of California Santa Barbara, has demonstrated efficacy of blood glucose management in diabetic rats. This work is being presented Oct. 27 at the 2015 American Association of Pharmaceutical Scientists (AAPS) Annual Meeting and Exposition.

Diabetes is a group of metabolic disorders that are caused by a deficiency in the ability to make insulin, a hormone that regulates glucose levels. According to the Center for Disease Control, diabetes affects roughly 29.1 million people in the U.S. alone, and is one of the major contributors to mortality, leading to over 230,000 deaths annually with its associated comorbidities. Insulin therapy is an important part of diabetes treatment — used to regulate the level of sugar in the bloodstream and storage of glucose. Existing marketed insulin formulations are injectables — currently, it is not possible for insulin to be taken by mouth, as digestive enzymes in the gastrointestinal tract break down the protein so that it is no longer active.

Samir Mitragotri, Ph.D., a professor in the College of Engineering at the University of California Santa Barbara, and Amrita Banerjee, a postdoctoral fellow, developed patches made of mucoadhesive polymers loaded with insulin and an intestinal permeation enhancer, then placed the patch devices in enteric-coated capsules. Once in the intestine, the patch-containing pills are specially designed to dissolve, releasing the patches so that they can attach to the intestinal wall for site-specific delivery of the insulin. “We’ve created a technology with several innovative features. Our mucoadhesive devices fit inside of a small capsule and then deliver the drug in the intestine in a very effective manner,” said Mitragotri. “There are many possible benefits and advantages of an oral delivery for insulin.”

The mucoadhesive strength of the patches was determined by placing patches on porcine intestine. After 30 minutes, the patches were gradually pulled away from the intestine and the strength required to completely detach the patches from the intestine was quantified using a microbalance. To further assess the efficacy of the patches, diabetic rats were fasted overnight and orally fed the capsules. Blood glucose levels were thereafter determined at different time points for up to eight hours using a commercial blood glucose meter to calculate the percent drop in glucose levels.

The patches showed a complete drug release profile, releasing 100 percent of the insulin and permeation enhancer content within five hours of study and demonstrated an excellent mucoadhesive strength of 24.22 ± 2.85 mN, which corresponded to greater than 100 times the individual patch weight. In vivo efficacy studies revealed that insulin patches containing 10 percent permeation enhancer were the most effective formulation, where the blood glucose levels dropped significantly to 69 ± 2.41 percent of initial levels in comparison to the no treatment control group, which showed no decrease in blood glucose levels over time.

“Diabetes is a growing problem in the U.S., with new survey data showing that 50 percent of adults living in the U.S. have diabetes or pre-diabetes,” said Banerjee. “The outcome of our studies suggest that this unique drug delivery approach could be used to deliver insulin orally in a continuous, time-dependent manner.

The next stage of Banerjee’s research is to continue in vivo rat studies to evaluate the intestinal patches for faster or extended release of insulin. Mitragotri’s group will also assess the oral delivery of other peptide drugs for diabetes (exenatide) and even osteoporosis (calcitonin).  Science Daily  Original web page at Science Daily


Medication dose needed for general anesthesia varies widely: Some patients may require less anesthesia

The amount of anesthetic required for general anesthesia during surgery varies widely from patient to patient and some may be able to receive a lower dose than typically administered, suggests a study being presented at the ANESTHESIOLOGY® 2015 annual meeting.

“Providing general anesthesia is a delicate balance, ensuring the patient receives enough, but not more than needed,” said Ana Ferreira, M.D., lead author of the study and a medical researcher in the Anesthesiology Department at Centro Hospitalar do Porto, Portugal. “Our research shows that there is no way to predict how much a patient will need. Administering the correct amount of anesthetic requires a physician anesthesiologist who has extensive knowledge of anesthesia and how to use it safely and effectively, understands the body, monitors vital functions closely and can instantly react to changes taking place. This expertise drives better outcomes and more personalized care.”

Physician anesthesiologists use a combination of anesthesia medications for surgery, including one — most commonly propofol — to render the patient unconscious. In the study, researchers determined that the amount of propofol required to produce unconsciousness varied widely between patients and was independent of age, gender, weight or height. Close monitoring of the patient’s neurological signs and brainwaves was used to determine when the correct dosage was achieved.

For the study, 126 patients were given propofol in a constant slow rate of infusion, enabling researchers to continuously monitor patient response and precisely determine when loss of consciousness occurred (e.g. not answering to name, not opening the eyes, etc.), as well as identify the exact amount of propofol required. Researchers found that there was a variation of 300 percent in the amount of propofol required to induce loss of consciousness and that more than two-thirds of the patients required less than the initial dose recommended by drug package inserts. The time needed to induce loss of consciousness varied from one minute and 22 seconds to nearly four minutes, researchers said. They also found significantly less propofol was required if pain medication (remifentanil) was given to the patient before propofol was provided, rather than after.

“We need to replace the recommendation of administering a specific amount of propofol based on a patient’s weight and age with a technique that allows individualization of a patient’s needs. That means administering propofol slowly at induction and monitoring the patient’s response every 10 seconds to precisely identify the moment loss of consciousness occurs, identifying the amount of propofol each patient requires and then using that information to guide the infusion rate of propofol required to maintain an adequate level of anesthesia,” said Pedro Amorim, M.D., co-author of the study, chief of staff of the Anesthesiology Department at Centro Hospitalar do Porto. “The time required for induction, using this method, is longer than if propofol is given based on the patient’s weight and age, but less than four minutes to induce loss of consciousness is acceptable and ensures safe and effective care.”  Science Daily  Original web page at Science Daily


Novel theoretical approach to reduce antibiotic resistance

The combination and sequence of antibiotics can promote or hinder the development of antibiotic-resistant bacteria.

It is estimated that each year in the United States 2 million people become infected with bacteria that are resistant to one or more types of antibiotics, and at least 23,000 people will die because of these infections. This problem is being exacerbated by overuse of antibiotics for livestock and also in community clinical practice. This overuse, combined with the slow pace of novel drug discovery is a growing threat to public health. In response to this, Moffitt Cancer Center researchers have developed a novel mathematical method inspired by Darwinian evolution to use current antibiotics to eliminate or reduce the development of antibiotic-resistant bacteria.

According to the Centers for Disease Control, one of the core actions that can be taken to fight antibiotic-resistant infections is to improve the use of antibiotics that currently exist. One approach to achieve this is by using different combinations or sequences of antibiotics; however, given the high number of antibiotics in existence, it would be extremely difficult to experimentally identify the best combination or sequence of drugs

Moffitt researchers overcame this problem by developing a novel mathematical approach to analyze antibiotic resistance. They showed that the ability of the bacterium E. coli to survive in antibiotics could be either promoted or hindered depending on the sequence of antibiotics given. They discovered that approximately 70 percent of different sequences of 2 to 4 antibiotics lead to resistance to the final drug

“Our results suggest that, through careful ordering of antibiotics, we may be able to steer evolution to a dead end from which resistance cannot emerge,” said Daniel Nichol, lead author and graduate student jointly in the Oxford University Department of Computer Science and Moffitt’s Department of Integrated Mathematical Oncology.

“Our results can be easily tested in the laboratory, and if validated could be used in clinical trials immediately, as all of the compounds we studied are FDA approved and commonly prescribed,” said Jacob G. Scott, M.D., senior author and member of Moffitt’s Radiation Oncology and Integrated Mathematical Oncology Departments.

The researchers explained that their results also serve as a caution to healthcare workers, as the careless or random prescription of drugs that occurs could inadvertently lead to antibiotic resistance.

“While I’m an oncologist, the problem of the evolution of resistance to antibiotics is completely analogous to that of cancer’s evolution of resistance to targeted therapy, and the mathematical model we’ve used can be applied to both situations. Our next efforts are jointly focused on targeted therapy in lung cancer as well as on validating our existing results in bacteria,” said Scott. Science Daily  Original we page at Science Daily


* Anti-parasite drugs sweep Nobel prize in medicine 2015

Chinese pharmacologist Youyou Tu developed key antimalarial drug artemisinin.

Three scientists who developed therapies against parasitic infections have won this year’s Nobel Prize in Physiology or Medicine.The winners are: William C. Campbell, a microbiologist at Drew University in Madison, New Jersey; Satoshi Ōmura, at Kitasato University in Japan; and Youyou Tu, a pharmacologist at the China Academy of Traditional Chinese Medicine (now known as the China Academy of Chinese Medical Sciences) in Beijing.

In the 1970s, Campbell and Ōmura discovered a class of compounds, called avermectins, that kill parasitic roundworms that cause infections such as river blindness and lymphatic filariasis. The most potent of these was released onto the market in 1981 as the drug ivermectin. Tu, who won a Lasker prize in 2011, developed the antimalarial drug artemisinin in the late 1960s and 1970s. She is the first China-based scientist to win a science Nobel.

In the 1960s, the main treatments for malaria were chloroquine and quinine, but they were proving increasingly ineffective. So in 1967, China established a national project against malaria to discover new therapies.

Working at the China Academy of Chinese Medical Sciences, Tu and her team screened more than 2,000 Chinese herbal remedies that showed potential antimalarial activity. An extract from the wormwood plant Artemisia annua proved especially effective and by 1972, the researchers had isolated chemically pure artemisinin.

“It’s great news, I’m very happy about this. She totally deserves it,” says Yi Rao, a neuroscientist at Peking University who has researched the discovery of artemisinin. But Rao points out that because of controversy over credit for the discovery, Tu has never won any major award in China. She has not been elected to either of China’s major academies — neither the Chinese Academy of Sciences nor the Chinese Academy of Engineering.

“Though other people were involved, Tu was clearly the undisputed leader,” says Rao. “But she’s never been given fair recognition within China.”

Working in Japan, Ōmura isolated strains of a group of soil bacteria called Streptomyces that were known to have antimicrobial properties. In 1974, he pulled out a promising strain from soil near a golf course, and sent it along, with others, to a team led by Campbell at the Merck Institute for Therapeutic Research in Rahway, New Jersey. (Ōmura’s institute had signed a research partnership with Merck in 1973).

Campbell’s team isolated the avermectins from the bacterial cultures, and tweaked the structure of one of the most promising compounds to develop it into a drug — ivermectin. In 1987, Merck announced that it would donate the drug to anyone who needed it for treatment of onchocerciasis (also known as river blindness). A decade later, the firm began giving away the drug to treat lymphatic filariasis. Each year, Merck gives away some 270 million treatments of the drug, according to the Mectizan Donation Program, in Decatur, Georgia.

The award highlights the global acceptance of the importance of parasitic infections, and neglected tropical diseases in general, says Stephen Ward, who researches drugs for neglected tropical diseases at the Liverpool School of Tropical Hygiene and Medicine. “It may refocus us on the idea that the immense diversity of products out there in the natural world is a great starting point for drug discovery,” he adds. Updates to follow.

Nature doi:10.1038/nature.2015.  Nature  Original web page at Nature


Use of personalized cancer drugs runs ahead of the science

More than 30% of cancer drugs are prescribed to treat conditions for which they have not been specifically approved. As the costs of genetic sequencing fall, oncologists are starting to prescribe expensive new drugs that target the genetic profiles of their patients’ tumours, even when those treatments have not been approved for the particular cancer involved.

But such ‘off-label’ use is running ahead of the state of scientific knowledge, suggests the first randomized clinical trial to test the idea. The study, published in Lancet Oncology, found that using personalized cancer drugs off-label provides no benefit over conventional chemotherapy. “This study is important because many oncologists have already adopted the personalized approach,” says Daniel Catenacci, an oncologist at the University of Chicago, Illinois, who was not involved in the trial. “Why have they abandoned the science?”

Lead author of the study Christophe Le Tourneau, an oncologist at the Curie Institute in Paris, says that he sees such off-label treatments “quite often” in practice. “I understand why it happens: patients want to live and physicians want to offer help,” he says. But Le Tourneau adds that patients whose tumours have genetic alterations that might be targeted by a non-approved drug are better served by entering clinical trials.

A small but growing number of personalized cancer drugs have been approved for treating particular cancers that involve specific mutations, but oncologists hope that these drugs will also work against related mutations in other cancers. By some counts, more than 30% of cancer drugs are prescribed off-label.

To test the benefits of off-label tailored drug regimens, researchers at eight French hospitals analysed their patients’ tumours to look for genetic or molecular abnormalities that might be amenable to precision medicine. The researchers randomly assigned 195 suitable patients either to one of 10 potentially relevant targeted treatment regimens, or to chemotherapy. There was no significant difference between the effects of the treatments.

Apostolia Tsimberidou, an oncologist at the University of Texas MD Anderson Cancer Center in Houston, says the study proves that it is feasible to run randomized trials of personalized medicine. But, in her view, the trial was poorly designed. It enrolled patients with advanced disease who were unlikely to benefit, she points out, and many patients received hormone therapy, which purists would not rate as truly targeted therapy. The trial also didn’t choose the best possible drugs to evaluate, and relied on a simplistic approach to matching cancer mutations to targeted treatment, she says.

Le Tourneau concedes the points, but notes that better drugs were not commercially available when the trial was set up in 2011. And he argues that many oncologists make similarly simple decisions when they prescribe off-label personalized drugs.

Catenacci agrees that many cancer physicians, for now, will be no better than the trial at matching possible targeted drugs to cancer mutations. The case for personalized medicine might become stronger if trials can get better at picking the most appropriate treatment to suit particular genetic and molecular signatures, he says.

A few such trials are under way. In 2012, Tsimberidou reported that an observational analysis of patients in clinical trials at her institute showed that enrolment in trials of targeted treatments conferred a benefit over prescribing non-targeted agents. She is now working to validate these results in a 1,400-patient randomized trial.

And in June, the US National Cancer Institute announced plans to start enrolling 1,000 patients in a precision-medicine trial called NCI-MATCH, which will match patients to more than 20 possible drugs on the basis of the genetic abnormalities in the patients’ tumours. The American Society of Clinical Oncology has also launched a registry called TAPUR, to compile data on what happens to patients who receive targeted cancer drugs off-label.

If any study does show that it is beneficial to prescribe personalized cancer drugs that target a patient’s tumour, regardless of whether the drug has been approved for the particular tissue type involved, that could pose a severe regulatory challenge, says Catenacci.

Le Tourneau adds that it is probably only a matter of time before the field has to face such challenges. Oncologists will eventually tailor treatments to the genetic and molecular profiles of tumours, rather than on the basis of where the tumour appears in the body, he says. “I’m pretty convinced we are getting there.”

Nature doi:10.1038/nature.2015.18389  Nature  Original web page at Nature


* Dramatic rise seen in antibiotic use

Antibiotic use is growing steadily worldwide, driven mainly by rising demand in low- and middle-income countries, according to a report released on 17 September. The research presents the clearest picture yet of how and where the drugs are used, and the prevalence of different types of antibiotic resistance.

The Center for Disease Dynamics, Economics and Policy (CDDEP), a non-profit group headquartered in Washington DC, based the analysis on data from scientific literature and national and regional surveillance systems. The organization used this to calculate and map the rate of antibiotic resistance for 12 types of bacteria in 39 countries, and trends in antibiotic use in 69 countries over the past 10 years or longer.

Global antibiotic consumption grew by 30% between 2000 and 2010. This growth is driven mostly by countries such as South Africa and India, where antibiotics are widely available over the counter and sanitation in some areas is poor.

In India, for instance, the number of Klebsiella pneumoniae infections that are resistant to a class of powerful antibiotics called carbapenems doubled from 29% in 2008 to 57% in 2014. By contrast, fewer than 10% of K. pneumoniae infections in the United States and Europe are carbapenem resistant.

The report also found that the use of antibiotics in livestock is growing worldwide. The problem is particularly acute in China, which used about 15,000 tons of antibiotics for this purpose in 2010; the country is projected to double its consumption by 2030.

Most high-income countries, by contrast, have begun instituting regulations on antibiotic use, and these are starting to pay off. According to the report, the number of methicillin-resistant Staphylococcus aureus (MRSA) infections, for example, has dropped precipitously in many areas, such as the United Kingdom, over the past eight years.

“I think it’s a very thorough and thought-provoking report,” says Daniel Sahm, chief scientific officer at International Health Management Associates in Schaumburg, Illinois. Because it is so difficult to gather data from developing countries, he says, the information used in the new analysis might contain holes: an argument for more-aggressive surveillance.

The report lists six steps for preventing antibiotic resistance in countries that do not yet have good policies. Some of those measures, such as improving sanitation, are obvious, whereas policies that restrict antibiotic use in agriculture and hospitals might be more difficult or controversial to implement.

But Timothy Walsh, a medical microbiologist at Cardiff University, UK, says that, although the suggestions offered are worthwhile, international cooperation in setting up a global surveillance network and regulations is necessary to limit the overuse of antibiotics. “We can pour as much money and sentiment and goodwill into the front end of the problem as we want,” he says. “But unless we start to have international action and accountability, we’re going to just keep on making the same mistakes over and over again.”

Nature doi:10.1038/nature.2015.18383  Nature  Original web page at Nature


* Virus re-engineered to deliver therapies to cells

Stanford researchers have ripped the guts out of a virus and totally redesigned its core to repurpose its infectious capabilities into a safe vehicle for delivering vaccines and therapies directly where they are needed.

The study reported today in the Proceedings of the National Academy of Sciences breathes new life into the field of targeted delivery, the ongoing effort to fashion treatments that affect diseased areas but leave healthy tissue alone.

“We call this a smart particle,” said James Swartz, the professor of chemical engineering and of bioengineering at Stanford who led the study. “We make it smart by adding molecular tags that act like addresses to send the therapeutic payload where we want it to go.” Using the smart particle for immunotherapy would involve tagging its outer surface with molecules designed to teach the body’s disease-fighting cells to recognize and destroy cancers, Swartz said.

For Swartz and his principal collaborator, Yuan Lu, now a pharmacology researcher at the University of Tokyo, the result is a vindication. When they first started the research four years ago, funding agencies said it couldn’t be done.

It will require much more effort to accomplish the second goal — packing tiny quantities of medicines into the smart particles, delivering the particles to and into diseased cells, and engineering them to release their payloads.

“This was a proof-of-principle experiment so there’s a lot of work to be done,” Swartz said. “But I believe we can use this smart particle to deliver cancer-fighting immunotherapies that will have minimal side effects.”

Massachusetts Institute of Technology Professor Robert Langer, a leader in targeted drug delivery research who was not connected to the Stanford experiments, also read the paper before publication.

“This is terrific work, a beautiful paper,” Langer said. “Dr. Swartz and colleagues have done a remarkable job of stabilizing viruslike particles and re-engineering their surface.” Targeted drug delivery is one of the ultimate goals of medicine because it seeks to focus remedies on diseased cells, minimizing the side effects that occur when, for instance, radiation or chemotherapies harm healthy cells while treating cancer.

Looking for a model in nature, many researchers focused on viruses, which target specific cells, sneak in and deliver an infectious payload. The new paper describes how the Stanford team designed a viruslike particle that is only a delivery vehicle with no infectious payload.

They started with the virus that causes Hepatitis B. This virus has three layers like an egg, and the researchers focused on the non-infectious middle layer, called the capsid. It is a complex protein structure, and when properly assembled this capsid looks like a skeletal soccer ball with lots of spikes sticking out.

Other researchers have had the same idea for repurposing the Hepatitis B capsid because its hollow structure is large enough, in theory, to carry a significant medical payload. But in practice this had proven so difficult that when Swartz floated the idea to funding agencies they said no.

But Swartz was so certain his approach would work that he found ways to bootstrap the project over the several years that it took to finish his experiments.

Biotechnologists know how to build the complex protein structures they find in nature, but the Stanford team took this further. They didn’t just build the capsid nature provided. They studied the DNA that directs the structure to assemble and re-engineered the code to custom-design a capsid that would be invisible to the immune system, sturdy enough to survive a trip through the bloodstream and have a surface that would be simple to attach molecular tags to.

Bioengineering the surface was important. If the researchers wanted the capsid to teach the immune system to destroy cancer cells, they would hang vaccine tags on the spikes. If, on the other hand, they wanted the capsid to deliver medicines to a sick cell, they would hang address tags on the spikes.

Finally, the researchers had to make all these modifications without destroying the miraculous capability of the capsid’s DNA code to direct 240 copies of one protein to self-assemble into a hollow sphere with a spiky surface.

Swartz said the next step is to attach cancer tags to the outside of this smart particle, to use it to train the immune system to recognize certain cancers. Those experiments would likely occur in mice.

After that he will add the next function — further engineering the DNA code to make sure that the protein can self-assemble around a small medicinal payload. “That will be quite complicated, but we’ve already gotten this far when they said it couldn’t be done,” Swartz said.

Stanford has patented the technology and different aspects are licensed to a biotechnology company in which Swartz has a founding interest. The approach is in its early stages and there is as yet no timetable for commercial development.  Science Daily  Original web page at Science Daily


* Researchers report long-term remissions in first personalized cell therapy trial

Eight of 14 patients in the first trial of the University of Pennsylvania’s personalized cellular therapy for chronic lymphocytic leukemia (CLL) responded to the therapy, with some complete remissions continuing past four and a half years. These results, published in Science Translational Medicine, represent the most mature data from clinical trials of an approach known as CTL019, developed by a team from Penn’s Abramson Cancer Center and the Perelman School of Medicine.

In 2011, the research team published initial findings from the first three patients to enroll in the trial. Two of those patients had complete responses, and their leukemia remains in remission today, more than four and a half years after receiving the therapy. The first patient to receive the therapy recently marked five years cancer-free.

“ The durability of the remissions we have observed in this study are remarkable and have given us great hope that personalized cell therapies are going to be important options for patients whose cancers are no longer treatable with standard approaches,” said lead author David L. Porter, MD, the Jodi Fisher Horowitz Professor in Leukemia Care Excellence and director of Blood and Marrow Transplantation in Penn’s Abramson Cancer Center. “The patients in this study are pioneers, whose participation has given us a foundation of knowledge and experience on which to build this new approach to help more patients.”

The new study details the completed, 14-patient pilot trial of CTL019 for CLL, which began in the summer of 2010. The overall response rate was 57 percent. All patients who received the experimental therapy, which is made from their own immune cells, had cancer that had relapsed or continued to progress after receiving multiple conventional Food and Drug Administration-approved therapies, and few were eligible for bone marrow transplants.

Four patients (29 percent) in the study achieved a complete remission. One patient died while in remission at 21 months after the therapy due to infectious complications that occurred after removal of a basal cell carcinoma on his leg. The three other patients remained alive at the time of this analysis with no evidence of leukemia at 28, 52, and 53 months after receiving their infusions, with no further therapy.

An additional four patients (29 percent) achieved partial responses to the therapy, with responses lasting a median of seven months. During the period analyzed, two of these patients had died of disease progression at 10 and 27 months after receiving CTL019, and one died after suffering a pulmonary embolism six months after T cell infusion. One patient’s disease progressed at 13 months but remained alive on other therapies at 36 months after receiving the therapy.

Six patients (43 percent) did not respond to the therapy and progressed within one to nine months; tests revealed that the modified T cells did not expand as robustly in these patients as in those who experienced remissions. Two of these subjects later died from their disease or complications of other therapies, and four are receiving other types of treatment.

CTL019 begins with each patient’s own T cells, collected through a procedure similar to dialysis. The cells are then reprogramed to hunt and potentially kill cancer cells in the patient’s body. After the patient undergoes lymphodepleting chemotherapy, they receive an infusion of their newly engineered cells. The modified T cells contain an antibody-like protein known as a chimeric antigen receptor (CAR), which is designed to target the CD19 protein found on the surface of B cells, including the cancerous B cells that characterize several types of leukemia and lymphoma.

All patients who responded to the investigational T cell therapy developed cytokine release syndrome (CRS) within several weeks after their infusions, typically during the time when the modified cells expanded to their greatest number in the body. This condition included varying degrees of flu-like symptoms, with high fevers, nausea, and muscle pain, and neurologic symptoms including hallucinations and delirium. Four patients experienced more severe symptoms, including low blood pressure and breathing difficulties, which required intensive care. Prior CAR studies have shown that CRS can be a very serious and life-threatening toxicity. The Penn team has developed a management strategy to treat these side effects, including the antibody drug tocilizumab, which was used in four patients, and two patients received steroids. All recovered from their CRS.

“Importantly, our tests of patients who experienced complete remissions showed that the modified cells remain in patients’ bodies for years after their infusions, with no sign of cancerous or normal B cells,” said the study’s senior author, Carl H. June, MD, the Richard W. Vague Professor in Immunotherapy in Penn’s department of Pathology and Laboratory Medicine and director of Translational Research in the Abramson Cancer Center. “This suggests that at least some of the CTL019 cells retain their ability to hunt for cancerous cells for long periods of time.

A laboratory experiment using CAR-modified T cells isolated from one of the first patients to receive the therapy confirmed the potential for long-term function of these cells: At nearly three years after infusion, the patient’s CTL019 cells demonstrated immediate and specific reactivity against cells expressing CD19. Typically, patients whose healthy B cells disappear after treatment receive regular immunoglobulin infusions.

This study did not identify demographic or disease-related factors, such as age or types of prior therapies, that could be used to predict response to the therapy, and no association between T-cell dose and response was observed. An ongoing dose-optimization study is exploring this relationship in greater detail. Further future areas of study may include strategies to combine CTL019 with immune checkpoint inhibitor drugs or other therapies to stimulate T cell recognition of tumor cells.  Science Daily  Original web page at Science


Long-term NSAID use may reduce colorectal cancer risk

Long-term, continuous use of low-dose aspirin and nonaspirin nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with decreased colorectal cancer risk. The findings of a population-based, case-control study are published in Annals of Internal Medicine.

Colorectal cancer is the third most common non-skin cancer in the world. Colorectal neoplasms have a long progression, making colorectal cancer an obvious target for preventive interventions. Studies have suggested that regular aspirin and other NSAID use can reduce colorectal cancer risk, but a recent comprehensive review concluded that more research is needed to determine the optimal use of aspirin for cancer prevention.

Researchers reviewed data on drug use, comorbid conditions, and history of colonoscopy from prescription and patient registries in Northern Denmark. Based on prescriptions filled, taking 75 to 150 mg of aspirin continuously for five years or longer was associated with a 27 percent reduced risk for colorectal cancer and five or more years of continuous nonaspirin NSAID use was associated with a 30 to 45 percent reduction in colorectal cancer risk. Nonaspirin NDAIDS with the highest COX-2 selectivity were associated with the largest risk reductions.

The authors caution that patients with the highest adherence comprised only about 2 to 3 percent of all low-dose aspirin users in the study population, and these persons may have a risk profile for colorectal cancer that differs from that of the general population. In addition, other lifestyle factors were not measured.  Science Daily  Original web page at Science Daily


* The growing global battle against blood-sucking ticks

Disease ecologist Rick Ostfeld says that Lyme disease should be tackled in part by targeting mice. On a balmy day in late June, Scott Williams waits for a white-footed mouse (Peromyscus leucopus) to fall asleep. Williams, a wildlife biologist with the Connecticut Agricultural Experiment Station in New Haven, has just transferred the animal from a trap to a plastic bag containing a cotton ball doused in anaesthetic. As soon as the mouse’s breathing slows to one breath per second, Williams will take it out, draw blood, weigh it, put an ear tag on it for identification and check the animal for ticks, saving any that are engorged with blood. He must work quickly. The mouse will wake up in about two minutes, and she might be grumpy.

Williams is testing whether vaccinating mice against Borrelia burgdorferi, the bacterium that causes Lyme disease in the United States, can reduce the proportion of ticks that are infected. Health officials are looking on with interest. Connecticut has one of the highest rates of human Lyme disease in the country, and June is peak time for transmission. Borrelia burgdorferi infects an estimated 329,000 people in the United States each year, according to the US Centers for Disease Control and Prevention (CDC) in Atlanta, Georgia. And although most people who get prompt treatment recover quickly — Williams has had Lyme three times — up to one in five develops long-term and potentially life-threatening symptoms, including heart, vision or memory problems, or debilitating joint pain.

Williams’s approach is one of several strategies being tested in an attempt to thwart the spread of tick-borne diseases. Some, like the mouse vaccine, interrupt the pathogen’s ecological circuitry by targeting the wild animals that pass along and amplify the disease. Others, such as efforts to revive a human Lyme vaccine, aim to protect people from infection directly. A more radical approach could hamper the ability of ticks to bite humans or animals, potentially protecting against dozens of illnesses spreading across the United States, Europe, Africa and Asia.

That the field needs creative solutions is clear. Many long-recommended interventions, such as pesticide application or controlling populations of deer, which are an important host for adult ticks, have had mixed success in scientific studies. Even the time-honoured protective strategies that most people use are not evidence-based. “We tell people to wear repellents, to do tick checks and to shower if they’ve been in the field, but there’s very little data to show that these things reduce human illness,” explains Ben Beard, chief of the CDC’s bacterial-diseases branch in the division of vector-borne diseases.

Diseases spread by ticks are on the rise around the world, spurred by a combination of factors, including shifting climates and population sprawl into rural areas. Reported cases of Lyme, the most common US tick-borne illness, have nearly tripled in the country since 1992, although some of the increase could be due to heightened awareness. Lyme is also a growing problem in parts of Europe, Mongolia and China. Yet as bad as it is, there are nastier threats on the rise. In parts of Africa, the Middle East, Asia and southern Europe, ticks can spread Crimean–Congo haemorrhagic fever, which is fatal in 40% of cases. And a tick-borne relapsing fever afflicts as many as 1 in 20 residents in parts of Senegal. In the United States, ticks spread at least 16 illnesses, including anaplasmosis, babesiosis, ehrlichiosis and Rocky Mountain spotted fever, all “serious, life-threatening infections”, Beard says. And many are increasing in incidence more quickly than Lyme. In a July 2015 position statement, the Entomological Society of America argued for a national strategy to combat tick-borne diseases. “The recent confluence of environmental, ecological, sociological, and human demographic factors,” it said, “has created a near ‘perfect storm’ leading to more ticks in more places throughout North America.”

Williams tags, weighs and releases his mouse just in time. It has no ticks to bring back to the lab for further analysis, but there will be other opportunities. Members of 32 Connecticut households have volunteered to place traps around their properties, and some will also get boxes of mouse treats laden with vaccine. The hope is that, over time, fewer mice and ticks will harbour the bacteria at the sites with the vaccine bait.

The plan is unconventional, because most Lyme-control measures focus on white-tailed deer (Odocoileus virginianus), which have exploded in number in the United States over the past century as young forests have become increasingly fragmented by human development and large predators have been all but eradicated. Adult blacklegged ticks (Ixodes scapularis) typically feed and mate on deer, so many scientists have argued that the only way to get rid of Lyme is to get rid of the deer.

But such efforts have had “an incredibly spotty record”, says Richard Ostfeld, a disease ecologist at the Cary Institute of Ecosystem Studies in Millbrook, New York, who has been studying tick-borne diseases for decades.

When Sam Telford, an epidemiologist at Tufts University in North Grafton, Massachusetts, and his colleagues cut the deer population on Great Island in Cape Cod by 50% in the early 1980s, they saw no drop in tick numbers — the number of tick larvae on the island actually increased. Ostfeld argues that you do not need many deer to maintain a large tick population. When deer numbers drop, ticks can either crowd in on the remaining deer or find other hosts. Only when almost all of the deer on Great Island had been eliminated did tick populations plummet. But, says Telford, “it is a nightmare trying to get the deer population down that low”. And anywhere that is not an island, keeping populations down is practically impossible.

Ostfeld and others contend that mice are a major driver for both the tick problem and the disease problem. Mice, like deer, flourish in fragmented woodlands — in part because predators such as foxes and opossums get displaced. Ticks then thrive on the rodents, which are poor groomers. Studies suggest that larval ticks have a 50% chance of surviving when they feed on mice, but only a 3.5% chance on opossums.

And mice are typically where ticks pick up B. burgdorferi. Most mice in Lyme-endemic areas get infected with the bacterium at a young age and, for reasons that are not completely clear, they are particularly good at transmitting it to other ticks. Almost all young ticks that feed on white-footed mice become infected, compared with a mere 1% of ticks that feed on deer. Interrupting the tick–mouse infection cycle, says Ostfeld, could make ticks a lot less dangerous.

Maria Gomes-Solecki, a medical microbiologist at the University of Tennessee Health Science Center in Memphis, agrees — which is why she invented the mouse vaccine that Williams is testing. It primes the mice to make antibodies against outer surface protein A (OspA), a molecule that B. burgdorferi expresses when it is in a tick’s gut. A mouse eats the vaccine, then starts to produce OspA antibodies. The next time a tick feeds on the mouse, the antibodies attack the bacteria in its gut, clearing the infection. As the proportion of ticks infected with B. burgdorferi drops, it becomes less likely that the next generation of mice will pick up the parasite, even without vaccination.

Ostfeld and his colleagues reported the first field tests of Gomes-Solecki’s vaccine in 2014, and found that although only 28% of the mice in an area that they targeted for 5 years developed protective levels of OspA antibodies, the prevalence of infected blacklegged-tick nymphs (the life stage between larvae and adults) dropped by 75%. The bait-based vaccine is also attractive because it is less ecologically destructive than other strategies — it does not kill animals or even ticks, just the pathogens.

Gomes-Solecki, who licensed her technology to a company she founded, US Biologic in Memphis, would like to see homeowners putting walk-through bait boxes for mice around their gardens. Or, she says, local governments could disperse the bait in parks or forests, much as they do with bait-based rabies vaccines for raccoons and coyotes. “The rodents seem to love them,” Williams says of the vaccine-laced treats. One of his colleagues calls them “Fritos for mice”

Other scientists argue for more a direct means of protecting people against Lyme, ideally with a human vaccine. When vaccine researcher Stanley Plotkin’s son was 35, he fell ill with Lyme disease. As often happens with the infection, a doctor missed the diagnosis and the young man went untreated for months. Bacteria invaded his heart and he collapsed one day while walking his dog. Plotkin, now an emeritus professor at the University of Pennsylvania in Philadelphia, says that when paramedics arrived, his son’s heart rate was dangerously low. He has since recovered, but the experience “further convinced me, if I needed any convincing”, Plotkin says, “that the lack of a Lyme-disease vaccine was a public-health tragedy”.

Plotkin worked on a vaccine in the 1990s. Ultimately, a competing product called LYMErix, manufactured by UK-based pharmaceutical company SmithKline Beecham (now GlaxoSmithKline), was approved by the US Food and Drug Administration in 1998. It reduced the risk of Lyme caused by US strains of Borrelia by 76% in clinical trials. But it faced problems from the start. First, it garnered lukewarm support from health officials in the United States and was recommended only for people aged 15 to 70 in regions where Lyme is endemic. Then, some recipients complained of autoimmune-related side effects such as arthritis and filed lawsuits against SmithKline Beecham. The company voluntarily shelved LYMErix in 2002. Plotkin maintains that this was a mistake. “The vaccine was safe,” he says.

Now, a new and potentially improved vaccine has completed safety trials. Developed by researchers at Stony Brook University and Brookhaven National Laboratory in New York, and licensed to Baxter Innovations in Vienna, the vaccine is similar to LYMErix in that it targets OspA, but it does not contain the protein segment that some scientists and consumers feared could cause an autoimmune reaction. It also contains several variants of OspA, so it protects against many Borrelia species known to cause Lyme in humans, including those that affect people in Europe.

Nevertheless, the vaccine’s future is uncertain: in 2014, Pfizer bought the rights to sell many of Baxter’s vaccine products, but not the Lyme candidate. Baxter is now in talks with Great Plains Biotechnology of Roca, Nebraska, which has expressed interest in purchasing and developing the Lyme vaccine.

Richard Marconi, a microbiologist and vaccinologist at Virginia Commonwealth University in Richmond, says that he and his colleagues are working on an even better vaccine. One downside of an OspA vaccine is that it requires frequent boosters, because OspA antibodies have to be circulating constantly in the blood if they are to attack B. burgdorferi inside a biting tick. Marconi’s team is developing a vaccine against immunologically relevant portions of the surface protein OspC, which B. burgdorferi expresses when it is inside mammals. On being bitten by infected ticks, vaccinated individuals can produce OspC antibodies from immunological memory; the antibodies do not have to be circulating already. Marconi and his colleagues have already licensed a version of the vaccine for use in dogs, and “the success of the canine vaccine and the uniqueness of the approach suggests that it’s going to be highly effective in humans”, he says.

In light of the problems faced by LYMErix, however, the question remains whether health officials and consumers will embrace a human vaccine. “I think, maybe optimistically, that the emotional situation has changed over the last 10 or 15 years — that is, that more people are convinced of the importance of Lyme disease,” Plotkin says. But it is hard to know whether fears about Lyme will trump fears about the vaccine.

Mouse vaccines would not raise such concerns, but some researchers, including Plotkin, are sceptical about whether they could dose enough mice to reduce Lyme rates. And both vaccine approaches are limited because they combat only one tick-borne disease, when more than a dozen others are spreading throughout the world.

There is one strategy that could conquer them all, and it involves turning one of the tick’s most ingenious tools — its saliva — against it. When a tick bites a host, molecules in its saliva help it to evade detection and start to feed by blocking pain, inflammation and immune signals. If a vaccine could raise an immune response to key salivary proteins, it could make tick bites more noticeable or block the tick’s ability to feed.

Ostfeld himself is a proof-of-concept for this approach. He has been bitten more than 100 times, and his body now reacts to tick saliva. “I realize when a tick is biting me because I get a burning sensation. It’s pretty intense,” he explains. Ostfeld has ample time to remove the tick before it can transfer an infection — if it even survives the experience. Often, Ostfeld says, he will remove a tick only to discover that, for unknown reasons, it is already dead.

A European Commission-funded consortium called ANTIDotE (Anti-tick Vaccines to Prevent Tick-borne Diseases in Europe) is characterizing the tick salivary proteins that could be targeted to thwart feeding. In 2011, a member of the group reported6 a technique to rapidly identify those proteins that react with the blood serum of tick-immune animals. When the team vaccinated rabbits against three salivary proteins that it had identified — including one that ticks use to inhibit blood coagulation and one that inhibits the host’s immune response — it found that ticks had trouble getting blood from them. Researchers in the group are also working to identify the salivary genes involved in B. burgdorferi transmission. “We think that an anti-tick vaccine could be immensely useful in protecting both humans and animals,” says Hein Sprong, an ANTIDotE leader at the National Institute for Public Health and the Environment in Bilthoven, the Netherlands.

Until an all-encompassing solution becomes available, controlling tick-borne diseases will probably require an array of smaller-scale approaches that attack the problem, bit by bit, on a number of levels. That an arsenal of such weapons might be needed to hold back the enemy is not particularly surprising, considering the complexity of tick-borne-disease ecology, how drastically humans have been changing it, and how close people live to these disease-carrying parasites. “We’ve disrupted the balance of nature,” Telford says. Steadying the scales again will be no small feat.

Nature 524, 406–408 (27 August 2015) doi:10.1038/524406a  Nature  Original web page at Nature


* High use of alternative medicine in senior oncology patients

Alternative medicines are widely thought to be at least harmless and very often helpful for a wide range of discomforts and illnesses. However, although they’re marketed as “natural,” they often contain active ingredients that can react chemically and biologically with other therapies. Researchers performed a comprehensive review of all of the medications taken by senior oncology patients and found that as 26 percent were using complementary or alternative medicines (CAM), in a report published August 12th, in the Journal of Geriatric Oncology.

“Currently, few oncologists are aware of the alternative medicines their patients take,” says Ginah Nightingale, PharmD, an Assistant Professor in the Jefferson College of Pharmacy at Thomas Jefferson University. “Patients often fail to disclose the CAMs they take because they think they are safe, natural, nontoxic and not relevant to their cancer care, because they think their doctor will disapprove, or because the doctor doesn’t specifically ask.”

There are a number of CAMs that are known to interfere with certain cancer treatments. For example, St. John’s wart can make some cancer therapy less effective, according to the National Institutes of Health. Others can interfere with anesthesia during surgery for cancer. But not all interactions have been studied. Because CAMs fall under the category of health supplements, they are not regulated by the Food and Drug Administration (FDA), which means that dose and potency (and therefore reaction in the body) can vary widely between products, and between patients.

In addition, in an elderly population of cancer patients, CAMs can simply add additional medications to an already long list of drugs taken for various ailments. “Numerous pills, or what we call polypharmacy in the field, can increase the risk for medication non-adherence, potential drug-drug interactions and increase the risk for drug-disease interactions in a population that has been reported to take several medications and have several medical conditions,” says Dr. Nightingale, “The use of CAM in this subpopulation warrants substantial interest and concern on behalf of medical oncologists and allied health professionals because of the potential clinical implications associated with CAM use. Patients may be combining these agents while receiving concurrent systemic chemotherapy, radiation therapy and/or surgical interventions which have the potential to compromise the safety and efficacy of treatment interventions.

Dr. Nightingale and colleagues surveyed the senior oncology patients who came to Jefferson for consultations in the Senior Adult Oncology Multi-Disciplinary clinic. Over the course of one visit, patients were seen by professionals from five different areas crucial to maintaining a senior’s health throughout oncology treatment, including a medical oncologist, geriatrician, clinical pharmacist, social worker and dietician. As part of this assessment, the patients brought in the contents of their medicine cabinets, and the medications that were actively used were reviewed and recorded.

The research team found that 26 percent of patients were taking CAMs at some point during the continuum of their cancer care, with the highest usage among women over the age of 80 — a population that hadn’t been captured by previous studies. Among those taking complementary medicine, 68 percent were in the over-80-year-old range.

Some of the alternative medications that were commonly used in this population were alternative therapies for macular degeneration, stomach probiotics, joint health, and mega-dose vitamins or minerals. While the current study did not examine the potential adverse events caused by these medications, “we know that some can have a biochemical effect on the body and other drugs.” says Nightingale.

“It is very important to do a comprehensive screen of all of the medications that older cancer patients take, including CAMs,” says Dr. Nightingale. “Clear and transparent documentation of CAM use should be recorded in the patient’s medical record. This documentation should indicate that patient-specific communication and/or education was provided so that shared and informed decisions by the patient can be made regarding the continued use of these medications.”

“Oncology healthcare is undergoing significant transformation in the delivery of effective clinical services and is ripe for greater engagement of pharmacists to reduce drug-related problems and unnecessary medications, in order to optimize medication prescribing,” says Dr. Nightingale.  Science daily  Original web page at Science Daily


New insights into the production of antibiotics by bacteria

The Leiden scientists discovered that in nature, too, antibiotics act as a weapon against rival bacteria. This seems logical, but remains controversial, because the concentrations in the soil appear to be far too low to act as a weapon against other bacteria. Rozen, Van Wezel and colleagues made the discovery by measuring the activity of thirteen strains of the antibiotic-producing bacterium Streptomyces. They looked at how strains behaved in nutrient-rich as well as nutrient-poor soil. They found that in soil with few nutrients and competing bacteria nearby the Streptomycetes start to produce more antibiotics in order to protect the food sources available. Computer simulations showed how the strains enter into a lot of ‘social interaction’ in a nutrient-rich environment, allowing the exchange of genetic material and the creation of new bacterial variants.

Apart from the fundamental question, it also offers important new insights into the search for new antibiotics, say Rozen and Van Wezel. ‘The Streptomyces bacteria are able to produce the antibiotics we seek, but they will not do this automatically. You have to, as it were, awaken the antibiotics in the bacteria by stimulating them in the right way. This research shows how the bacteria can be stimulated to produce antibiotics by growing them in the presence of competing strains.’

Antibiotics are an important substance for combating diseases, but pathogens are becoming increasingly resistant to existing antibiotics. The research into new antibiotics carried out by Gilles van Wezel, Professor of Molecular Biotechnology, is linked to the research at Leiden University which is aimed at developing new drugs. For more information, please consult the research dossier on Effective Drug Development.  Science Daily Original web page at Science Daily


* Genetically engineered yeast produces opioids

For thousands of years, people have used yeast to ferment wine, brew beer and leaven bread.

Now researchers at Stanford have genetically engineered yeast to make painkilling medicines, a breakthrough that heralds a faster and potentially less expensive way to produce many different types of plant-based medicines

Writing today in Science, the Stanford engineers describe how they reprogrammed the genetic machinery of baker’s yeast so that these fast-growing cells could convert sugar into hydrocodone in just three to five days.

Hydrocodone and its chemical relatives such as morphine and oxycodone are opioids, members of a family of painkilling drugs sourced from the opium poppy. It can take more than a year to produce a batch of medicine, starting from the farms in Australia, Europe and elsewhere that are licensed to grow opium poppies. Plant material must then be harvested, processed and shipped to pharmaceutical factories in the United States, where the active drug molecules are extracted and refined into medicines

“When we started work a decade ago, many experts thought it would be impossible to engineer yeast to replace the entire farm-to-factory process,” said senior author Christina Smolke, an associate professor of bioengineering at Stanford.

Now, though the output is small — it would take 4,400 gallons of bioengineered yeast to produce a single dose of pain relief — the experiment proves that bioengineered yeast can make complex plant-based medicines.

“This is only the beginning,” Smolke said. “The techniques we developed and demonstrate for opioid pain relievers can be adapted to produce many plant-derived compounds to fight cancers, infectious diseases and chronic conditions such as high blood pressure and arthritis.”

Many medicines are derived from plants, which our ancestors chewed or brewed into teas, or later refined into pills using chemical processes to extract and concentrate their active ingredients. Smolke’s team is modernizing the process by inserting precisely engineered snippets of DNA into cells, such as yeast, to reprogram the cells into custom chemical assembly lines to produce medicinal compounds.

An important predecessor to the Stanford work has been the use of genetically engineered yeast to produce the anti-malarial drug artemisinin. Traditionally artemisinin has been sourced from the sweet wormwood tree in similar fashion to how opiates are refined from poppy. Over the last decade, as yeast-based artemisinin production has become possible, about one third of the world’s supply has shifted to bioreactors.

The artemisinin experiments proved that yeast biosynthesis was possible, but involved adding only six genes. The Stanford team had to engineer 23 genes into yeast to create their cellular assembly line for hydrocodone.

“This is the most complicated chemical synthesis ever engineered in yeast,” Smolke said. Her team found and fine-tuned snippets of DNA from other plants, bacteria and even rats. These genes equipped the yeast to produce all the enzymes necessary for the cells to convert sugar into hydrocodone, a compound that deactivates pain receptors in the brain.

“Enzymes make and break molecules,” said Stephanie Galanie, a PhD student in chemistry and a member of Smolke’s team. “They’re the action heroes of biology.” To get the yeast assembly line going, the Stanford team had to fill in a missing link in the basic science of plant-based medicines

Many plants, including opium poppies, produce (S)-reticuline, a molecule that is a precursor to active ingredients with medicinal properties. In the opium poppy, (S)-reticuline is naturally reconfigured into a variant called (R)-reticuline, a molecule that starts the plant down a path toward the production of molecules that can relieve pain.

Smolke’s team and two other labs recently independently discovered which enzyme reconfigures reticuline, but even after the Stanford bioengineers added this enzyme into their microbial factory, the yeast didn’t create enough of the opioid compound. So they genetically tweaked the next enzyme in the process to boost production. Down the line they went, adding enzymes, including six from rats, in order to craft a molecule that emerged ready to plug pain receptors in the brain

In their Science paper, the Stanford authors acknowledged that a new process to make opioid painkillers could increase concerns about the potential for opioid abuse

“We want there to be an open deliberative process to bring researchers and policymakers together,” Smolke said. “We need options to help ensure that the bio-based production of medicinal compounds is developed in the most responsible way.”

Smolke said that in the United States, where opioid medicines are already widely available, the focus is on potential misuse. But the World Health Organization estimates that 5.5 billion people have little or no access to pain medications

“Biotech production could lower costs and, with proper controls against abuse, allow bioreactors to be located where they are needed,” she said

In addition to bioengineering yeast to convert sugar into hydrocodone, the Stanford team developed a second strain that can process sugar into thebaine, a precursor to other opioid compounds. Bio-produced thebaine would still need to be refined through sophisticated processes in pharmaceutical factories, but it would eliminate the time delay of growing poppies.

“The molecules we produced and the techniques we developed show that it is possible to make important medicines from scratch using only yeast,” she said. “If responsibly developed, we can make and fairly provide medicines to all who need.  Science Dail  Original web page at Science Daily


‘Organs-on-chips’ go mainstream

Miniature devices that mimic human organs could help to replace animals used in drug testing. Researchers who are developing miniature models of human organs on plastic chips have touted the nascent technology as a way to replace animal models. Although that goal is still far off, it is starting to come into focus as large pharmaceutical companies begin using these in vitro systems in drug development.

“We are pretty excited about the interest we get from pharma,” says Paul Vulto, co-founder of the biotechnology company Mimetas in Leiden, the Netherlands. “It’s much quicker than I’d expected.” His company is currently working with a consortium of three large pharmaceutical companies that are testing drugs on Mimetas’s kidney-on-a-chip. At the Organ-on-a-Chip World Congress in Boston, Massachusetts, last week, Mimetas was one among many drug and biotechnology firms and academic researchers showing off the latest advances in miniature model organs that respond to drugs and diseases in the same way that human organs such as heart and liver do.

“We’re surprised at how rapidly the technology has come along,” says Dashyant Dhanak, global head of discovery sciences at Johnson & Johnson in New Jersey, which announced last month that it would use a thrombosis-on-chip model from Massachusetts biotechnology firm Emulate to test whether experimental and already-approved drugs could cause blood clots.

Proponents of organs-on-chips say that they are more realistic models of the human body than are flat layers of cells grown in Petri dishes, and could also be more useful than animal models for drug discovery and testing. A lung-on-a-chip, for instance, might consist of a layer of cells exposed to a blood-like medium on one side and air on the other, hooked up to a machine that stretches and compresses the tissue to mimic breathing.

But while some companies are developing chips to mimic diseased organs, most are still testing whether existing drugs behave in the chips as they do in healthy human tissues. And chips or not, any new drug must first be tested in healthy humans for safety, says James Hickman, a bioengineer at the University of Central Florida in Orlando. Using an in vitro organ might help to eliminate or shorten this step.

The chips could also help companies to pinpoint the dose of a drug that is both effective and safe, says Matthew Wagoner, a drug-safety scientist at AstraZeneca in Waltham, Massachusetts. If regulators accept such data, the method might eventually allow companies to skip the portion of a clinical trial that tests a wide range of drug doses on patients.

Other researchers are eager to use organs-on-chips to illuminate differences between animal models and humans. Adrian Roth, head of in vitro safety research at Roche in Basel, Switzerland, says that such comparisons were useful when one of Roche’s experimental drugs was found to cause liver tumours in rats. Roche used data from in vitro models of human and rat livers to argue that the mechanism causing the liver tumours was unique to rodents and should not prevent studies in humans.

But some users are concerned that the hype is getting ahead of reality. The danger, Roth says, is that companies will abandon the technology if it fails to live up to inflated expectations, as has happened with the use of genomics for personalized medicine. “As a pharma company, you have to be very pragmatic,” he says, and not expect the chips to replace animals all at once.

There is reason to be hesitant. Many presenters at the Boston meeting validated their model organs by showing that they responded to drugs in the same way that a human organ does. A model heart might be tested to see whether it speeds up after a dose of adrenaline, for instance. But such tests do not capture anything like the full complexity of organ function, and chips may struggle to recreate aspects of functioning that are governed by complex signals from, say, the endocrine and immune systems.

Even testing a known drug in a system that hitches multiple organ chips together might be difficult to validate, Roth adds, because researchers might not know what to look for. The potentially toxic effect of the painkiller paracetamol on the liver, for instance, is well characterized, but less is known about how other organs respond to the drug.

Nevertheless, many pharmaceutical companies say that organs-on-chips are now sufficiently advanced to justify investment in their use and refinement. “We think it’s important to be involved,” says Michelle Browner, senior director of platform innovation at Johnson & Johnson. Only that way can the technology be developed in line with what the company needs, she says.

And government regulators are also interested. This autumn, the US National Center on Advancing Translational Sciences (NCATS) in Bethesda, Maryland, will bring together academic scientists, pharmaceutical companies and regulators to discuss the chips’ use. NCATS is also funding 11 research teams, each of which is developing a different organ or system that will eventually be linked together to build an entire ‘body-on-a-chip’.

Nature 523, 266 (16 July 2015) doi:10.1038/523266a  Nature  Original web page at Nature


Fears for bees as UK lifts insecticide ban

A UK government agency has used emergency rules to make controversial neonicotinoid insecticides available to some farmers, despite a European ban.

These chemicals have been linked to declines in bee populations in numerous scientific studies, and the European Union (EU) imposed a temporary ban on much of their use in 2013. But the UK’s Department for Environment, Food and Rural Affairs (Defra) has now said that some farmers should be able to use them anyway under EU rules that permit the “emergency” use of banned chemicals to protect crops .

In a statement, the department said it had “fully applied the precautionary ban on the use of neonicotinoids introduced by the EU”. But it also said: “Based on the evidence, we have followed the advice of the UK Expert Committee on Pesticides and our Chief Scientist that a limited emergency authorisation of two pesticides requested by farmers should be granted in areas where oil rape crops are at greatest risk of pest damage.”

The National Farmers Union, which applied for the authorisation, says it is needed to protect around 300 square kilometres of oilseed rape in England from cabbage stem flea beetles. The union says that amounts to around 5% of the total oilseed rape crop in England.

The risk neonicotinoids pose to bees is disputed and the EU ban has been controversial. Manufacturers of the chemicals and some scientists say that the evidence that use can harm bees is limited, and that laboratory studies showing harm do not reflect the true situation in the field.

But researchers who worry about the chemicals say that there is now enough evidence – including from real-world trials – to say that use should be restricted. Earlier this year Nature published work by Maj Rundlöf, an ecologist at Lund University in Sweden, and her colleagues that showed wild-bee density in fields treated with neonicotinoids was around half the bee density in untreated, control fields.

Lynn Dicks, a pollinator researcher at the University of Cambridge, says that in the light of the Rundlöf work, “I find this [Defra] decision extraordinary”. Based on that research, she says, “areas with 5% of the UK’s rape crop might expect to lose two-thirds of their wild bumblebee queens going into the winter of 2016/17 because of this decision”.

Nature doi:10.1038/nature.2015.18052 Nature Original web page at Nature


Antibody drugs for Alzheimer’s show glimmers of promise

After a string of failed trials, drugs that target protein build-up in the brain appear to slow disease progress.

Alzheimer’s disease is marked by cognitive decline and the accumulation of proteins in the brain. After years of disappointment, clinical-trial results released on 22 July suggest that antibody treatments may produce small improvements in people with Alzheimer’s disease.

The drugs — Eli Lilly’s solanezumab and Biogen’s aducanumab — target the amyloid-β protein that accumulates in the brains of people with Alzheimer’s. Many researchers question whether the findings will hold up, given that antibody drugs against amyloid have failed in every previous test against the disease. Details of the results were presented at the Alzheimer’s Association International Conference in Washington DC.

Lilly, of Indianapolis, Indiana, says that in a trial with 440 participants, solanezumab seemed to slow the cognitive decline of people with mild Alzheimer’s by about 30%. The loss of mental acuity in these patients over 18 months was equivalent to the deterioration that participants with a similar level of Alzheimer’s disease in a placebo group experienced in just 12 months.

Lilly snatched this small victory from the jaws of defeat. In 2012, the company reported no difference between patients who had taken solanezumab for 18 months and those who had received a placebo. But when the company reanalyzed that trial it found a slight improvement in participants whose symptoms were mild when the trial began. Lilly continued the test for six months and began giving solanezumab to the 440-member control group, whose disease was by then more advanced.

At the meeting, Lilly showed that giving the drug to the ‘late start’ group slowed their cognitive decline to match the rate seen in the 440 people who had been treated for the entire study. This suggests that the drug targeted the root of Alzheimer’s disease, rather than just relieving its symptoms.

Biogen, of Washington DC, presented results that show a moderate dose of its drug aducanumab reduced amyloid in 23 people, but did not have statistically significant clinical benefits. In March, the company reported that 27 people who received high doses of aducanumab for one year showed significantly less cognitive decline than people who received a placebo, and had less amyloid build-up in their brains.

Both sets of results provide support for the ‘amyloid hypothesis’: the idea that amyloid deposits in the brain are a cause of Alzheimer’s, rather than an effect, and that removing them stops the disease. “We’re creeping in the right direction,” says Samuel Gandy, a neurobiologist at Mount Sinai School of Medicine in New York. “A lot of the euphoria is because things were so negative for so long.”

Solanezumab failed in several previous trials, and drug firms Pfizer and Johnson & Johnson discontinued development of their antibody drug bapinezumab in 2012 after trials in 2,400 people failed. Roche halted a 3,000-person trial of its anitbody candidate, gantenerumab, last December — although it presented results this week showing that the highest dose of the drug had at least entered the brain and reduced the amount of amyloid protein in patients with fast-progressing disease.

Experts are greeting those results, along with the Biogen and Lilly news, with tempered excitement, given the relatively small size of the clinical trials.

But Eric Siemers, an Alzheimer’s researcher at Lilly, is optimistic. “It’s surprising to me that [solanezumab] worked so well,” he says. “There’s a lot of promise to slow progression.”

Lilly launched a larger phase III trial of solanezumab in 2013, enrolling 2,100 people with mild symptoms and amyloid deposits in their brains. The company will end the study in October 2016. In December, Biogen said that it would launch a phase III trial with 2,700 participants that would run for 18 months.

Lon Schneider, an Alzheimer’s researcher at the University of Southern California in Los Angeles, questions the decision to start large trials before the drugs, and the amyloid hypothesis, have been well validated. “Why are there so many antibodies when none so far have proven efficacy?” he says, noting that behavioural interventions, such as diet and exercise, have been shown to slow Alzheimer’s as much as any drug.

But not everyone agrees. “This is the time to be bold,” says Randall Bateman, a neurologist of Washington University in St. Louis, Missouri. “It seems to me the cost of delay from a human suffering standpoint is much more expensive than cost of moving forward and being active.”

Bateman is leading a trial that is testing Lilly’s solanezumab and Roche’s ganetenerumab in 160 people between 18 and 80 years old who have a genetic risk of Alzheimer’s, but no symptoms. It is one of several efforts that are trying to determine whether the disease can be prevented by destroying amyloid protein before the brain is damaged. That damage occurs over decades, and many Alzheimer’s researchers suspect that antibody trials have failed because they have treated people too late.

This hypothesis is supported by Lilly’s finding that only people with mild disease benefit from solanezumab. The latest results also demonstrate for the first time in humans that slowing amyloid deposition can slow cognitive decline, says Eric Reiman, executive director of the Banner Alzheimer’s Institute in Phoenix, Arizona.

That is important because the US Food and Drug Administration has said that it will not approve drugs that block amyloid deposits without sufficient evidence of a clinical benefit. If one drug company can prove the cause and effect between amyloid accumulation and Alzheimer’s progression, all companies will benefit, says Reiman, who is leading a trial of Roche’s antibody drug crenezumab, which has also failed in large trials.

If such drugs falter in larger trials, that would be a setback for Alzheimer’s research in general, says Gandy. “The main concern is that the pipeline behind amyloid-reducing agents is really pretty spare,” he says, although at least three companies are developing alternate therapies. including antibodies, that target a different protein, tau, which destroys neurons in advanced Alzheimer’s disease.

Nature doi:10.1038/nature.2015.18031 Nature Original web page at Nature


* New method may eliminate antibiotic use in livestock

A University of Wisconsin-Madison animal scientist has developed an antibiotic-free method to protect animals raised for food against common infections. The innovation comes as growing public concern about antibiotic resistance has induced McDonald’s, Tyson Foods and other industry giants to announce major cuts in antibiotic use in meat production. About 80 percent of antibiotics in the United States are used by farmers, because they both protect against disease and accelerate weight gain in many farm animals.

The overuse of antibiotics in agriculture and medicine has created a public health crisis of drug-resistant infections, such as multidrug resistant staphylococcus aureus (MRSA) and “flesh-eating bacteria.” “You really can’t control the bugs forever; they will always evolve a way to defeat your drugs,” says Mark Cook, a professor of animal science and entrepreneur. Cook’s current work focuses on a fundamental immune “off-switch” called Interleukin 10 or IL-10, manipulated by bacteria and many other pathogens to defeat the immune system during infection. He and animal science associate researcher Jordan Sand have learned to disable this switch inside the intestine, the site of major farm animal infections such as the diarrheal disease coccidiosis.

Cook vaccinates laying hens to create antibodies to IL-10. The hens put the antibody in eggs that are then sprayed on the feed of the animals he wants to protect. The antibody neutralizes the IL-10 off-switch in those animals, allowing their immune systems to better fight disease. In experiments with 300,000 chickens, those that ate the antibody-bearing material were fully protected against coccidiosis. Smaller tests with larger animals also show promise. Dan Schaefer, a professor of animal science, and his graduate research assistant, Mitch Schaefer, halved the rate of bovine respiratory disease in beef steers by feeding them the IL-10 antibody for 14 days.

“That’s a very enticing early result,” Dan Schaefer says. “Bovine respiratory disease is the number one health risk for feeder cattle coming into a confinement situation.” He is planning a larger trial in collaboration with colleagues at other universities. In a test in newborn dairy calves, Sheila McGuirk, a professor of medical sciences at the School of Veterinary Medicine, found less than half as much respiratory disease among calves that ate the antibody for 10 days compared to those that did not. The treated calves also showed less shedding of Cryptosporidium parvum, a protozoa that causes diarrhea, although the trend was not statistically significant. “These diseases cause long-term reproduction, production and growth impairments in livestock,” says McGuirk. “The affected animals are suboptimal in health, performance and profitability. To have something affordable, safe and nonantibiotic that controls these very important diseases is absolutely awesome. We are eager to study this further.”

In the past few years, scientists have learned that a large group of pathogens — including bacteria, single- and multicelled parasites, protozoa, even certain viruses — make a chemical called macrophage migratory inhibition factor, or MIF, which activates the IL-10 mechanism to shut down the host animal’s immune system. “This apparently arose deep in the evolutionary past, and it’s wholesale piracy of the immune system,” says Sand. “People have manipulated the immune system for decades, but we are doing it in the gut. Nobody has done that before,” Cook says.

Cook and Sand, who have been working on the IL-10 system since 2011, are forming Ab E Discovery LLC to commercialize their research. One of the four patents they have filed through the Wisconsin Alumni Research Foundation has just been granted, and WARF has awarded a $100,000 Accelerator Program grant to the inventors to pursue the antibiotic-replacement technology. Cook previously founded Isomark LLC, which is developing a technology for early detection of infection in human breath.

The benefits of reducing farm usage of antibiotics should extend to workers’ families and the wider population. Significantly more people working in conventional chicken farms carry multidrug-resistant pathogens than those who work in antibiotic-free farms, Sand notes. A nonantibiotic method to prevent pathogens from shutting down the immune system seems far less conducive to resistance than the current routine feeding of antibiotics, Cook says. “We are not focused on the pathogens. We are focused on what they are trying to do to the immune system. We are getting encouraging data from dairy and beef. We have conducted experiments involving 300,000 chickens in commercial farms, half receiving the product. We know it works. The market is interested, and now it’s a matter of making a product.”  Science Daily  Original web page at Science Daily


How bacteria survive antibiotics may improve treatment of infectious diseases

Infectious diseases kill more people worldwide than any other single cause, but treatment often fails because a small fraction of bacterial cells can transiently survive antibiotics and recolonize the body. A study reveals that these so-called persisters form in response to adverse conditions through the action of a molecule called Obg, which plays an important role in all major cellular processes in multiple bacterial species.

Infectious diseases kill more people worldwide than any other single cause, but treatment often fails because a small fraction of bacterial cells can transiently survive antibiotics and recolonize the body. A study published June 4 in Molecular Cell reveals that these so-called persisters form in response to adverse conditions through the action of a molecule called Obg, which plays an important role in all major cellular processes in multiple bacterial species. By revealing a shared genetic mechanism underlying bacterial persistence, the study paves the way for novel diagnostic tools and more effective treatment strategies for a range of bacterial infections.

“Persisters pose a fundamental hurdle to the treatment of chronic and biofilm infections by bacterial and fungal pathogens,” says co-senior study author Jan Michiels of KU Leuven — University of Leuven. “Our findings suggest that combining antibiotic treatment with a therapy specifically targeting the novel persistence pathway we discovered would prove advantageous by enhancing patient responses to antibiotic treatment and by shortening antibiotic therapy duration.”

Persistence is triggered in part by bacterial toxins that shut down critical cellular processes, such as protein synthesis or energy production, forcing the bacterial cells to enter a dormant state in which they are no longer susceptible to killing by antibiotics. But the mechanisms underlying toxin-mediated persistence have not been clear, and little is known about how environmental signals trigger bacterial persistence.

To answer these questions, Michiels and his team focused on the potential role of Obg because this enzyme is at the nexus of major cellular processes, such as protein and DNA synthesis, and it triggers dormancy when cellular energy levels are low. They found that high levels of Obg protected nutrient-starved intestinal bacteria called Escherichia coli and the pathogen Pseudomonas aeruginosa from two antibiotics that interfere with DNA and protein synthesis. “This indicates that a common mechanism to produce persisters is active in different bacterial species,” Michiels says. “Therefore, Obg could be a target for the development of novel therapeutics against infectious diseases.”

Obg induced persistence in E. coli by increasing levels of a toxic molecule called HokB, which causes small holes to form in the bacterial membrane, thereby halting energy production and triggering dormancy. However, deletion of hokB did not decrease persistence in E. coli, and this gene was absent in P. aeruginosa, suggesting that persistence is controlled by at least one other Obg-regulated pathway waiting to be discovered. Another question for future research is how persistent cells can recover from toxin-induced damage and switch back to the normal, non-persistent state. “Answering these fundamental questions will pave the way for translational research that could ultimately lead to better therapies to combat bacterial infections.”  Science Daily  Original web page at Science Daily


New data on botulinum toxin as treatment for nerve pain

Botulinum toxin could offer an effective new treatment for two forms of neuropathy — pain caused by different types of nerve injury, according to an experimental study published in Anesthesia & Analgesia. Treatment with botulinum toxin type B (BoNT-B) produces lasting reduction in abnormal pain responses caused by physical nerve injury or chemotherapy-related nerve damage in mice, reports Tony L. Yaksh, Ph.D., of University of California, San Diego, and colleagues. Their study shows differing effects of local versus spinal injection of botulinum toxin and lends new insights into the molecular-level explanations for how “Botox” works to affect pain processing.

Building on previous studies, the researchers performed experiments in mice to evaluate the effects of BoNT-B on exaggerated pain responses to touch (allodynia) in one or both hind paws after nerve injury. Mononeuropathy (single nerve injury) was induced by cutting a single spinal nerve and polyneuropathy (multiple nerve injury) by giving the chemotherapy drug cisplatin. For both types of neuropathy, the study evaluated the effects of injecting BoNT-B directly into the affected paw or into the spine (intrathecal injection). Botulinum toxin is most familiar from the use of BoNT-A — commonly known by the trade name Botox — for cosmetic plastic surgery. Both BoNT-A and BoNT-B are used for treatment of various neuromuscular disorders

Over the past decade, BoNT-A has been successfully used to treat certain chronic pain syndromes. Since botulinum toxin causes temporary muscle paralysis, the pain-reducing effects have been attributed to muscle relaxation. However, recent studies have suggested that other analgesic mechanisms may be operating as well. In mononeuropathy, injecting BoNT-B into the affected paw significantly reduced abnormal pain responses. In polyneuropathy, local BoNT-B injection reduced allodynia in the injected paw only. This shows that the effects of locally injected botulinum toxin aren’t due to more general spread of the toxin.

The reduction in allodynia after local BoNT-B injection lasted about two weeks before wearing off. That’s consistent with the temporary effect of botulinum toxin used for other purposes — the injections must be repeated to sustain the beneficial effects.

In polneuropathy, intrathecal injection of BoNT-B relieved the allodynia on both affected sides. Spinal BoNT-B didn’t alter normal reflexes in the paws, and didn’t alter other types of pain perception.

Cellular-level studies showed that the two types of BoNT-B injection had differing effects in the pain-processing centers of the spinal cord. The results provided new insights into the specific molecular targets involved in local and intrathecal injection. Neuropathies are common and difficult-to-treat chronic pain problems. Mononeuropathy results from nerve injury of many possible causes — for example, spinal cord injury or other trauma. Polyneuropathy can occur as a toxic effect of chemotherapy drugs, although diabetes is the most common cause. The findings add to previous studies suggesting that botulinum toxin could be a useful new approach to treating neuropathic pain. They aid in understanding BoNT’s mechanisms of action in mononeuropathy versus polyneuropathy, as well as the differing effects of local and spinal injection.

The study is also one the first to focus on BoNT-B, which is shorter-acting than BoNT-A. Dr. Yaksh and colleagues conclude, “Further work focusing on transport and uptake of these and other BoNT serotypes will likely provide important insights into the mechanisms whereby these toxins exert their effects upon nociceptive [pain] processing.” Science Daily  Original web page at Science Daily


* New drug triggers tissue regeneration: Faster regrowth and healing of damaged tissues

Research focuses on select tissues injured through disease, surgery and transplants, but early findings indicate potential for broad applications. Researchers have now announced steps toward turning this idea into reality. They have detailed how a new drug repaired damage to the colon, liver and bone marrow in animal models — even saving mice who would have died in a bone marrow transplantation model. The concept sounds like the stuff of science fiction: take a pill, and suddenly new tissues grow to replace damaged ones.

Researchers at Case Western Reserve and UT Southwestern Medical Center this week announced that they have taken significant steps toward turning this once-improbable idea into a vivid reality. In a study published in the June 12 edition of Science, they detail how a new drug repaired damage to the colon, liver and bone marrow in animal models — even going so far as to save the lives of mice who otherwise would have died in a bone marrow transplantation model.

“We are very excited,” said Sanford Markowitz, MD, PhD, the Ingalls Professor of Cancer Genetics at the university’s School of Medicine and a medical oncologist at University Hospitals Case Medical Center’s Seidman Cancer Center. “We have developed a drug that acts like a vitamin for tissue stem cells, stimulating their ability to repair tissues more quickly. The drug heals damage in multiple tissues, which suggests to us that it may have applications in treating many diseases.”

The institutions collaborating on this work next hope to develop the drug — now known as “SW033291” — for use in human patients. Because of the areas of initial success, they first would focus on individuals who are receiving bone marrow transplants, individuals with ulcerative colitis, and individuals having liver surgery. The goal for each is the same: to increase dramatically the chances of a more rapid and successful recovery.

The key to the drug’s potential involves a molecule the body produces that is known as prostaglandin E2, or PGE2. It is well established that PGE2 supports proliferation of many types of tissue stem cells. Markowitz and University of Kentucky Professor Hsin-Hsiung Tai earlier had demonstrated that a gene product found in all humans, 15-hydroxyprostaglandin dehydrogenase (15-PGDH), degrades and reduces the amount of PGE2 in the body.

Markowitz, also a Harrington Discovery Institute Scholar-Innovator, and James K.V. Willson, MD, a former Case Western Reserve colleague now at UT-Southwestern, hypothesized that inhibiting 15-PGDH would increase PGE2 in tissues. In so doing, it would promote and speed tissue healing. When experiments on mice genetically engineered to lack 15-PGDH proved them correct, the pair began searching for a way to inactivate 15-PGDH on a short-term basis.

The preliminary work began in test tubes. Yongyou Zhang, PhD, a Case Western Reserve research associate in Markowitz’s lab and a lead author on the study, developed a test where cells glowed when 15-PGDH levels changed. Zhang then traveled to UT Southwestern’s Harold C. Simmons Comprehensive Cancer Center, where Willson serves as director. Zhang and UT Southwestern researchers Bruce Posner, PhD, and Joseph Ready, PhD, collaborated to comb through the center’s library of 230,000 different chemicals. Ultimately they identified one chemical that they found inactivated 15-PGDH.

“The chemical, SW033291, acts in an incredibly potent way,” Markowitz said. “It can inactivate 15-PGDH when added at one part in 10 billion into a reaction mixture, which means it has promise to work as a drug.”

A series of experiments showed that SW033291 could inactivate 15-PGDH in a test tube and inside a cell, and, most importantly, when injected into animal models. The third finding came through collaboration between Markowitz and Stanton L. Gerson, MD, director of the Case Comprehensive Cancer Center, UH Seidman Cancer Center, and the National Center for Regenerative Medicine, as well as the Asa and Patricia Shiverick-Jane Shiverick (Tripp) Professor of Hematological Oncology.

Case Western Reserve research associate Amar Desai, PhD, worked between the Markowitz and Gerson laboratories to determine the effect of SW033291 on mice that had received lethal doses of radiation and then received a partial bone marrow transplant. Without SW033291, the animals died. With it, they recovered.

From there, more detailed studies showed that mice given SW033291 recovered normal blood counts six days faster than mice that were transplanted without receiving SW033291. In addition, SW033291-treated mice showed faster recovery of neutrophils, platelets and red blood cells. Neutrophils battle infection, platelets prevent bleeding, and red blood cells deliver oxygen throughout the body

In addition, Desai’s work showed that when SW033291 increases PGE2 in bone marrow, the body also begins to produce other materials that bone marrow stem cells need to survive. Finally, these benefits emerged without any adverse side effects, even at SW033291 doses much higher than would be required for 15-PGDH inhibition.

When investigators treated mice with other diseases, the SW033291 drug again accelerated tissue recovery. For example, the investigators teamed with Fabio Cominelli, MD, PhD, a Case Western Reserve Professor and Chief of the Division of Gastroenterology and Liver Disease, to study a mouse model of ulcerative colitis. SW033291 healed virtually all the ulcers in the animals’ colons and prevented colitis symptoms. In mice where two-thirds of their livers had been removed surgically, SW033291 accelerated regrowth of new liver nearly twice as fast as normally happens without medication.

Because bone marrow, colon, and liver are significantly different tissues, the investigators believe the pathway by which SW033291 speeds tissue regeneration is likely to work as well for treating diseases of many other tissues of the body. However, the next stages of the research will concentrate on three diseases where SW033291 already shows promise to provide dramatic improvement.

In bone marrow transplants, for example, effects of SW033291 in accelerating tissue growth would provide the body the cells required to fight off the two most common and sometimes fatal complications, infection and bleeding. For those suffering the debilitating impact of colitis, accelerating tissue growth could heal colon ulcers more quickly, which in turn could allow patients to take lower dosages of other medications that treat colitis — some of which have serious side effects. Finally, the promise of tissue growth could increase survival rates for patients with liver cancer; in some cases today, physicians are unable to perform surgery because the amount of the liver to be removed would be so great as to pose severe risk to the patient. But having a drug to accelerate the liver’s regrowth could make surgery a viable option.

The team’s next step will be to complete studies showing safety of SW033291-related compounds in larger animals, a required part of the pathway to secure approval from the U.S. Food and Drug Administration for trials in humans. If the drugs prove safe and effective in those clinical trials, they could then become available for general use by physicians. Investigators hope to partner with pharmaceutical companies to be able to start human trials within three years.

“These are thrilling times for us as researchers, and it is also an exciting time for Case Western Reserve,” Markowitz said. “In Cleveland, there has been a major effort in the last two to three years to figure out how all our institutions can together work to develop drugs. This discovery is really something we should celebrate. It helps put us on the map as a place where new drugs get invented.”

Markowitz added that this research received crucial financial assistance from Case Western Reserve University School of Medicine’s Council to Advance Human Health (CAHH), from the Harrington Discovery Institute at University Hospitals, and from multiple National Institutes of Health grants that included the Case GI SPORE, led by Markowitz, and the National Center for Accelerating Innovation at the Cleveland Clinic. Additional support was received from the Marguerite Wilson Foundation; the Welch Foundation; the Cancer Prevention & Research Institute of Texas; Inje University; and the Korean National Research Foundation. Generous major gifts also came from the Leonard and Joan Horvitz Foundation and the Richard Horvitz and Erica Hartman-Horvitz Foundation.  Science Daily  Original web page at Science Daily