Category Archives: Gene Medicine

Presently, the process of DNA sequencing to discover a genes function is a bit time-consuming because it has to be done one gene at a time. But with the invention of a team of researchers from Rutgers University-New Brunswick, Johns Hopkins University and Harvard Medical School, that process can now be considerably shortened as they have found a way to simultaneously clone thousands of genes.

The new technique is called LASSO cloning LASSO is an acronym for long-adapter single-strand oligonucleotide and through it, isolating thousands of DNA sequences can now be done at the same time. As a result, the new technology can supposedly expedite the creation of proteins the end product of genes which can in turn lead to faster discovery of new medicines and biomarkers for scores of diseases.

The technique is considered as quite an improvement over an existing method known as molecular inversion probes (MIPs), which can only capture about 200 bases of DNA. Raising this number to a thousand is especially significant because the typical size of a genes protein-coding sequence can reach up to thousands of DNA base pairs.

The technology works through a tool the team refers to as a LASSO probe. Using a number of these probes enables grabbing of target DNA sequences, similar with how a lasso (a rope) is used to round up cattle. What makes this special is the fact that with a single effort, the technique can grab thousands of DNA sequences at the same time.

In their proof-of-concept study, the team used their LASSO probes to simultaneously capture over 3,000 E. coli bacteria DNA fragments. They were successful in capturing around 95% of their gene targets. More importantly, the sequences were captured in such a way that allowed the researchers to observe and evaluate what the expressed proteins do.

As an added bonus, the team also helped solved a perennial problem in the genome sequencing field. As it is, genetic sequencing currently involves sequencing small fragments of DNA one at a time, then overlaying them in order to map out the entire genome. This doesnt just take time; its also harder to interpret and kind of prone to errors. With the LASSO probes, sequencing long fragments has now been made possible, which also translates to a faster and more accurate gene sequencing process.

As one of the researchers, Biju Parekkadan of the Rutgers University-New Brunswick, said: We think that the rapid, affordable, and high-throughput cloning of proteins and other genetic elements will greatly accelerate biological research to discover functions of molecules encoded by genomes and match the pace at which new genome sequencing data is coming out.

Going forward, the team is now working on improving the cloning process, building libraries and discovering the therapeutic proteins found in our genes.

The research was recently published in the journal Nature Biomedical Engineering.

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Gene Cloning Just Became A Thousand Times Easier - Wall Street Pit

In the last few years, CRISPR the precise and easily available gene-editing technique has gone from strength to strength. Right now, its more potential than practical, but its uses are almost countless. From removing genetic diseases from babies before they are born to causing cancerous cells to self-destruct, its more likely than not it will rapidly become a key tenet of modern medicine.

The technique is being used in a massive number of trials right now, and a few of them have highlighted that its far from fully understood and far from being perfected. One particularly controversial study released back in May claimed that CRISPR was in fact dangerous, but now another study, currently sitting on the bioRxiv pre-print server, has dismissed this research as flawed.

The original study looked at the effect of using CRISPR in mice, and found that it introduced a large number of previously unknown mutations into their genome. The mice were blind, and the gene-editing technique was used to effectively cure them of this affliction.

While it was successful, it also appeared to inadvertently lead to mutations elsewhere at least 1,500 of them, in fact. Of these, just over 100 mutations were more serious, involving not just DNA base pair changes, but full deletions or insertions of new segments of DNA.

What is CRISPR? Wired via YouTube

Although there were no physiological side effects, unwanted mutations are always a cause for concern. As a result, the authors concluded that CRISPR has the potential to be quite hazardous to the normal operation of biological systems.

When this study was released, it caused quite a stir. Similar studies had only shown a handful of changes, which turned out to be harmless. People were quick to point out that the study was very small, involving just three mice, and that the changes made elsewhere on their genomes could easily be attributed to normal genetic mutations that take place all the time.

Now, a Harvard University-led team have suggested that these unwanted mutations have a far more innocuous explanation.

Apart from the fact that there is no direct line of evidence demonstrating that CRISPR caused the mutations, the team note that the mice used in the study were very closely related. This means that whatever mutations one had, the other would have had too.

Combined with the fact that the mutations were found nowhere near the actual gene-editing site, the authors conclude that, once again, CRISPR is probably safe after all. Plenty more trials are needed to verify this, of course but the point here is that this study raised a massive red flag when it wasnt justified in doing so.

[H/T: New Scientist]

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Debate Rages Over Safety Of CRISPR Gene-Editing Technique - IFLScience

BEECH ISLAND The brand-new bright pink wheelchair sits in a corner in the darkened living room while 5-year-old Kylee OShields sits in the old one in the living room. There is an improvised foam padding to cover the metal where the headrest fell off and she loses a piece of her wheelchair wherever she goes, said her father, Rick.

The OShields like the new wheelchair provided by South Carolina Medicaid but its just too heavy and the family is trying to raise money to buy a wheelchair van for the nearly daily trips the girl must make to doctors appointments and therapy. It is just the latest challenge for a family with a girl born with a very rare genetic disorder.

Kylee has Bohring-Opitz syndrome and it is a bit of a mystery how many other children there are like her. The Genetics Home Reference of the National Library of Medicine cites two previous studies, one of which includes Kylee, of 40 documented cases worldwide. But the OShields are part of a Facebook support group for parents of children with the syndrome and they think there is closer to 100 worldwide.

The syndrome is caused by a gene mutation and children with it often have distinctive eye and skull shapes, developmental delay and poor muscle tone, among other health problems. In Kylees case, when she was born she was diagnosed with a joint disorder but after the family started a Facebook page for her that got international attention, other mothers messaged her to tell her to look into different syndromes.

A blood test sent to a lab in the Netherlands turned up the genetic defect. The syndrome also has a high prevalence of a particular kidney cancer called Wilms tumor and when the family had her checked there was one already covering 75 percent of her kidneys. Quick treatment probably saved her life, but the family said it showed divine intervention.

In recent years Kylee has nearly doubled in size to about 50 pounds, making it difficult for her mother to get her in and out of their current van as well. Medicaid will help pay for a conversion of the current van but it already has 115,000 miles on it and the family is wary of putting all of that money into a van that wont last.

The family has started a GoFundMe page and will hold a fundraiser July 29 at Midland Valley Community Church of the Nazarene. They think it will take about $50,000 to get a suitable van.

Because the syndrome is so rare and because each child is different, there is no roadmap for the family to follow on what Kylees future might hold. She cant crawl or walk but her therapists are working on strengthening her legs and use a type of walker to get her hips used to standing. One mother of a child with the syndrome proudly posted a photo of her daughter sitting up for 30-40 seconds.

We share in the achievements, Laura OShields said. The support group allows them to keep in touch and offer advice. When one child had problems with constant vomiting, something Kylee went through, I was able to suggest things to them, Laura OShields said.

Sometimes, when they are out with Kylee in public, people will offer their sympathies but Laura OShields has a polite response to their pity.

Why? she asked. Shes fine. Shes growing. Shes happy.

Reach Tom Corwin at (706) 823-3213

or tom.corwin@augustachronicle.com.

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Family coping as daughter suffers from rare genetic disorder - The Augusta Chronicle

The levels of one gene in particular may play a key role in protecting from depression or accelerating its severity, according to a new study from researchers at the University of Maryland School of Medicine.

Depression, which affects over 300 million people,changing the waythey interact with the world, is the mostcommon cause of disabilityglobally.

The study, published Thursday in the Journal of Neuroscience, pinpoints the importance of the levels of gene Slc6a15, which works in neurons of the brain involved with the brains reward system. The levels of this gene, which acts as a neutral amino acid transporterin brain neurons, could affect peoples mood, according to Dr. Mary Kay Lobo, the senior author of the study and an assistant professor in the department of anatomy and neurobiology at the University of Maryland School of Medicine.

The study focused on vulnerable neurons, or parts of the brain that react to stress. While previous studies had indicated Slc6a15 was associated with depression susceptibility, Lobo and her team wanted to examine how levels of this particular gene would correlate with mediating susceptibility to stress.

In their research, the team found that mice who had been genetically modified to have lower levels of the gene were found to exhibit depression-like outcomes after experiencing stress. In mice they had modified to enhance the level of the gene, they found a resilient response to stress, according to Lobo.

They also found that the level of gene Slc6a15 was reduced in the post-mortem analysis of individuals who had suffered from depression.

If we can find ways to actually enhance levels of this molecule in this particular vulnerable neuron population that would be a way to combat depression, Lobo said. This is also a druggable target.

Put more simply, the study of this previously understudied gene could be critical in advancing the understanding of depression and its underlying causes, according to Dr. A.J. Robison, a professor of physiology at Michigan State University who was not involved in the study.

In order to improve, we really need to understand not only how the disease is happening and what went wrong to cause depression, but how the drugs work to combat it, Robison said.This study should lead to a continuing body of work that can really make genuine progress in understanding how depression works and maybe even in treating it.

For Lobo, the next steps entail identifying more of these types of genes and their impact.

We have to go in and find these vulnerable neuron subtypes, perhaps to alleviate depression-like symptoms, she said.

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Researchers Identify Levels Of Gene That Could Play A Key Role In Depression - HuffPost

Recently, a kerfuffle in the world of CRISPR illustrated just how easily moneyand our perception of itcan impact science.

In late May, a paper came out questioning how effective the gene-editing technology really is. Working with mice, researchers found that edits made with CRISPR can also result in thousands of unintended changes to a genome. The study cast serious doubt on whether CRISPR is ready for prime time.

The fallout was swift. Stock prices of three CRISPR companiesEditas Medicine, Intellia Therapeutics and CRISPR Therapeuticstumbled. Scientists affiliated with those companies fired back, questioning the studys methodology. Stocks bounced back. The scientific world was set atwitter, questioning not only the validity of the initial study, but how to trust a rebuttal against that study when it came from those who stood to lose the most from its publication.

Conflicts of interest arent a new problem in science. One frequently-cited example is the role that tobacco industry-funded scientists played in distorting the health consequences of smoking. There is a significant body of evidence suggesting financial interests can correlate with favorable results. But, conflicts of interest arent always all bad. Research funding from sources with a vested interest in a topic can sometimes help advance science that otherwise might not get funded at allthink the patient advocacy groups funding cures for little-known diseases.

Whats undoubtedly true is that money plays a significant role in science. And rarely has there been as much money at stake as with CRISPR, the nascent gene-editing technique that promises to cure everything from genetic disease to global famine by allowing researchers to easily cut and paste particular genes. When scientists whose fortune and reputation hinges on a particular technology speak out against a paper questioning that technology, its hard not to wonder how that bias might factor in.

There is this unspoken assumption the people in academia are driven primarily by the quest for knowledge and the science, Josephine Johnston, a bioethicist at The Hastings Institute, told Gizmodo. But in recent history, controversies over things like tobacco and GMOs have begun to erode that perception. When it became clear that more and more scientists have a specific financial stake, it caused a lot of concern, Johnston said.

When it comes to CRISPR, the financial stakes are certainly complicated. Two separate groups of scientists have long been embroiled in a battle over the patent for the technology, with one headquartered at The Broad Institute of MIT and Harvard, and the other at U.C. Berkeley (so far, the US has awarded the patent to Broad but Europe and China have sided with Berkeley). The patent gives the scientists the ability to license the technology. In this case, Broad has licensed the technology to Editas, a company founded by scientists at both Berkeley and Broad. Berkeley licensed its patents Intellia, which Berkeleys Jennifer Doudna is also a founder of, as well as to CRISPR Therapeutics.

Most of the headline-grabbing scientists associated with CRISPR have major financial stakes in publicly traded CRISPR companies, creating a strong incentive across the industry for CRISPR to succeed. The concern is that a CRISPR-favoring bias could potentially cause researchers to misinterpret or skew study results, or forge ahead with human clinical trials before CRISPR is really ready.

Thats not to say that theres necessarily anything wrong with the points industry-affiliated CRISPR scientists raised in their rebuttal to the paper questioning their science. In fact, several other scientists raised similar concerns.

Finances certainly can influence science. Not just companies, but also the premises supporting government grant finances, George Church, an author of the rebuttal paper and founder of Editas, told Gizmodo via email. We were basically raising issues that the original authors can address. This, fortunately, doesnt require perfect unbiased authors. Anyone can point out a potential problem.

Michael Kalichman, director of UC San Diegos research ethics program, pointed out that financial interest isnt the only bias that scientists have to be wary of.

Weve talked about conflicts of interest for many years in science and for many reasons much of that focus has been on financial conflicts. For one, its easy to see, he told Gizmodo. What I find astonishing is that even scientists forget that there are other conflicts that can influence work, like tenure, your reputation or just being excited about an idea.

Kalichman said his biggest concern is less that scientists are actually doing anything unethical, and more that financial conflicts of interest create the perception that they are. The paper that sparked the CRISPR controversy received press in most major news outlets, and the blowback against it has received significant attention, too.

Part of me is worried about the way [this CRISPR fight] is playing out because of the picture it paints of science, he said. We have this battle going on in the pages of scientific journals that creates this perception that this is what science is about when most of science is not about this.

Johnston echoed those concerns.

The introduction of these financial interests muddies the water enough that people dont know who to trust, she said. Whether or not we can see anything wrong with either study, or anyone else can, theres still this suspicion that the financial stakes must have played some role here. Thats a very corrosive thing across science.

In the initial Nature Methods paper, scientists from Stanford and University of Iowa working to cure blindness in mice found that while CRISPR did successfully edit the gene for blindness, it also caused mutations in more than a thousand unrelated genes. The consequences of those off-target effects, far more extensive than previously realized, are largely unknown. This finding warns that CRISPR technology must be further tailored, particularly before it is used for human gene therapy, the researchers wrote.

As mentioned, scientists associated with CRISPR companies were not the only ones, or even the first, to criticize the studys design. Many scientists raised red flags about basic mistakes, such as misidentifying genes, mislabeling genetic defects, and the small number of animals the researchers had included in their research. But other scientists found the reaction against the paper, was written as a brief letter to the editor intended mainly to point to an area where more study might be needed, to be overwrought. Some, like UC Davis professor Paul Knoepfler, suggested the real problem was that the results had been over-interpreted and blown up in the press, setting in motion an out-sized blowback.

Scientists from Intellia and Editas both sent separate letters to Nature Methods, forcing it to eventually add a note to the study about the controversy surrounding the letter. Whats more, in publishing their own study taking down the initial works methodology, scientists associated with Editas opted to publish a pre-print online before it was peer-reviewed, though the initial paper did go through a peer review process. And while the response paper mentions the institutions and companies each author is affiliated with, there is no clear conflict of interest section. (Church said conflicts of interest will be included with journal publication.)

This week, a pre-print of a second paper published by scientists at Intellia that reanalyzed the original papers data and found far fewer off-target edits also appeared online.

In a statement, the Broad Institute said that the peer review process should weed out the impact of any conflict.

Scientific paperswhether making a new claim, or analyzing an existing scientific claimshould always be subject to rigorous evaluation by the scientific community to establish whether the scientific evidence actually supports the argument in the paper, the Broad Institute told Gizmodo. Such review by the community provides protection against incorrect arguments, whether due to a scientific error, financial or reputational interest, or something else.

Most journals and research institutions have a comprehensive conflict of interest policy. In 2010, UNESCO called for journals to adopt a common standard of dealing with the complex and growing financial arrangements that have developed in recent years between vested interests and independent scientists. Even so, sometimes those ties wind up omitted.

Kalichman said more might be needed to address conflicts of interest in the realm of basic science.

In clinical research, you do everything you can to separate financial interests from the people doing the work, Kalichman said. We dont really talk about that in basic research, but maybe we need to do something like that. Maybe if you have a financial interest, youre not the one that looks at the raw data.

Its next to impossible to fully weed out conflict in sciencebe it financial or otherwise. Besides, it makes sense that scientists should be able to make money off of their own work. But its also impossible not to acknowledge that those interests can influence the science. How could they not?

Update: This story has been updated to include mention of the Intellia study.

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Gene Editing Controversy Reminds Us Just How Much Money Influences Science - Gizmodo

July 6, 2017 Credit: CC0 Public Domain

Globally, depression affects more than 300 million people annually. Nearly 800,000 die from suicide every yearit is the second-leading cause of death among people between the ages of 15 to 29. Beyond that, depression destroys quality for life for tens of millions of patients and their families. Although environmental factors play a role in many cases of depression, genetics are also crucially important.

Now, a new study by researchers at the University of Maryland School of Medicine (UM SOM) has pinpointed how one particular gene plays a central roleeither protecting from stress or triggering a downward spiral, depending on its level of activity.

The study, published today in the Journal of Neuroscience, is the first to illuminate in detail how this particular gene, which is known as Slc6a15, works in a kind of neuron that plays a key role in depression. The study found the link in both animals and humans.

"This study really shines a light on how levels of this gene in these neurons affects mood," said the senior author of the study, Mary Kay Lobo, an assistant professor in the Department of Anatomy and Neurobiology. "It suggests that people with altered levels of this gene in certain brain regions may have a much higher risk for depression and other emotional disorders related to stress."

In 2006, Dr. Lobo and her colleagues found that the Slc6a15 gene was more common among specific neurons in the brain. They recently demonstrated that these neurons were important in depression. Since this gene was recently implicated in depression by other researchers, her lab decided to investigate its role in these specific neurons. In this latest study, she and her team focused on a part of the brain called the nucleus accumbens. This region plays a central role in the brain's "reward circuit." When you eat a delicious meal, have sex, drink alcohol, or have any other kind of enjoyable experience, neurons in the nucleus accumbens are activated, letting you know that the experience is pushing the proper buttons. In depression, any kind of enjoyment becomes difficult or impossible; this symptom is known as anhedonia, which in Latin means the inability to experience pleasure.

The researchers focused on a subset of neurons in the nucleus accumbens called D2 neurons. These neurons respond to the neurotransmitter dopamine, which plays a central role in the reward circuit.

They studied mice susceptible to depression; when subjected to social stressexposure to larger, more aggressive micethey tend to withdraw and exhibit behavior that indicates depression, such as social withdrawal and lack of interest in food that they normally enjoy. Dr. Lobo found that when these animals were subjected to chronic social stress, levels of the Slc6a15 gene in the D2 neurons of the nucleus accumbens was markedly reduced.

The researchers also studied mice in which the gene had been reduced in D2 neurons. When those mice were subjected to stress, they also exhibited signs of depression. Conversely, when the researchers enhanced Slc6a15 levels in D2 neurons, the mice showed a resilient response to stress.

Next, Dr. Lobo looked at the brains of humans who had a history of major depression and who had committed suicide. In the nucleus accumbens of these brains, the gene was reduced. This indicates that the link between gene and behavior extends from mice to humans.

It is not clear exactly how Slc6a15 works in the brain. Dr. Lobo says it may work by altering neurotransmitter levels in the brain, a theory that has some evidence from other studies. She says her research could eventually lead to targeted therapies focused on Slc6a15 as a new way to treat depression.

Explore further: Brain protein influences how the brain manages stress; suggests new model of depression

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Here and throughout the article, shouldn't it say the Slc6a15 gene was expressed more? The wording used makes it sound like these brain cells have more of the gene than other cells in the body, but if I remember high school biology correctly, that isn't true.

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New study identifies gene that could play key role in depression - Medical Xpress

Lexington Herald Leader

Tumor gene testing urged to tell if drug targets your cancer Lexington Herald Leader The government has recently approved the first cancer therapy that's based on a tumor's genetics instead of the body part the cancer struck first. Now thousands of patients whose cancer is growing worse despite standard treatment can try this new ... and more »

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Tumor gene testing urged to tell if drug targets your cancer - Lexington Herald Leader

In Brief Researchers have developed a new gene cloning technique that works on thousands of genes at once: the LASSO probe. The tool will enable far more rapid discovery of biomarkers for numerous diseases and new treatments for them. LASSO Cloning

Scientists from Harvard Medical School, Johns Hopkins, Rutgers, and the University of Trento in Italy have developed LASSO cloning, a new molecular technique. LASSO cloning can be used to simultaneously isolate long DNA sequences faster than was previously possible. This new technique speeds up protein creation, which means that genes (the final product of the process) are arrived at more quickly. This, in turn, can enable far more rapid discovery of biomarkers for numerous diseases and their treatments.

In the past, researchers have sussed out what a gene does by cloning its DNA and then expressing the protein it codes for single gene by single gene. With this novel molecular approach, a single reaction can clone and express thousands of DNA sequences at once. The technique involves the use of a novel captured DNA strand, the LASSO probe (Long Adapter Single-Stranded Oligonucleotide). Researchers can use collections of these tools to grab DNA sequences theyre after. Unlike a cowboy roping cattle, however, scientists using the LASSO probe can capture thousands of sequences in a single try.

The LASSO technique improves on molecular inversion probes (MIPs), an older method which is limited to capturing only about 200 DNA bases at once. This is minuscule compared to each LASSO target gene sequence which can be as much as a few thousand DNA base pairs longaround the length of a typical genes protein-coding sequence.

The team used LASSO probes to simultaneously capture more than 3,000 DNA fragments from the E. coli genome as part of a proof-of-concept study. They captured at least 75 percent of their gene targets successfully. More importantly, however, the tool allows researchers to capture sequences in a way that allows them to analyze what the corresponding proteins do.

Were very excited about all the potential applications for LASSO cloning, Larman said in the release. Our hope is that by greatly expanding the number of proteins that can be expressed and screened in parallel, the road to interesting biology and new therapeutic biomolecules will be dramatically shortened for many researchers.

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Powerful New Cloning Technique Can Clone Thousands of Genes at Once - Futurism

Scientists at Johns Hopkins, Rutgers and Harvard universities, as well as the University of Trento in Italy, have created a new technique that allows thousands of genes in a DNA sequence to be cloned at once.

Researchers hope the advance in gene cloning will allow them to more quickly identify markers for diseases and discover new medicines.

Until now genes had to be cloned individually in a time-consuming process. The new molecular method allows thousands of the long DNA strands that make up genes to be isolated and cloned at the same time.

The discovery was published June 26 in Nature Biomedical Engineering.

"Our goal is to make it cheap and easy for any researcher in any field to clone and express the entire set of proteins from any organism," said Ben Larman, an assistant professor of pathology in the Johns Hopkins School of Medicine and the study's co-senior author, in a statement. "Until now, such a prospect was only realistic for high-powered research consortia studying model organisms like fruit flies or mice."

The scientists call their technique for capturing DNA strands that make up genes the LASSO method, for long adapter single-stranded oligonucleotid. They also liken it to capturing cattle with a rope.

The new process speeds up the genes' creation of proteins, which manage cell activity, compared to the old process of cloning individual genes.

To test the method, the scientists sought to capture more than 3,000 DNA strands from the E. coli bacterial genome, commonly used as a model organism, and were successful with most of the targets. They also were able to use the strands to analyze what the gene's proteins do.

"We're very excited about all the potential applications for LASSO cloning," Larman said. "Our hope is that by greatly expanding the number of proteins that can be expressed and screened in parallel, the road to interesting biology and new therapeutic biomolecules will be dramatically shortened for many researchers."

The next step, already underway, is improving the cloning process and building libraries of proteins from DNA samples for use in research, said Biju Parekkadan, an associate professor in the Department of Biomedical Engineering at Rutgers University-New Brunswick.

Funding for the research came from the Shriners Hospitals for Children, the Prostate Cancer Foundation and the National Institutes of Health.

Larman, Parekkadan and a Harvard scientist on the project have sought a patent for the method, which is pending.

meredith.cohn@baltsun.com

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Hopkins joins gene cloning project to advance medicine development - Baltimore Sun

ANN ARBOR, Mich. -- After 12 weeks of taking an anti-inflammatory asthma drug, obese patients with type 2 diabetes showed a clinically significant drop in blood glucose.

The drug amlexanox, prescribed in Japan to treat asthma, appeared to free the metabolic system to burn more energy. A subset of patients had improved fatty liver disease and insulin sensitivity, a response seen among those who started the clinical trial with higher levels of inflammation in their fat tissue than others.

While the discovery at Michigan Medicine and the University of California at San Diego is not ready for the clinic, it reveals an inflammatory link between obesity and type 2 diabetes.

Inflammation is the bodys natural response to injury and illness, but chronic inflammation caused by obesity is believed to promote insulin resistance, a main feature of diabetes.

We are beginning to understand the role this form of internal inflammation plays in the development of chronic diseases like diabetes, says lead study author Elif Oral, M.D., director of the MEND Obesity and Metabolic Disorder Program at Michigan Medicine. Ultimately we may be able to personalize therapy based on the degree of inflammation present at baseline which is a new concept.

Oral is an endocrinologist and translational scientist at Michigan Medicine, the University of Michigans academic medical center where the clinical trial was conducted and analyzed.

Tissue analysis was led by study author Alan R. Saltiel, Ph.D., at U-C San Diego, along with scientists at the Salk Institute for Biological Sciences.

In the Cell Metabolism study, researchers identified a molecular signature in obese patients with type 2 diabetes who responded to the drug amlexanox.

When we looked at the drug-treated group we saw a bimodal distribution, that is, there were some responders and some nonresponders. We didnt understand why, so we did a molecular analysis from biopsies of fat cells we took from patients at the beginning and end of the study, says Saltiel, director of the Institute for Diabetes and Metabolic Health at U-C San Diego

In the responder group, the level of inflammation in fat was higher than in the nonresponder group at the beginning of the study, indicating that there is something about inflammation that predisposes a person to respond. And, what was really amazing was that there were more than 1,100 gene changes that occurred exclusively in the responders.

The glucose-lowering effects of amlexanox were first discovered in mice during research at the University of Michigan where Saltiel served as director of the Life Sciences Institute at the U-M.

Promising results

Amlexanox is an inhibitor of two enzymes, IKK and TBK1. In previous studies, Saltiel and U-M researchers discovered that these two enzymes are induced in obese mice, causing a drop in energy expenditure or reduction in calories burned.

This prompted them to look for inhibitors of these enzymes by screening a library of 150,000 chemicals. They found amlexanox. Giving obese mice the inhibitor caused them to lose weight, while their sensitivity to insulin increased, improving their diabetes and fatty liver disease.

The human trial revealed that gene changes that occurred in the mouse model also happened in the human responder group. Blood sugar in the clinical trial patients went down as genes involved in the expenditure of energy changed.

The proof of concept trial began with an unblinded safety trial of six patients. It was followed by a controlled trial of 42 obese patients with type 2 diabetes.

Half of the patients were randomized to a placebo group while the other half received amlexanox for three months. Blood sugar, insulin sensitivity, weight and liver fat were measured. A biopsy of fat cells from each patients midsection was taken before and after the trial to measure changes in gene expression.

The most exciting part of this is that we have a new drug that has never been studied before, says Saltiel. Its a new mechanism for a diabetes and fatty liver drug. Its promising, but there are a lot of questions that need to be answered still.

Among them: Which gene changes are the most important to target? Whats the right drug dosage? What time of day should it be administered? How often should patients take the drug? Can the percentage of responders be increased? Will the beneficial effects of the drug be sustained for a longer time?

One-third of the participants in the blinded study responded. Among responders with nonalcoholic fatty liver disease, an improvement was also seen.

Researhers are planning follow-up trialsto look at whether its possible tostratify patients who are likely to respond based on the degree of underlying inflammation, and explore if other drug combinations can be used with amlexanox.

We are grateful for patient participation and hope that our patients will respond with the same enthusiasm to our new trials. Without patients volunteering, the sort of study can never happen, says Oral.

Primary support for the research came from the National Institutes of Health High Risk High Reward grant R21DK098776.

Additional authors include Shannon M. Reilly, Andrew V. Gomez, Rasimcan Meral, Laura Butz, Nevin Ajluni, Thomas C. Chenevert, Evgenia Korytnaya, Adam H. Neidert, Rita Hench, Diana Rus, Jeff Horowitz, BreAnne Poirier, Peng Zhao, Kim Lehmann, Mohit Jain, Ruth Yu, Christopher Liddle, Maryam Ahmadian, Michael Downes and Ronald M. Evans.

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Asthma drug shows promise in treating obesity and diabetes - University of Michigan Health System News (press release)