Autoimmunity, Brain & Beyond

The Lupus Research Institute (LRI) Announces 2009 Research Awards

The Lupus Research Institute (LRI) today named 12 new grant recipients for 2009. The awards, totaling $3.6 million, recognize innovative work across a broad spectrum of lupus research. Anne Davidson, MD, a lupus researcher at The Feinstein Institute for Medical Research, was one of this year's recipients. To read more about Dr. Davidson's research grant go to:

http://lupusresearchinstitute.org/research/grant_recipients/davidson/anne

Epilepsy Medicine Tested to Treat Cocaine Addiction

They were Mexican parolees with an addiction to cocaine. They were also desperate pioneers whose drug use had gotten the better of them every day for years. They signed on to a double-blind, placebo-controlled study to test whether an epilepsy drug could reduce their use of cocaine. In the end, 14 of the 50 parolees who were taking a medicine called vigabatrin spent the final three weeks of the study with no signs of cocaine use on twice weekly urine tests, compared to four of 53 who swallowed a placebo dose. They were also less likely to be drinking alcohol during this same time period.

    The study, conducted by Stephen L. Dewey, PhD of The Feinstein Institute for Medical Research in Manhasset, NY, and Jonathan D. Brodie, MD, PhD, of New York University School of Medicine and their colleagues, appears in the November issue of the American Journal of Psychiatry.

    Dr. Dewey and Dr. Brodie have spent more than a decade working on animal models, and now drug abusers, following their initial findings that the drug blocks important reinforcement regions of the brain tied to addiction. The scientists just received a $1.2 million grant from the U.S Department of Defense to continue their work in treating human addictions.

    “In animal models, vigabatrin works to reduce the use of virtually every addictive substance,” said Dr. Dewey. The work was conducted at Brookhaven National Laboratory, where Dr. Dewey had worked from 1996 until moving his laboratory to the Feinstein Institute earlier this year. It was in 1998 when he discovered that the epilepsy drug, which had been approved for use in Europe but not in the United States, showed potential to end cocaine addiction. A year later, it was used for smoking cessation and then methamphetamine. The drug was even used to see if it could reduce cravings for high-sugar, high-fat food.

    It was recently approved by the US Food and Drug Administration for use in epilepsy treatment. "If this can do for humans what it did for animals, we may have opened the door for addicts around the world to kick their habit," said Dr.  Dewey. Gamma vinyl GABA, or GVG, blocks the chemical process that triggers the "high." The substance increases the amount of the brain's most common neurotransmitter, GABA. The increased GABA allows brain cells to communicate more effectively.

    The researchers became interested in GVG because it also reduces the level of another brain chemical called dopamine. This brain substance has been shown to modulate pleasure and reward, as well as other behaviors. Cocaine users experience a "high" because the drug - and other mind-altering substances - seems to stimulate a flood of dopamine in the brain regions that govern reinforcing and rewarding behavior in humans and animals alike. Dopamine is known as the "feel-good" transmitter, although it has many different roles in the brain. Vigabatrin reduces levels of dopamine in the circuits of the brain that govern reward.

    About 30 million people in the United States have used cocaine, and about one to three million would be considered addicted, experts say. There are no medicines approved for cocaine addiction.

    The current study is the first double-blind, placebo-controlled study of the drug in addicts. The men and women who signed on to the trial arrived to the clinic as part of their parole requirements after being released from prison. They had an average daily use of two grams per day for about nine years. They agreed to be part of the study even though half of them would end up on a placebo. The medicine is a powder that they mixed with orange juice.

    At the end of three months, four times as many people taking vigabatrin completely stopped using cocaine for at least three weeks compared to those swallowing a placebo powder in their juice. They were also far more likely to report abstinence from alcohol.

    There have been concerns moving forward with this drug. One of the reasons it was not approved in the U.S. until recently was that there is a rare but troubling side effect: a narrowing of visual field. And there are indications these defects could grow more serious over time.

    Dr. Dewey and Dr. Brody teamed with a biotech company – Catalyst Pharmaceutical Partners – that has licensed the use of the drug for the treatment of cocaine addiction. They have a long way to go before vigabatrin could be used to treat addictions. They need much larger studies and must figure out how much to give and whether it could be given over a long-term period. In the current study, the only side effect was tiredness.

    Dr. Dewey’s research on the addicted brain has led him into Long Island schools to educate young people, parents and teachers on the dangers of the brain on drugs. His lectures and town hall meetings have become so popular that he was asked last month to speak to The Welfare to Work Commission of the Suffolk County Legislature during a public meeting on a growing network of “sober homes.”

Experimental Medicine Protects Against Organ Failure

Seventy-five thousand people who undergo surgery or are admitted to the Emergency Department experience a potentially life-threatening condition: A temporary loss of oxygen that can set in motion a rogue inflammatory response that can lead to multiple organ failure.

 

Ping Wang, MD, a scientist at The Feinstein Institute for Medical Research, is testing the benefits of an experimental medicine that can clear away dying cells and reduce the risk for ischemia reperfusion injury in the gut. In a study published in the American Journal of Respiratory Critical Care Medicine, Dr. Wang and his colleagues used an experimental medicine called MFG-E8 on the heels of ischemia and found that it significantly lowered the risk for reperfusion injury.  Normally, when tissue suffers from a temporary loss of oxygen the body makes an unusual response when the oxygen starts to flow again. It sets off an inflammatory response. These inflammatory cells actually target tissue and can trigger multiple organ failure. The lung is most susceptible to this type of injury, which is why in humans it can be deadly.

 

MFG-8 blocked the acute lung injury in an animal model of ischemic reperfusion. Forty-seven percent of the animals exposed to MFG-8 survived for at least 24 hours while none of placebo mice survived, according to Dr. Wang. MFG-8 is a protein normally produced by the spleen to enhance clearance of dying cells. The Feinstein scientists at Dr. Wang’s laboratory made a recombinant human protein. The idea to use the protein emerged after their studies showed that MFG-8 levels drop markedly on the heels of ischemia reperfusion. Spleen cells just can’t produce enough of the substance to clean up the dying cells. If the cells are not removed – and this cellular garbage continues to accumulate – this necrosis (or cell death) can cause acute lung injury.

 

They found that the medicine helped clear out the majority of the dying cells in the hard-hit lung. It also reduced inflammation at the site. And the most hopeful news was that about half of the animals survived the injury. The work in the laboratory will continue to address questions that need answering: Will the recombinant human protein be safe to patients? How much will be enough to protect against organ failure?

 

Right now, there is no approved effective medicine to treat intestinal ischemic reperfusion. Dr. Wang said that there are 25,000 to 50,000 deaths a year related to this intestinal injury.

Lymphatic Research Foundation Launches Tissue Bank at the Feinstein

The Lymphatic Research Foundation has launched the National Lymphatic Disease and Lymphedema Patient Registry and Tissue Bank in collaboration with Dr. Peter K. Gregersen and his colleagues at The Feinstein Institute for Medical Research. This registry will enable scientists and clinicians to better understand the course of lymphedema and other lymphatic diseases. Collecting medical data and identifying genetic fingerprints of the condition is critical in understanding the nature and the progression of these conditions. The Patient Registry has already begun and the Tissue Bank (Biorepository) will begin early next year. Robert Lundsten and the Feinstein Institute's Biomedical Informatics Group created and rolled out the LRF registry. For more information contact the Lymphatic Research Foundation at 516-625-9675.

Feinstein scientist Todd Lencz, PhD, gets federal GO award to study schizophrenia

The National Institutes of Health (NIH) has awarded a “Grand Opportunity” (GO) grant to a team of researchers – led by Todd Lencz, PhD, at The Feinstein Institute for Medical Research and Zucker Hillside Hospital, and Ariel Darvasi, PhD, of Hebrew University – to use cutting-edge technologies to help unravel the genetic basis of schizophrenia. More than two million dollars was awarded to the team, which also includes Anil Malhotra, MD, and Peter Gregersen, MD, of the Feinstein Institute and David Goldman, MD, of the National Institute of Alcohol Abuse and Alcoholism, to conduct this research.

    As described by the NIH, the GO grant program was designed to support “high impact ideas” that can “accelerate critical breakthroughs” in our understanding of human disease. The program was made possible by an infusion of money to the NIH under the American Recovery and Reinvestment Act (also known as the “economic stimulus package”), representing “the single largest boost to biomedical research in history,” according to President Barack Obama. In announcing the awards, President Obama singled out genetic research as “one of the most exciting areas of research to move forward as a result of this investment.” Eventually, it is hoped that this research may be used to more accurately predict, treat, and prevent serious mental illnesses such as schizophrenia.

    It has long been known that schizophrenia – a complex brain disease marked by hallucinations and delusions – tends to run in families and therefore has a genetic component to its cause. However, scientists have struggled to conclusively identify the genes that contribute to risk for this disease. “Current evidence suggests that many genes are likely to be involved in schizophrenia, which theoretically should provide a large target for scientists,” Dr. Lencz said. “Unfortunately, these genes are individually either very rare or very weak in effect, making them very elusive to traditional forms of genetic analysis.”

    The newly funded GO grant builds on prior gene-hunting efforts with several distinctive features. Most notably, the sample consists entirely of individuals (patients and controls) of Ashkenazi Jewish descent, recruited in Israel by Dr. Darvasi, who explains “The unique demographic history of the Jewish Ashkenazi population results in a more homogeneous genetic background compared to the general population. This should allow disease-related genetic signals to stand out more clearly in our analyses.” Additionally, this study will utilize the most advanced genetic technologies, which will permit examination of many more pieces of the genetic code than prior generations of research.

Zucker Hillside Researchers to Receive Large Federal Grant

     

     

   John Kane, MD, chair of psychiatry at The Zucker Hillside Hospital

 

     People with schizophrenia have long received an inconsistent mix of treatments depending on where they lived and what doctors they saw. Now, the federal government has announced an innovative study to test the impact of the best available treatments and whether the interventions will reduce future episodes of schizophrenia and help young people get their brains and lives back on track.

 

      The study, called RAISE, is a contract funded by the National Institute of Mental Health, the National Institutes of Health and the American Recovery and Reinvestment Act (ARRA).  The government will fund $40 million over six years -- of which about half is earmarked for scientists at The Zucker Hillside Hospital campus of The Feinstein Institute for Medical Research. The project will involve two independent teams of researchers, one being led by Zucker Hillside/Feinstein scientists and another at  Columbia University’s New York State Psychiatric Institute.

      The interventions include the latest pharmacological and psychosocial treatments; the study design includes doctors, patients, families and scientists who will weigh in on the interventions to identify what works and what doesn’t. Once the intervention package is complete, scientists will train doctors and other health professionals throughout the country and then test the treatments in small towns and big cities around the nation where one in every 100 young adults and their families are handed the devastating diagnosis. This brain illness can cause hallucinations, delusions and life-disrupting changes in thought, mood and behavior.

 

      Studies have shown that people with schizophrenia generally do not get appropriate treatments early enough in the course of the disease and this may lead to a more disabling form of the illness. Symptoms generally appear in late adolescence or early adulthood, and can disrupt the normal course of life and derail even the smartest minds.

 

      Traditionally, patients have been given an inconsistent variety of treatments and studies show that most people never make it back to where they were before the symptoms hit. No one really knows how early, consistent, state-of-the-art treatments will affect the course of this illness, and this federal initiative is the first attempt to figure it out. The teams will be led by John Kane, MD, chairman of psychiatry at Zucker Hillside Hospital in Glen Oaks, NY, and Jeffrey Lieberman, MD, of Columbia University.  “This is novel because there has never been an attempt to study the impact of carefully integrated modern pharmacologic and psychosocial treatments in first-episode patients,” he said. “This project will give us strategies that may change the course of illness for patients early in the disease process. We have some promising approaches that need to be combined and then tested on individuals in many different kinds of settings.

   

    “We have a sense of what treatments work, but these interventions haven’t been tested in an integrated approach. This study is uniquely designed to answer the question of how best to treat people in the early stages of schizophrenia,” added Dr. Kane, internationally known for his work in the treatment of schizophrenia patients.

           

            Once the interventions are selected and people trained to deliver them in a consistent fashion, 200 newly-diagnosed patients will be identified and enrolled in the study. The scientists will follow the patients over time to see whether their symptoms improve and if their social and vocational functioning get better with the selected interventions. The group will be tested against patients participating in the study and receiving standard psychiatric care in community clinics around the country.

 

      “Can we do a better job helping patients with a more comprehensive treatment package? We definitely think so,” said Dr. Kane. “We hope this study will not only help us to change the course and outcome of schizophrenia, but also to change the way that people think about this brain disease. We hope the study will demonstrate that schizophrenia can be effectively treated and managed so that individuals who experience its onset can have a high likelihood of recovering and doing many of the things that we all take for granted: going to school, working, having hobbies, friends and intimate relationships. We’re very excited about this opportunity.”

 

“This new initiative will help us determine whether intervention that is started early, incorporates diverse treatment and rehabilitation approaches, and is sustained over time, can make it possible for more people with schizophrenia to return successfully to work and school,” said NIMH Director Thomas R. Insel, M.D.  “Moreover, the interventions being tested will be designed from the outset to be readily adopted in real-world health care settings and quickly put into practice.”    

 

            RAISE is a model example of how money from the Recovery Act can accelerate science related to public health problems and potentially benefit those citizens most in need.

For more information on the study: http://www.nimh.nih.gov/health/topics/schizophrenia/raise/index.shtml. 

MIF Protein Involved in Colorectal Cancer

A molecule that has many functions in the human body has been found to promote the growth and migration of colorectal cancer cells, according to a new study by scientists at The Feinstein Institute for Medical Research. Yousef Al-Abed, PhD, and his colleagues have been studying macrophage migration inhibitory factor, or MIF, for years and in 2002 Dr. Al-Abed, a chemist, developed an MIF inhibitor that they dubbed ISO-1. MIF is made in the body by activated lymphocytes and is involved in endocrine regulation, lymphocyte immunity and signal modulation and has a major role as a pro-inflammatory molecule. Now, a growing number of studies are also showing that MIF is involved in cancers.

Their latest study was  published in Molecular Medicine.

Dr. Al-Abed’s team looked for the expression of MIF in human tissues culled from 77 cancer patients and others with benign tumors. They also tested samples from the intestines of volunteers with no evidence of cancer. They found that MIF was increased in those with colorectal cancer and the concentrations went up in the sickest patients. “MIF was dramatically upregulated in human colorectal tissue, with 20 to 40 times as many MIF-positive cells found in the mucosa of patients with colorectal carcinoma than in normal tissue,” the investigators wrote. “Taken together, these data demonstrate that MIF expression was not only correlated 

Dr. Al-Abed added that “MIF has many functions. In cancer, it seems to be involved in migration and invasion. MIF seems to have a role in the spread of the tumor from one location to another.” If that’s the case, drugs that inhibit MIF — like the ISO-1 compound — could be used to slow or prevent migration of cancerous tumors. As part of the study, they screened various cell lines to test the impact of MIF on the growth and invasion of tumor cells. MIF that was added to cell lines enhanced invasion of the cancerous cells, Dr. Al-Abed said. The increase was close to 50 percent. When an MIF inhibitor was introduced, the proliferation of the tumor cells was reduced by about 80 percent within the first 24 hours. In experimental models, ISO-1 reduced tumor mass by about 30 percent when it was given twice a week for a month. Dr. Al-Abed expects a more robust response when given daily. Those tests are underway.

Scientists at Yale University and The Bay Pines Veteran's Affairs Healthcare Sytem in Florida have conducted similar studies on prostate cancer. The Feinstein scientists are now looking at MIF’s role in other cancers and they are now designing clinical trials to test MIF inhibitors in cancer patients. The study was a collaborative effort with Thomas Coleman, PhD, of the Feinstein Institute, scientists at Roswell Park Cancer Institute and others at the First Affiliated Hospital of Guangdong in China.

 

What’s the (Gray) Matter with Obsessions?

Scientists at the Zucker Hillside Hospital have discovered that people with obsessive-compulsive disorder (OCD) have an increase in gray matter in regions of the brain associated with worrying and other behaviors that go hand in hand with OCD. Philip R. Szeszko, PhD, and his colleagues at The Feinstein Institute’s research center at Zucker Hillside Hospital used a brain scanning device called voxel-based morphology to study the gray matter regions of the brains of 21 people with obsessive-compulsive disorder and 21 healthy volunteers. The increase in gray matter was identified in an area called the thalamus — the brain’s Grand Central Station through which information is funneled on its way to higher regions of the brain, including areas that Dr. Szeszko says are part of the brain’s worry circuit. This structural anatomy appears to have functional consequences. The more gray matter, the more severe the symptoms. Dr. Szeszko suspects that an abnormally large amount of gray matter could cause impulses to travel too quickly without the normal brakes that are necessary to stop an action or thought.

Accounting for Ancestry - New Genetic Discovery

• Ask someone where their ancestors were from and odds are that they know. Or maybe not. A new study published in Human Molecular Genetics suggests that scientists using the latest tools to scan the human genome must pay attention to ancestry when analyzing and interpreting their results.

• Chao Tian and Michael F. Seldin, MD, PhD, of University of California Davis, and Peter K. Gregersen, MD, of The Feinstein Institute for Medical Research, have identified allele frequency differences among ethnic groups and subgroups that can result in statistical errors in genetic studies and alter the outcome of the study.

• Dr. Gregersen of the Feinstein Institute said that about half of the Caucasian people in the U.S. who were asked where in Europe their ancestors come from did not have clue. Dr. Gregersen collaborated with Dr. Seldin to identify a few thousand genetic markers that are powerful enough to point to the region where an individual’s ancestors once resided, a tool that is much more reliable than asking a person about his or her ancestry.

• And this finding has more than just genealogical significance. In the Human Molecular Genetics paper, they showed that it is critical to account for ancestry in genome-wide association studies or the results may not be accurate. “We believe the ancestral differences should also be examined in the context of any clinical epidemiological study,” the scientists concluded.

• “Until now, scientists have depended on a person’s knowledge of their ancestral roots when they study human populations to look for risk genes,” said Dr. Gregersen. But what new findings in genetics show is that even among racial groups there can be significant differences in the frequencies of certain genetic alleles.

• For instance, Dr. Gregersen studies rheumatoid arthritis, and in 2004 his team discovered an important risk gene called PTPN22. In the U.S. the disease associated variant of PTPN22 is present in about 8 to 10 percent of the population. Since the vast majority of Caucasians living in the U.S. had ancestors who once lived in Europe, the few thousand genetic markers identified by Dr. Seldin were used to track with European origins. They tested the DNA from hundreds of people in Europe and found that there was an enormous difference in the frequency of the risk variant for PTPN22, according to whether a person’s ancestors are from southern vs. northern Europe. In Southern Italy, for instance, only about three percent of the population had this specific PTPN22 allele. Moving North into Sweden, about 12 to 15 percent of the population carries this variant, which increases risk for rheumatoid arthritis and a number of other autoimmune conditions.

• With these same genetic markers in hand – so called “ancestry informative makers”, or “AIMs”, the scientists went after their U.S. sample, asking whether these markers could be used to identify where a person’s ancestors were from – even if the subjects themselves did not know this information. Indeed, the study showed that they could.

• Earlier this month, Dr. Gregersen presented findings from their work at the American Society of Human Genetics meetings in Philadelphia. The team showed that these markers distinguish ancestry more precisely than any tool available today. The genetic information is so specific that one could look at genes from an Asian individual living in New York and tell whether their ancestors migrated from Cambodia, Japan, Korea or any other country in Asia.

  Related studies have also shown that five to 10 percent of Caucasians have evidence of mixture with populations of Asian or African descent, and Dr. Seldin’s genetic markers can identify these differences. 

• Going back to the PTPN22 gene, this team of investigators found that it is not a risk factor for rheumatoid arthritis in the Asian population. That means that if Asians were mixed into a genetic study on rheumatoid arthritis it could greatly skew the findings.

• “When you put thousands of these markers together, you get a probability of who comes from Sweden or Southern Italy,” said Dr. Gregersen. “This information is important if anyone wants to use population studies to identify risk genes. These new genetic markers are a powerful tool. The practical consequence is that we no longer have to fully rely on a person’s self report. It will increase a scientist’s confidence that their finding is not a spurious association.”

• In addition to the study in Human Molecular Genetics, the investigators also published a similar study in PLoS Genetics earlier this year.

Feinstein Institute Geneticist Peter K. Gregersen talks to Illumina about the future of genetic testing

Peter K. Gregerson, MD, is a world leader in finding risk genes for autoimmune disease, which are very common in the population. To hear what he told a panel last week see link below http://www.xconomy.com/san-diego/2008/11/07/illumina-shows-its-stuff-to-wall-street-stock-still-slides/