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December 18, 2007

Michael J. Fox Foundation Awards $4.4 Million for Development of New Class of Parkinson's Therapy


The Michael J. Fox Foundation has awarded $4.4 million to jump-start the development of a new class of symptomatic Parkinson’s disease drugs targeting glutamate receptor mGluR4. The funding was awarded to a multidisciplinary team of researchers led by Jeffrey Conn, PhD, of Vanderbilt University under the Foundation’s LEAPS (Linked Efforts to Accelerate Parkinson’s Solutions) 2007 initiative.

The LEAPS 2007 program was funded with a lead gift from the Edmond J. Safra Philanthropic Foundation. The Edmond J. Safra Philanthropic Foundation has been one of the most steadfast supporters of The Michael J. Fox Foundation since its inception.

“Dopamine replacement therapies have long been considered the ‘gold standard’ of Parkinson’s treatment. But they lose efficacy over time, alleviate only some of PD’s symptoms, and cause side effects that can be as debilitating as the disease itself,” said Katie Hood, CEO of MJFF. “Patients don’t think this status quo is good enough, and neither does our Foundation. Dr. Conn and colleagues are aiming to bring about a 180-degree turn in PD treatment by developing an entirely new class of drugs that would bypass the dopamine system altogether.”

The death of dopamine neurons is a hallmark of PD pathology, and Parkinson’s scientists traditionally have focused their efforts on modulating aspects of the dopamine system. But recent insights into the physiology of the basal ganglia (a brain region affected in Parkinson’s disease) have shed light on the potential for treatments that could alleviate PD symptoms by “resetting” brain circuits. The glutamate system in particular has shown promise as a target for such treatments.

Glutamate, like dopamine, is a neurotransmitter — a signaling molecule that plays a role in transporting brain messages and controlling body functions. In previous work, Dr. Conn showed in an animal model that increasing activity of a specific glutamate receptor, mGluR4, may alleviate symptoms of Parkinson’s. In further work supported by MJFF’s Target Validation initiative, his team identified molecules that increase mGluR4 activity. The researchers will now use a combination of medicinal chemistry, molecular biology, and animal studies to engineer these molecules into a compound that can be clinically tested for use as a drug that could provide sustained symptomatic relief.

LEAPS are multi-year, multi-million, multi-disciplinary projects that bring together “all-star” teams of researchers to address questions with significant practical impact on the treatment of Parkinson’s disease. Continued funding is dependent on completion of predetermined milestones at specific stages.

In addition to coordinating principal investigator Dr. Conn, who is professor of pharmacology and director of the Vanderbilt Program in Drug Discovery, this LEAPS team includes:

C. David Weaver, PhD, Research Associate Professor of Pharmacology; Director, Vanderbilt Institute of Chemical Biology High-throughput Screening Facility; Director, New Leads Discovery, Vanderbilt Program in Drug Discovery — Dr. Weaver will oversee the high-throughput screening to identify initially promising lead compounds.

Colleen Niswender, PhD, Research Assistant Professor, Department of Pharmacology; Head, Molecular Pharmacology Team, Vanderbilt Program in Drug Discovery — Once lead compounds have been identified through high-throughput screening, Dr. Niswender will be responsible for screening them in cell-based assays to determine which hold the most promise to move on to testing in animal models.

Carrie K. Jones, PhD, Research Associate Professor, Department of Pharmacology; Head, In Vivo and Behavioral Pharmacology Group, Vanderbilt Program in Drug Discovery — Dr. Jones will spearhead the screening of lead compounds in rodent behavior models of Parkinson’s disease.

Yoland Smith, PhD, Professor, Department of Neurology, Yerkes National Primate Research Center, Emory University — Dr. Smith, an expert in the neurophysiology of primate models of Parkinson’s, will oversee the testing of the most promising lead compounds in the final preclinical phase of the project.

Craig W. Lindsley, PhD, Associate Professor of Pharmacology and Chemistry; Director of Medicinal Chemistry, Vanderbilt Program in Drug Discovery; Director, Vanderbilt University MLSCN (Molecular Libraries Screening Center Network) Chemistry Center and Vanderbilt Institute of Chemical Biology Synthesis Core — Dr. Lindsey, a medicinal chemist, will hold ultimate responsibility for optimizing engineering of the compound that will be tested in the clinic.

About The Michael J. Fox Foundation
Founded in 2000, The Michael J. Fox Foundation for Parkinson’s Research is dedicated to ensuring the development of a cure for Parkinson’s disease within this decade through an aggressively funded research agenda. The Foundation has funded over $104 million in research to date.


http://www.michaeljfox.org/newsEvent...cle.cfm?ID=225

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December 21, 2007

A Different Approach to Parkinson's

By Daniel S. Levine, The Journal of Life Sciences

For people who suffer from Parkinson’s disease, a progressive neurodegenerative condition that manifests itself with telltale tremors as the cells that produce dopamine die off, there are limited choices for treatment. Dopamine helps control muscle movements and the drugs available to treat Parkinson’s seek to replace the lost neurotransmitter. But patients grow resistant to these drugs, which also carry adverse side effects.

Two recent agreements—one corporate and the other academic—have researchers working to develop a new class of orally-available drugs that would bypass dopamine neurons. Instead, they would offer a chemical approach to interrupt the same brain circuitry that lies behind the success of deep brain stimulation. Deep brain stimulation uses a surgically implanted pacemaker-like device to send electrical stimulation to the brain to block the overactive signaling that cause tremors and other Parkinson’s syndromes.

This month, drug giant Merck entered into an early stage development deal worth up to $170.5 million with Addex Pharmaceuticals, a small Swiss biopharmaceutical focused on a new class of drugs known as allosteric modulators, to develop new drugs for treating Parkinson’s and for other undisclosed indications. The news was followed this week with the announcement that the Michael J. Fox Foundation for Parkinson’s Research had made a four-year, $4.4-million grant to researchers at Vanderbilt University for pre-clinical development focused on the same target as Merck and Addex. “The ideal outcome would be the development of lead molecules ready to go to the clinic,” said Todd Sherer, vice president of research for the Michael J. Fox Foundation, speaking of the Vanderbilt grant.

With 1.5 million people in the United States afflicted with Parkinson’s and another 60,000 diagnosed each year, sales of drugs to treat the disease are expected to grow to $3.8 billion by 2010, up from $2.5 billion in 2005. If successful in their efforts and a resulting drug could be used in combination with existing therapies to treat both early and late stage patients, analysts said it could represent a billion dollar a year product.

A New Approach
At the heart of both agreements is a receptor called metabotropic glutamate receptor or MgluR4. Unlike the active binding sites on cells that constitute the typical target for drugs, MgluR4 is an allosteric target. Rather than acting like a switch that either activates or inhibits activity involved in a disease process, allosteric targets act more like dimmer switches that can modulate the level of activity.

“Merck has been pioneering the MgluR4 field,” said Vincent Mutel, CEO of Addex. “They were the first to demonstrate the potential use of this receptor in the Parkinson’s pathology. They have really opened up the field and been very active on it. It’s great for us to have this collaboration and it’s a recognition of our competence.”

Like other allosteric targets, MgluR4 is attractive because drugs that target it have the potential for fewer side effects and have the potential to be used in combination with conventional Parkinson’s drugs because they take advantage of this alternate receptor. But in the case of Parkinson’s disease, MgluR4 is particularly important because researchers have been stymied in efforts to develop small molecule drugs that could safely and effectively target active receptors in brain cells involved in the disease.

“It’s a more subtle way of modulating the brain and targeting the things that are more specific to disease versus normal function in the brain,” said Darryle Schoepp, senior vice president and franchise head, Neuroscience, at Merck Research Laboratories.

Less Invasive
MgluR4 targets neurons involved in the portion of the brain known as the basel ganglia, which is involved in controlling movement. Researchers became interested in MgluR4 because it was seen as a potential way to achieve chemically the effect seen through the invasive process of deep brain stimulation, which though effective, requires the implantation of electrodes into the brain.

“Instead of trying to replace the dopamine, we’re trying to change the activity of the circuit in a way that a corrects for the problems that occurred after the dopamine cells were lost,” said Jeffrey Conn, director of the Vanderbilt Program in Drug Discovery and professor of pharmacology Vanderbilt University and lead investigator on the Fox grant. “This is really designed as a pharmacological approach to do the same thing that’s been accomplished with this very invasive brain surgery.”

Though the concurrence of the two announcement was described as coincidental by Conn, he worked on developing allosteric modulators where he headed neuroscience efforts for Merck until leaving five years ago. He also serves as a consultant to Merck and is a member of the Addex Scientific Advisory Board.

For Addex, which in May raised $111 million in what was the largest biotech IPO in Europe during the past three years, the Merck deal is further validation of its approach to pursuing allosteric modulators. The Merck agreement follows an earlier deal between Addex and Johnson & Johnson to develop drugs targeting MgluR2 for anxiety and schizophrenia. And Addex is pursuing a range of allosteric modulators in a wide range of disease areas including gastroesophageal reflux disease, migraine, osteoporosis, depression and Type 2 diabetes.

Though MgluR4 drugs are being pursued as a way to improve the symptoms from Parkinson’s disease, some researchers have hope that they may also provide neuroprotective activities. But for now, Addex is being cautious about the potential for any of these drugs.

“There are some hypotheses about the potential of slowing down the disease progression, but these are a hypotheses for the time being. We should not give false expectation,” said Addex’s Mutel. “The goal is symptomatic treatment. We will look at the potential of slowing down the disease progression, but the first priority is looking at the symptomatic effects

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