February 8, 2008

Grant bolsters ‘fragile X’ research

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Members of the Conn research group include (front row, from left) Colleen Niswender, Ph.D., Jeff Conn, Ph.D., Alice Rodriguez, Ph.D., (back row, from left) Craig Lindsley, Ph.D., David Weaver, Ph.D., and Carrie Jones, Ph.D. (photo by Neil Brake)

Grant bolsters ‘fragile X’ research

Vanderbilt University Medical Center has received a $4.5 million grant from Seaside Therapeutics to find potential treatments for fragile X syndrome, the most common inherited form of mental retardation and the most common genetic cause of autism.

“It's a really innovative idea,” said Jeffrey Conn., Ph.D., director of the Vanderbilt Program in Drug Discovery and principal investigator of the fragile X project. “If it works, it could be transformative … it could totally change the way people view developmental disorders.”

Research conducted by founders of Seaside Therapeutics and others indicates that excessive signaling through a receptor for the neurotransmitter glutamate, called mGluR5, may be responsible for the neurological and psychiatric consequences of fragile X syndrome.

Selective inhibition of the receptor potentially could reduce or eliminate these devastating effects, company officials said.

That's where the Vanderbilt researchers come in.

They are internationally known for their discovery of “allosteric modulators,” compounds that do not directly activate receptors in the same way as neurotransmitters, but instead work like the dimmer switch in an electrical circuit.

In the case of mGluR5, Conn and his colleagues have identified more than 400 “negative” allosteric modulators, compounds that selectively “turn down” the activation of the receptor when glutamate binds to it.

Supported by the three-year Seaside Therapeutics grant, the Vanderbilt researchers will use medicinal chemistry, molecular biology, pharmacology and efficacy studies to develop compounds with the drug-like properties required for further study in fragile X.

Seaside Therapeutics will contribute scientific and drug-development expertise, and will select compounds from the collaboration to carry forward into clinical development.

“Importantly, the Vanderbilt team shares Seaside's passion for helping children with fragile X — creating a strong partnership focused on rapidly translating new discoveries in neurobiology into desperately needed novel treatments,” said Randall Carpenter, M.D., co-founder, president and CEO of the Cambridge, Mass.-based firm.

Conn's colleagues in this effort include Craig Lindsley, Ph.D., director of Medicinal Chemistry in the drug discovery program, who will oversee chemical optimization of compounds for testing in the clinic.

Lindsley helped discover the first “positive” allosteric modulators of mGluR5, which “turn up” the receptor's activation when it binds to glutamate.

David Weaver, Ph.D., directs the high-throughput screening facility in the Vanderbilt Institute of Chemical Biology, which is capable of testing tens of thousands of small molecules for drug-like activity in a single day.

He and Alice Rodriguez, Ph.D., a research instructor in Pharmacology, will lead the search for novel compounds that can “dim” the mGluR5 “switch,” and they will oversee molecular pharmacology efforts required to screen lead compounds in cell-based assays.

Carrie Jones, Ph.D., research assistant professor of Pharmacology and director of Behavioral Pharmacology in the drug discovery program, will spearhead the screening of lead compounds in rodent behavior models.

“We're at a very early stage,” said Conn, a professor of Pharmacology who serves on the scientific advisory board of Seaside Therapeutics. “It now becomes a really high-level molecular engineering effort.”

Protein’s absence spurs symptoms of fragile X syndrome

Fragile X syndrome is relatively rare, affecting approximately 90,000 people in the United States. It is caused by a mutation in the FMR1 gene on the X chromosome that prevents expression of a single protein, the fragile X mental retardation protein (FMRP).

The absence of FMRP gives rise to the major symptoms of fragile X syndrome in humans — impaired cognitive function, developmental delay, attention deficit and hyperactivity, anxiety, obsessive-compulsive and autistic behaviors.

A key advance for understanding fragile X was the isolation of the FMR1 gene and subsequent generation of the Fmr1 knockout mouse — an animal model that lacks FMRP and mimics the human condition.

By studying the brains of these mice, Mark Bear, Ph.D., and colleagues at Brown University discovered a connection between metabotropic glutamate receptor subtype 5 (mGluR5) signaling and fragile X syndrome.

Metabotropic glutamate receptors are activated by the neurotransmitter glutamate. Another receptor in this family, mGluR4, is implicated in Parkinson's disease.

Studies by Bear and others indicated that excessive signaling through mGluR5 may be responsible for the neurological and psychiatric consequences of fragile X syndrome, and suggested that selective inhibition of the receptor could reduce or eliminate them.

Bear, currently the Picower Professor of Neuroscience at the Massachusetts Institute of Technology, co-founded Seaside Therapeutics in 2006 “to translate promising research discoveries into effective treatments for … disorders of brain development.”

Conn and his colleagues have pioneered the discovery of novel drug-like compounds that modulate metabotropic glutamate receptors. They recently received a $4.4 million grant from the Michael J. Fox Foundation for Parkinson's Research to help develop a new class of Parkinson's disease drugs.