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 particular receptor in the brain 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.
Using Vanderbilt’s high-throughput screening facility, which is capable of testing tens of thousands of small molecules for drug-like activity in a single day, Conn and his colleagues have identified more than 400 novel compounds that inhibit mGluR5.
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.
“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.”
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. About 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 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, Seaside scientific founder Mark Bear, Ph.D.,Picower Professor of Neuroscience at MIT, discovered a connection between metabotropic glutamate receptor subtype 5 (mGluR5) signaling and fragile X syndrome.
Studies by Bear and others indicate that excessive signaling through mGluR5 may be responsible for the consequences of fragile X syndrome. About Seaside Therapeutics: Seaside Therapeutics is creating new drug treatments to correct or improve the course of fragile X syndrome, autism and other disorders of brain development. We are dedicated to translating breakthrough discoveries in genetics and neurobiology into therapeutics that improve the lives of patients and their families. About the Vanderbilt Drug Discovery Program:
Vanderbilt scientists led by Jeffrey Conn, Ph.D., have pioneered the discovery of “allosteric” compounds that modulate (“turn up” or “turn down”) the activation of certain receptors, called metabotropic glutamate receptors, when the neurotransmitter glutamate binds to them.
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” 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 “negative modulators” 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 for the drug discovery program, will spearhead the screening of lead compounds in rodent behavior models.