Fragile hope for brain disorders

Seaside Therapeutics, Vanderbilt collaborate on novel therapeutics to treat Fragile X, autism, other brain disorders

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CAMBRIDGE, Mass.—Seaside Therapeutics has joined hands with the Vanderbilt University Medical Center to discover and develop small molecules targeting neurologic receptors implicated in Fragile X syndrome, autism and other brain development disorders. If successful, this collaboration takes science and medicine one step closer toward treating typical hallmark symptoms of autism—such as learning and memory problems and obsessive-compulsive behavior—with a new drug.

"Fragile X, caused by a mutation on the X chromosome, is the most frequent inherited cause of mental retardation and an identified cause of autism," says Dr. Randall L. Carpenter, president and CEO of Seaside Therapeutics. "Our focus on identifying the molecular pathophysiology of single-gene disorders associated with autism has provided insights for developing targeted therapeutics with the potential to correct or fundamentally alter the course of brain development and function."

Vanderbilt's expertise in drug discovery and commitment to developing novel therapeutics for brain development disorders makes for an exceptional partner, Carpenter says.

Fragile X syndrome, which affects 90,000 Americans, is caused by a mutation of a gene that prevents the body from making a protein key to normal brain function, he says. Research has shown that neurological and psychiatric symptoms of the syndrome have been linked to excessive signaling of a separate gene, and scientists have identified more than 400 chemical compounds that could inhibit that gene.

This joint venture is the second between Seaside and the Nashville, Tenn.-based Vanderbilt Program in Drug Discovery (VPDD). In 2007, Vanderbilt and Seaside collaborated for the first time to develop compounds that inhibit excessive signaling through the metabotropic glutamate receptor subtype 5 (mGluR5), which may be responsible for the neurological and psychiatric consequences of Fragile X syndrome, Carpenter says.

"We believe that negative modulators of a specific subtype of these receptors (mgluR5) will be therapeutic in Fragile X syndrome," he says. "We also have insights regarding the role of muscarinic signaling in Fragile X syndrome and believe that inhibiting signaling via the M1 receptor will provide therapeutic benefit."

For this project, Vanderbilt scientists led by Dr. Jeffrey Conn, director of the VPDD and a member of Seaside's Scientific Advisory Board, have identified novel small-molecule compounds that are M1 antagonists.

"We were aware that Jeff Conn had discovered the first select M1 antagonist compound, and we established our recent collaboration to discover and develop selective M1 antagonists," Carpenter says. "Vanderbilt's team of scientists are world experts, having not only very deep drug development expertise for modulation activity of metabotropic glutamate receptors, but also for their expertise in muscarinic receptors, known to regulate learning and memory."

Conn, recruited from Merck and Co. to Vanderbilt six years ago, says, "Selectively inhibiting M1 receptors represents an innovative and very promising approach to treating brain development disorders. Seaside is an ideal partner for this research. Seaside has deep expertise in drug development and is heavily focused on establishing relationships with Fragile X clinics and establish a base for patient recruitment for clinical trials. In addition, they are developing clinical rating scales that can be used for a disorder for which there is no precedent or established path for clinical development."

"On the other hand, our expertise is drug discovery," Conn adds. "While Seaside has expertise in drug development, they do not have the expertise or infrastructure required to execute a successful drug discovery effort. Thus, we see this collaboration as a perfect fit that builds on the complementary expertise and resources of each of the two partners. In addition, the funding provided by Seaside is obviously critical to our ability to discover new drug candidates for these targets."

For their first collaboration, Seaside provided $4.5 million in funding to Vanderbilt over a three-year period to develop a novel molecule ready to advance into clinical testing, and came up with $5 million over four years for the current project, Conn says. The New England Journal of Technology reported that Seaside received $30 million earmarked toward Fragile X research from an anonymous private, family investment firm.

"This is a four-year agreement," Conn says. "The goal is delivery of a compound that meets very clear criteria for advancing into clinical development. Our goal is to develop one primary lead candidate to advance to the clinic and one structurally distinct 'backup' clinical candidate. It is hoped that this research will pave the way for expanding clinical development into patients with other developmental disorders."

As far as Carpenter and Conn are concerned, coming up with effective treatment for those suffering from autism symptoms can't come soon enough.

"What you need is a company to be successful to show that the FDA will approve you, and that you can make money," Carpenter says. "Then everybody will jump in."

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