Seaside Therapeutics, a startup based in Cambridge, MA, is testing two compounds for the treatment of fragile X syndrome, a rare, inherited form of intellectual disability linked to autism.
The treatments have emerged from molecular studies of animal models that mirror the genetic mutations seen in humans. Researchers hope that the drugs, which are designed to correct abnormalities at the connections between neurons, will ultimately prove effective in other forms of autism spectrum disorders.
“I think that fragile X-targeted treatments are at the cutting edge of reversing cognitive deficits in individuals with neurodevelopmental disorders,” says Randi Hagerman, medical director of the M.I.N.D. Institute at the University of California, Davis. Hagerman consults with a number of companies, including Seaside, that are developing treatments for fragile X syndrome. “This could lead to reversing intellectual disabilities and behavioral problems with this disorder,” she says. “That is extremely exciting.”
Fragile X is a genetic form of mental retardation caused by an abnormal expansion of part of the X chromosome. The disorder is rare, affecting about 1 in 4000 males in the United States and about 1 in 6000 females. But it is the most common known cause of autism–it’s responsible for 2 to 5 percent of cases, and is the most common inherited cause of intellectual disability.
The fragile X mutation blocks production of a protein called FMRP (fragile X mental retardation protein), whose normal task is to inhibit molecular activity at the connections between nerve cells. Loss of the protein appears to throws the system out of whack. “It’s like driving a car with your foot on the accelerator and no brake,” says Randall Carpenter, a physician and cofounder of Seaside. “There is too much activation of that pathway.”
In 2007, Mark Bear, a neuroscientist at MIT and cofounder of Seaside, and his collaborators discovered that they could reverse the deficits caused by the fragile X mutation in mice by turning down the activity of a receptor called metabotropic glutamate receptor 5 (mGluR5), found on the surface of brain cells. By doing this they effectively added a new brake to the system. Animals engineered to produce 50 percent less of this receptor suffered fewer seizures–a hallmark of fragile X–and had fewer brain abnormalities compared to mice producing the full amount of the receptor.
Dozens of academic labs across the globe have since shown that small molecules designed to block the activity of mGluR5 have the same effect, reducing abnormalities in mice with the fragile X mutation. Those abnormalities include seizures, atypical rates of protein synthesis, and other molecular glitches. While it’s not yet clear if there is a critical window during development for giving the drug, adult animals still benefit from the treatment. “These compounds have made remarkable changes in animal models of fragile X, rescuing abnormal synaptic connections,” says Hagerman. “We’re very hopeful it will do the same for humans.”
Seaside, which licensed some of these compounds from Merck, has just finished initial safety studies of one candidate. (Large pharmaceutical companies have been developing these molecules, called mGluR5 antagonists, for years for a variety of diseases, including schizophrenia and Parkinson’s disease. None have yet been approved for human use, however.) Seaside aims to begin studies in people with fragile X later this year or early in 2011.