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.
Inspired in part by Bear’s work, pharmaceutical giant Novartis is also testing an mGluR5 antagonist in people with fragile X, as is Neuropharm, a pharmaceutical company based in the United Kingdom. “If we see even a percentage of what we see in the mouse, it will be an important treatment,” says Carpenter.
Seaside is also testing a second compound that dampens synaptic activity through a different mechanism–by mimicking the brain’s major inhibitory chemical messenger, known as GABA. Previous research has shown that a specific form of an existing drug called Baclofen, which activates GABA receptors and is currently used to treat muscle spasms, can reverse symptoms in mice with a mutation similar to fragile X. The company has just completed a clinical trial of the drug in 60 people with fragile X syndrome and expects results from the study in April. A second study of the drug in people with autism is also underway.
The company is funded almost entirely by an undisclosed family investment of $60 million, with $6 million from the National Institutes of Health. Carpenter says that Seaside has enough funding to take its compounds through clinical testing and approval. “We are prepared to do it ourselves,” he says. “But if there is a partnership that allows us to more rapidly advance compounds, then we would embrace that opportunity.”
While it’s not yet clear whether people with non-fragile X forms of autism would benefit from the same types of drugs, Carpenter and others say those people may share similar molecular problems. For example, genetic studies have linked some cases of autism to mutations in genes controlled by FMRP. Since autism is thought to be a collection of related diseases with different molecular causes, Seaside is looking for protein or DNA biomarkers in the patients in its trials that might predict who would benefit from the molecules being tested.
One theory for the cognitive impairment associated with fragile X, and perhaps with autism in general, is deregulation at the synapse, the connection between two neurons. Our ability to learn is dependent upon the tightly regulated ability to continually change the strength of synapses in response to new information. People with fragile X syndrome and other types of cognitive impairment have immature-looking synapses and inefficient signaling, says Carpenter. That means the brain is “interpreting almost everything that is happening as noise, rather than important information.”