Does Fragile X Syndrome Hold the Key to Autism Treatment?

Reducing expression of a specific gene in the brain may not only reverse the effects of fragile X syndrome but also hold promise for autism treatment.

A recent article in Forbes discussing the work of MIT neuroscientist Mark Bear, PhD, claims that Bear’s research may have uncovered a “radical new theory that offers a real glimmer of hope that some forms of autism may be treatable with drugs.”

Bear, the Picower Professor of Neuroscience at the Picower Institute for Learning and Memory and the Department of Brain and Cognitive Sciences and an investigator at Howard Hughes Medical Institute, suggests that fragile X syndrome, which “hits one in 5,000 kids and causes mental retardation, anxiety and autism-like symptoms,” may be treatable with an old class of experimental anxiety drugs called mGluR5 inhibitors.

According to the Forbes article, “Bear’s experiments with mice with fragile X indicate that the brain makes too much of key proteins that prevent proper learning from occurring.” In 2007, Bear and MIT colleague Gül Dölen published a study in the journal Neuron that, according to a news release from the Howard Hughes Medical Institute (HHMI), “found that many of the symptoms of fragile X syndrome, the most common cause of inherited mental retardation, can be eliminated in mice by reducing the expression of a single gene in the brain.” Theorizing that the fragile X mental retardation protein (FMRP) suppressed protein synthesis in the brains of affected individuals and “worked in opposition” to metabotropic glutamate receptor-5 (mGluR5), the researchers tested this by removing one of two copies of the gene for mGluR5 in mice that also lacked the gene for FMRP. By removing one copy of mGluR5 (creating mice that produce only half the normal amount of mGluR5 protein), the researchers “hoped that this would compensate for the lack of FMRP and eliminate the symptoms of fragile X.” Bear and his colleagues were correct: reducing mGluR5 “eliminated many of the symptoms of the disorder,” including “seizures, impaired memory, and accelerated body growth.”

These results led Bear and others to propose the drugs that block mGluR5 could be used to treat fragile X syndrome. Bear also saw the potential to apply these findings to the treatment of autism. He told an interviewer that “A picture is beginning to emerge that many single-gene disorders that cause autism might turn out to be genes that are similarly involved in the negative regulation of protein synthesis… Thus, a significant fraction of cases of autism might be accounted for by excessive cerebral protein synthesis. If that were true, then mGluR5 antagonists might be therapeutically useful for much more than just fragile X."

Three years later, and Bear still thinks that regulating the levels of specific proteins in the brain may hold promise for patients with some form of autism. The Forbes article states that the current version of Bear’s theory “holds that similar protein production problems may be at play in many cases of autism of unknown cause. There may be an optimal level of protein production inside brain cells needed for learning. If there is too much or too little, learning disabilities may occur and grow over time. Under this view, rather than an unfixable problem, many forms of autism may be more like a chronic disease that starts at birth and gradually gets worse. Tweaking protein levels with various drugs may be able to help.”

Accordingly, Roche and Novartis are testing mGluR5 inhibitors, with Seaside Therapeutics (in which Bear owns a 5% stake) also set to begin testing its own compound (STX107) in patients with fragile X syndrome.

Additional Resources:

Here’s a video of a presentation Bear gave in 2009 on “important insights into the etiology and treatment of brain disorders, including autism.” Bear provides a primer on this developmental disorder and discusses his work with Fragile X syndrome.

What Do You Think about This?

Is this research and theory as promising as some commenters have claimed?

How do your patients react to stories about potential new discoveries in the search for a treatment and/or cure for autism and other neurological disorders?

What other studies into the causes of autism and/or potential targets for treatment have caught your eye in the last couple of years?