Nature Medicine | Spoonful of Medicine

Common autism pathway opens the door for new drug treatments

main_bg.jpgThe definition of autism has undergone constant evolution — as any architect of the Diagnostic and Statistical Manual of Mental Disorders can attest — and now refers to a broad spectrum of various developmental and social disorders with many distinct genetic causes. This understanding of the disorder obviously complicates the development of therapeutics: if every person with autism is different, identifying drugs to treat everyone seems like a Sisyphean task. But research published today suggests that the disorder’s complexity may not beckon the end of drug development.

Neuroscientist Mark Bear and his colleagues from the Massachusetts Institute of Technology’s Picower Institute for Learning and Memory in Cambridge compared how a protein found in neurons called metabotropic glutamate receptor 5 (mGluR5), which is involved in the translation of other proteins, is regulated in two mouse models for autism: one for fragile X syndrome, the other for tuberous sclerosis. Reporting online in Nature, Bear’s team showed that levels of mGluR5 go up in mice with Fragile X, leading to elevated rates of protein synthesis, but decline in mice with tuberous sclerosis. And despite mGluR5 expression going in opposite directions for the two genetic forms of autism, the researchers managed to fix both defects with experimental compounds that have been demonstrated to either ramp up or dampen mGluR5 signaling. “We’ve identified this single core biochemical pathway of protein synthesis that, if you correct it, you can alleviate those symptoms,” says study author Emily Osterweil, a research associate in Bear’s lab.


“The mGluR5 story is tremendously exciting in representing the real first case where it might be possible to cure a neurodevelopmental disorder,” says Bernard Crespi, an evolutionary geneticist at Simon Fraser University in Burnaby, British Columbia who was not involved in the research. “It’s a complicated system, but mGluR5 seems to be the most important sort of rate regulating factor here.”

Drugs to treat fragile X syndrome that block mGluR5 and the resulting flurry of protein synthesis are already in development. The Swiss drug giant Novartis and Seaside Therapeutics of Cambridge, Massachusetts are currently recruiting for phase 3 trials of mGluR5 inhibitors in the their pipelines, and Switzerland’s Roche completed a phase 2 trial for its own drug last week. There are currently no mGluR5 activators in the works for tuberous sclerosis, but the Seaside website notes it as a future possibility.

Future drug development should benefit from the finding that these two distinct autism-related disorders are regulated by the same pathway, says Crespi. It also dovetails with a theory advanced by Crespi and others that some psychiatric diseases are simply different ends of a common spectrum and can be treated with drugs with opposing effects for opposite conditions (see ‘A meeting of minds’).

“They’re doing exactly what should be done to figure out the causes and treatments of the disorders,” Crespi says. And with enough comparisons amongst the many autism models available, he adds, “maybe some commonalities will start to appear.”

Image: Daren Newman

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