Fragile X syndrome is the second leading cause of mental retardation, after Down syndrome. Caused by a defect on the X chromosome, the syndrome affects boys more frequently and severely than girls; one-third of men with Fragile X are autistic and have trouble with communication and social interaction.
There is no cure or specific medical treatment for the genetic condition—at least not yet. Drug companies large and small, spurred by recent discoveries in neuroscience, are now working on possible treatments.
Among the more intriguing companies to enter the hunt is aFraxis, a San Diego startup backed by Avalon Ventures. The company, led by Avalon partner Jay Lichter, is leveraging discoveries from the lab of Nobel laureate Susumu Tonegawa of MIT to develop a pill that might reduce or reverse the brain abnormalities and related behavioral symptoms of Fragile X.
Lichter agreed to talk with me last month about aFraxis, but missed our appointment. His assistant explained that Lichter was dealing with a company emergency; she said his schedule was so jam-packed that he couldn’t speak with me until sometime in March.
Fortunately, my colleague Luke had a conversation with Lichter in mid-December and shared some of his notes with me. So here’s what we know about aFraxis so far.
The company was formed in 2007, the same year Tonegawa’s research in Proceedings of the National Academy of Sciences (PNAS) identified a possible drug target for Fragile X. That target was PAK, an enzyme that affects the number, size and shape of connections between neurons in the brain.
In people with Fragile X, these connections-small protrusions called “spines” on the branches of neurons-are longer, thinner and more abundant than in people without the condition. When Tonegawa inhibited PAK in mice that had been genetically alerted to have the symptoms of Fragile X, the spines became thicker and less numerous. Just as significantly, the animals behaved much like normal mice.
Tonegawa speculated that PAK inhibitors might be an effective therapy in babies diagnosed with Fragile X; developmental delays typically emerge between ages 9-12 months, he noted in the paper published by PNAS.
Lichter told Luke that he was intrigued by Tonegawa’s research because the mouse model for Fragile X is biologically similar to the condition in humans. The FMR1 gene is affected in mice and humans, and they share the same anatomic changes in the brain. The mice are hyperactive and engage in repetitive behaviors, symptoms seen in some people with Fragile X.
PAK is a family of enzymes and the question for aFraxis was whether it could make an oral drug to block PAK1, the specific member of the PAK family believed responsible for the symptoms. Lichter told Luke that after two years of work, the company now has a library of several hundred compounds that can turn off PAK1.
In animal studies, the company’s experimental drugs have been able to produce changes in the brains of mice “in as little as a few hours,” Lichter said. He told Luke the company aims to begin human tests in 2012.
The company’s program sounds a lot like research conducted at another San Diego biotechnology company, Ambit Biosciences. Tonegawa and collaborators from Ambit are named as inventors on a patent that describes a method for treating Fragile X and other neurodevelopmental disorders with specific small molecule PAK inhibitors. Interestingly, Ambit is an owner of aFraxis according to this SEC filing. And like aFraxis, Ambit is backed by Avalon Ventures. I left messages with Ambit and its PR firm to find out if aFraxis is a spinout of Ambit, but didn’t get an answer by deadline.
Lichter told Luke that aFraxis sees opportunities in other disorders as well, including schizophrenia and Alzheimer’s disease. For neuropsychiatric conditions, the company is experimenting with drugs that turn on PAK, at least judging from this patent filing.
Advisers to aFraxis include Tonegawa, Gary Lynch of UC Irvine and Dennis Selko of Harvard Medical School, Lichter said. David Campbell, formerly of Phenomix, is chief scientific officer.
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