Wednesday, March 20, 2013

It’s not just mGluR5…there’s more than one way to fix fragile X

In case you somehow got the impression that FRAXA is only interested in mGluR5 research, or that we’ve quit funding basic research altogether, the most recent edition of the Proceedings of the National Academy of Sciences (PNAS) illustrates just why that’s not true.

Long after the seminal finding of increased mGluR-LTD in fragile X by Kim Huber and Mark Bear, FRAXA funded studies by Nobel-laureate Susumu Tonegawa investigating the role of the enzyme PAK in regulating the shape and function of dendritic spines. The results of this FRAXA-funded project demonstrated that genetic reduction of PAK could rescue most fragile X knockout “phenotypes” (the animal model equivalent of human symptoms.) This was essential proof of concept work which established PAK inhibitors as potential therapeutics for fragile X, and was the basis for a new company called Afraxis. The only problem was that no specific PAK inhibitors actually existed at that time, but Afraxis has been busy trying to find useful drugs that inhibit PAK (actually a family of enzymes, not one single enzyme.) The paper just published by Tonegawa and his collaborators from MIT, Afraxis, and universities in India and Korea, shows that a new compound which Afraxis calls FRAX486, inhibits all the PAKs in the brain at relatively low doses, and displays all the properties you’d expect of a useful drug. Most importantly, it appears to reverse most of the important animal model phenotypes with a single dose (though, presumably, daily dosing would work better as a human therapy.)

Read the whole thing:

At this point, FRAXA has developed a large pipeline of drug candidates for the disease-modifying treatment of fragile X. We continue to fund basic research looking for more promising leads, but our main emphasis is on developing treatments based on the work we’ve already funded, which has given us plenty of candidates for therapeutics that can alter the course of fragile X. We’re excited about our partnerships with companies big and small, like Afraxis, because these partnerships are essential to bring new treatments to fragile X families in need.