Years ago, families across the US and several other countries participated in large-scale clinical trials of experimental Fragile X treatments from Novartis and Roche. While these trials ultimately failed to demonstrate that the treatments worked, many families reported exciting improvements.
Why did these trials fail? One possible explanation is that tolerance rapidly develops to the drugs, so they lose their effectiveness. Indeed, some caregiver reports have suggested some early improvement that was lost over time. To learn the answer and find a solution, FRAXA awarded $180,000 to Dr. Mark Bear’s lab at MIT beginning in 2015.
FRAXA Postdoctoral Fellow Dr. Patrick McCamphill sat down with FRAXA’s co-founders Michael Tranfaglia, MD, and Katie Clapp to share what they have discovered and what they are working on now in the lab.
The team’s major findings:
- They found that significant tolerance to mGluR5 drugs occurs in multiple brain regions of Fragile X mice.
- They are working to pinpoint the exact mechanism for this tolerance. Their goal is to find an “antidote” for the tolerance, which would allow the mGluR5 drugs to live up to their full potential.
- They are zeroing in on another target – GSK3 – which is likely in the same general molecular pathway as mGluR5, but less likely to trigger tolerance. They are now testing drugs which inhibit GSK3 in Fragile X mice. This class of drugs is probably the next best validated treatment target for Fragile X syndrome, after mGluR5. One well-known GSK3 inhibitor is lithium, which was showed positive effects in mouse studies and a pilot clinical trial both funded by FRAXA. This new work opens the possibility that combining lithium and mGluR5 drugs might be very effective.