Over the past few years, both Novartis and Roche sponsored large-scale clinical trials of metabotropic glutamate receptor 5 (mGlu5) negative allosteric modulators (NAMs) to treat Fragile X syndrome (FXS). When the trials failed to show efficacy in the patient population, both Novartis and Roche discontinued their Fragile X development programs.
During the trials, caregiver reports suggested the possibility that tolerance to mGluR5 NAM treatment developed quickly, consistent with some preclinical findings in the mouse model. FRAXA funded this project to find out if mGluR5 NAMs dosed chronically causes tolerance, and if so, how it develops and to probe new avenues to prevent or circumvent it.
During the first year of this two-year project, Dr. Senter and Dr. Bear showed that there is indeed tolerance after just three doses of an mGluR5 NAM in mice that have been bred to mimic Fragile X syndrome. They are now investigating how and why the tolerance occurs and – most importantly – how to combat it.
“Not only will our results provide a possible mechanism for why tolerance develops to chronic mGlu5 antagonism and how to circumvent it, it may also provide insight into other therapeutic mechanisms in the future,” said Dr. Senter.
Tolerance is an enormous problem in many drugs, and particularly in drugs which affect the brain. The results of this project is especially important now because development of mGlu5 drugs continues: the NIH has funded a new multi-center trial of mGluR5 NAMs in children with Fragile X syndrome.
This project provided preliminary evidence of tolerance.
The project is being continued with a 2018 FRAXA Fellowship to Dr. Patrick McCamphill in the Bear Lab.
Rebecca Senter, PhD
FRAXA Postdoctoral Fellow
Previous Grants to the Bear Lab
Results Published: Lovastatin Corrects Excess Protein Synthesis in Mouse Model of Fragile X
$456,000 over 2000-2008
Dilja Krueger, PhD, FRAXA Postdoctoral Fellow
Kimberly Huber, PhD, FRAXA Postdoctoral Fellow