High-profile publication by FRAXA-funded team at MIT, led by Dr. Mark Bear, suggests an available medication may treat Fragile X.
The new issue of the prestigious neuroscience journal Neuron includes an exciting report from the Mark Bear lab at MIT. In Lovastatin Corrects Excess Protein Synthesis and Prevents Epileptogenesis in a Mouse Model of Fragile X Syndrome, first author and past FRAXA Postdoctoral Fellow Emily Osterweil, PhD demonstrates that this available cholesterol-lowering drug may also normalize runaway dendritic protein synthesis in mice bred to mimic Fragile X.
One implication of the mGluR theory of Fragile X is that there are exaggerated consequences of activation of signaling pathways which link metabotropic glutamate receptors (mGluRs) to the cellular machinery of neurons. It has been known for some time that lovastatin can indirectly decrease the activity of these ras-ERK signaling pathways (an action only remotely related to its primary cholesterol-lowering function). This effect is relatively weak, but more potent ERK inhibitors are usually quite toxic. Lovastatin and related “statins” have a long track record of safe administration to millions of patients around the world, including children. The experiments described in this paper show convincingly that lovastatin inhibits ras-ERK signaling enough to have significant therapeutic effects in Fragile X animal models.
Drs. Osterweil and Bear, along with their collaborators from SUNY Downstate (also previous FRAXA grantees) show that lovastatin not only corrects abnormal ERK-mediated protein synthesis, but it also rescues the classic Fragile X phenotypes of mGluR-LTD and audiogenic seizures. They also demonstrated normalization of a number of electrophysiologic functions of Fragile X neurons, indicating correction of the disease mechanisms at the molecular, cellular, and neural circuit levels, all at concentrations which should be achievable with typical human doses of lovastatin.
This kind of multi-level preclinical validation strongly suggests that lovastatin could have disease-modifying effects in people with Fragile X. To prove efficacy in humans, clinical trials in Fragile X subjects are still necessary before lovastatin can be recommended as a new treatment.
Fortunately, these results have been known to FRAXA for some time, having been presented at the 2011 FRAXA Investigators Meeting. Shortly after that meeting, plans were laid for a pilot trial and FRAXA authorized funding for an open trial of lovastatin directed by Francois Corbin, MD, PhD at the Fragile X Clinic at University of Sherbrooke, Canada.
The trial is well underway, as the graphic shows. So far, 13 patients have been screened for the trial, 8 have completed the first treatment phase (a low dose of Lovastatin for one month) and 4 have gone into the second phase (a higher dose of Lovastatin for two months). No one has withdrawn from the trial after starting treatment.
When all participants have completed the treatment phase, results will be analyzed and reported. If results are positive, the next step will be a larger double-blind placebo-controlled trial. Stay tuned!