Available medication Lovastatin corrects excess protein synthesis in Fragile X mice
At the opening dinner of the 2011 FRAXA Investigators Meeting in Southbridge, MA, Dr. Emily Osterweil was awarded the FRAXA Pioneer Award for work demonstrating that Lovastatin could treat Fragile X. Dr. Osterweil conducted her experiments in the MIT laboratory of Dr. Mark Bear; she has since established her own laboratory at the University of Edinburgh.
The team discovered that lovastatin, a drug widely prescribed for high cholesterol, can correct excess hippocampal protein synthesis in the mouse model of FXS and can prevent epileptogenesis.
The work is published in the prestigious neuroscience journal Neuron: Lovastatin Corrects Excess Protein Synthesis and Prevents Epileptogenesis in a Mouse Model of Fragile X Syndrome.
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.
Clinical Trials of Lovastatin Funded
Based on this finding, FRAXA initiated funding for a pilot clinical trial of Lovastatin in patients with Fragile X syndrome under the direction of Dr. Francois Corbin at the Fragile X Clinic at the Centre Hospitalier Universitaire de Sherbrooke (CHUS), Sherbrooke, Quebec, Canada. Based on encouraging results from this trial, FRAXA has gone on to fund a new trial of two available drugs: Lovastatin and minocycline.