Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease that targets the motor neurons leading to paralysis and eventually death by respiratory failure 3 to 5 years from diagnosis. There is no known cure for ALS, and only riluzole (Rilutek) improves survival for typical patients by a period of time of 3 to 6 months.

Despite the many attempts to translate promising preclinical mouse trials into effective treatments in humans, no drug has been identified that exceeds efficacy of riluzole in patients. While we should continue to search for new candidate drugs to cure ALS, we should also re-focus on riluzole and, rather than being discouraged by its modest but solid effect, we should find ways to improve its therapeutic potential.

It is well known that cellular proteins called multidrug efflux transporters represent an obstacle to effective therapies as they limit entry into the brain and spinal cord of a large number of drugs. Modulating and/or blocking the function of these transporters may therefore improve drug delivery and bioavailability in brain and spinal cord, ultimately enhancing the therapeutic potentials of many drugs. Riluzole is a substrate for the multidrug transporter P-glycoprotein (P-gp), which seems to pump riluzole out of the brain in mice models. Thus, blocking P-gp function to stop riluzole extrusion from the spinal cord, should improve riluzole bioavailability and efficacy.

In this project, we will test whether pharmacological inhibition of P-gp function improves efficacy of riluzole in the mouse model of ALS (the mutant SOD1 mouse).

Our ultimate goal is to limit the time and cost of bringing a drug to patients by improving the therapeutic potentials of the sole drug that has already proven efficacy in ALS. If validated on riluzole, our therapeutic idea to enhance therapeutic potentials of a drug through improvement of its bioavailability will give us the opportunity to re-consider many drugs discharged as non-effective in previous pre- and clinical trials of ALS.