Posted March 16, 2015
Piera Pasinelli, Thomas Jefferson University
Amyotrophic Lateral Sclerosis (ALS), also known as Lou Gehrig’s disease, is a progressive neurodegenerative condition that affects nerve cells in the brain. As the disease progresses, the brain’s ability to control or provide muscle nourishment to the lateral part of the spine diminishes. As a result, muscles under voluntary control are affected throughout the body. Patients in the later stages of the disease become paralyzed and eventually die due to respiratory failure three to five years after diagnosis. There are currently no known therapies to effectively halt the progression of ALS, although one FDA-approved drug, Riluzole, modestly slows progression of symptoms. Riluzole is presumed to be a glutamate antagonist, but the exact mechanism of action is unclear. Despite attempts to translate promising preclinical mouse trials into effective treatments in humans, no drug has been identified that exceeds the efficacy of Riluzole in ALS patients.
Drs. Piera Pasinelli, Davide Trotti, and colleagues at Thomas Jefferson University believed that the modest effect of Riluzole might be due to membrane transporter proteins in the central nervous system that pump the drug out of cells preventing it from accumulating to effective concentrations inside the cells. These membrane transporters normally play a critical role in healthy cells by pumping out toxic foreign substances; however, in the case of Riluzole, the export pump expels the needed drug. Dr. Pasinelli observed that this effect is the cause of some types of pharmacoresistance observed in cancer chemotherapy. P-glycoprotein (P-gp) is the most common pump that moves foreign substances across the membrane and belongs to the superfamily of “ATP-binding cassette transporters.” Another drug efflux transporter, called the breast cancer resistance protein (BCRP), also works to pump foreign molecules out of the cells. P-gp and BCRP bind molecules present in the inside of the cell, deep within its pocket, then flips its conformation exposing the interior of the pocket to the external environment and expelling the contained molecule.
With support from a Therapeutic Idea Award from the CDMRP ALS Research Program, Dr. Pasinelli explored the possibility of enhancing the effectiveness of Riluzole by crippling the P-gp/BCRP proteins that would normally pump Riluzole out of the cell. As proof-of-principle, Dr. Pasinelli and the Jefferson team first demonstrated that ALS patients have tissue-specific increases in P-gp and BCRP protein expression in the membranes of endothelial cells at the blood-spinal cord barrier. Using a mouse model of ALS, Dr. Pasinelli established that when the P-gp protein could be blocked either by genetic manipulation or by the use of a known P-gp/BCRP-inhibiting drug, Elacridar, the effectiveness of Riluzole therapy was improved. In the same mouse model, Elacridar treatment by itself was not found to alter survival or P-gp levels nor was Riluzole by itself effective when administered at the onset of symptoms. Inhibition of P-gp/BCRP by chronic treatment with Elacridar increased penetration of Riluzole in the central nervous system, improved behavioral measures, including muscle function, and significantly extended the survival of the mice. Thus, blocking P-gp and BCRP significantly slowed disease progression in the ALS mice by enhancing Riluzole effectiveness. Based on these findings, Dr. Pasinelli advocates reassessing previous failed trials of other compounds and recommends that, when designing new ALS therapeutic trials, P-gp/BCRP-driven pharmacoresistance should be targeted as a way to improve bioavailability.
While this preliminary study does not guarantee the success of this regimen in human ALS patients, it nonetheless provides an important novel therapeutic approach that needs to be considered when developing new drugs and that may one day help improve ALS treatments. Although Riluzole is not a “blockbuster” drug, it is consistently effective in patients. Thus, ways to improve Riluzole brain penetration and prolong its proven therapeutic effects should be developed for clinical use while we search for more highly effective treatments.
Publication:
Jablonski MR, Markandaiah SS, Jacob D, Meng NJ, Li K, Gennaro V, Lepore AC, Trotti D, Pasinelli P. 2014. Inhibiting drug efflux transporters improves efficacy of ALS therapeutics. Annals of Clinical and Translational Neurology 1(12):996-1005.
Links:
Public and Technical Abstracts: Rethinking Drug Treatment Approaches in ALS by Targeting ABC Efflux Transporters
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