Inhibiting drug efflux transporters improves efficacy of ALS therapeutics

Michael R. Jablonski, Shashirekha S. Markandaiah, Dena Jacob, Ni J. Meng, Ke Li, Victoria Gennaro, Angelo C. Lepore, Davide Trotti, and Piera Pasinelli

Objective

Research identified promising therapeutics in cell models of Amyotrophic Lateral Sclerosis (ALS), but there is limited progress translating effective treatments to animal models and patients, and ALS remains a disease with no effective treatment. One explanation stems from an acquired pharmacoresistance driven by the drug efflux transporters P-glycoprotein (P-gp) and breast cancer-resistant protein (BCRP), which we have shown are selectively upregulated at the blood-brain and spinal cord barrier (BBB/BSCB) in ALS mice and patients. Pharmacoresistance is well appreciated in other brain diseases, but overlooked in ALS despite many failures in clinical trials.

Methods

Here, we prove that a P-gp/BCRP-driven pharmacoresistance limits the bioavailability of ALS therapeutics using riluzole, the only FDA-approved drug for ALS and a substrate of P-gp and BCRP. ALS mice (SOD1-G93A) were treated with riluzole and elacridar, to block P-gp and BCRP, and monitored for survival as well as behavioral and physiological parameters.

Results

We show that riluzole, which normally is not effective when given at onset of symptoms, is now effective in the ALS mice when administered in combination with the P-gp/BCRP inhibitor elacridar. Chronic elacridar treatment increases riluzole Central nervous system (CNS) penetration, improves behavioral measures, including muscle function, slowing down disease progression, and significantly extending survival.

Interpretation

Our approach improves riluzole efficacy with treatment beginning at symptom onset. Riluzole will not provide a cure, but enhancing its efficacy postsymptoms by addressing pharmacoresistance demonstrates a proof-of-principle concept to consider when developing new ALS therapeutic strategies. We highlight a novel improved therapeutic approach for ALS and demonstrate that pharmacoresistance can no longer be ignored in ALS.

Citation:Jablonski, M. R., Markandaiah, S. S., Jacob, D., Meng, N. J., Li, K., Gennaro, V., Lepore, A. C., Trotti, D. and Pasinelli, P. (2014), Inhibiting drug efflux transporters improves efficacy of ALS therapeutics. Annals of Clinical and Translational Neurology. doi: 10.1002/acn3.141
Received: 5 SEP 2014; Accepted 16 OCT 2014; Published 21 NOV 2014
Copyright © 2014 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association.This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.


Acknowledgments:
We thank N. Maragakis and T. Heiman-Patterson for contributing ALS patient tissue; L. Kenyon for human control tissue and T. Hala for technical assistance of tissue collection. This work was funded by DOD W81XWH-11-1-0767 to P. P.; Landenberger Foundation to P. P.; National Institutes of Health- RO1-NS074886 to D. T.; National Institutes of Health- F31-NS080539 to M. R. J.; MDA Developmental Award to D. J.; Farber Family Foundation to P. P. and D. T.

Conflict of Interests: Dr. Jablonski reports grants from National Institutes of Health, during the conduct of the study; In addition, has a patent Novel Methods of Treating a Neurodegenerative Disease in a Mammal pending. Dr. Jacob reports grants from Muscular Dystrophy Association, during the conduct of the study. Dr. Trotti reports grants from National Institutes of Health, during the conduct of the study; In addition, has a patent Novel Methods of Treating a Neurodegenerative Disease in a Mammal pending. Dr. Pasinelli reports grants from Department of Defense, Landenberger Foundation, during the conduct of the study; In addition, has a patent Novel Methods of Treating a Neurodegenerative Disease in a Mammal pending.