Inhibiting drug efflux transporters improves efficacy of ALS therapeutics.
Publication/Presentation Date
12-1-2014
Abstract
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.
Volume
1
Issue
12
First Page
996
Last Page
1005
ISSN
2328-9503
Published In/Presented At
Jablonski, M. R., Markandaiah, S. S., Jacob, D., Meng, N. J., Li, K., Gennaro, V., Lepore, A. C., Trotti, D., & Pasinelli, P. (2014). Inhibiting drug efflux transporters improves efficacy of ALS therapeutics. Annals of clinical and translational neurology, 1(12), 996–1005. https://doi.org/10.1002/acn3.141
Disciplines
Business Administration, Management, and Operations | Health and Medical Administration | Management Sciences and Quantitative Methods
PubMedID
25574474
Department(s)
Administration and Leadership
Document Type
Article