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Ann Clin Transl Neurol. 2014 Dec;1(12):996-1005. doi: 10.1002/acn3.141. Epub 2014 Nov 21.

Inhibiting drug efflux transporters improves efficacy of ALS therapeutics.

Author information

1
Weinberg Unit for ALS Research, Farber Institute for Neuroscience, Department of Neuroscience, Thomas Jefferson University 900 Walnut Street, Philadelphia, Pennsylvania, 19107.
2
Farber Institute for Neuroscience, Department of Neuroscience, Thomas Jefferson University 900 Walnut Street, Philadelphia, Pennsylvania, 19107.

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.

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