title: Inhibiting drug efflux transporters improves efficacy of ALS therapeutics.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Weinberg Unit for ALS Research, Farber Institute for Neuroscience, Department of Neuroscience, Thomas Jefferson University 900 Walnut Street, Philadelphia, Pennsylvania, 19107.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Jablonski
authors.affiliation: Weinberg Unit for ALS Research, Farber Institute for Neuroscience, Department of Neuroscience, Thomas Jefferson University 900 Walnut Street, Philadelphia, Pennsylvania, 19107.
authors.forename: Shashirekha S
authors.initials: SS
authors.lastname: Markandaiah
authors.affiliation: Weinberg Unit for ALS Research, Farber Institute for Neuroscience, Department of Neuroscience, Thomas Jefferson University 900 Walnut Street, Philadelphia, Pennsylvania, 19107.
authors.forename: Dena
authors.initials: D
authors.lastname: Jacob
authors.affiliation: Weinberg Unit for ALS Research, Farber Institute for Neuroscience, Department of Neuroscience, Thomas Jefferson University 900 Walnut Street, Philadelphia, Pennsylvania, 19107.
authors.forename: Ni J
authors.initials: NJ
authors.lastname: Meng
authors.affiliation: Farber Institute for Neuroscience, Department of Neuroscience, Thomas Jefferson University 900 Walnut Street, Philadelphia, Pennsylvania, 19107.
authors.forename: Ke
authors.initials: K
authors.lastname: Li
authors.affiliation: Weinberg Unit for ALS Research, Farber Institute for Neuroscience, Department of Neuroscience, Thomas Jefferson University 900 Walnut Street, Philadelphia, Pennsylvania, 19107.
authors.forename: Victoria
authors.initials: V
authors.lastname: Gennaro
authors.affiliation: Farber Institute for Neuroscience, Department of Neuroscience, Thomas Jefferson University 900 Walnut Street, Philadelphia, Pennsylvania, 19107.
authors.forename: Angelo C
authors.initials: AC
authors.lastname: Lepore
authors.affiliation: Weinberg Unit for ALS Research, Farber Institute for Neuroscience, Department of Neuroscience, Thomas Jefferson University 900 Walnut Street, Philadelphia, Pennsylvania, 19107.
authors.forename: Davide
authors.initials: D
authors.lastname: Trotti
authors.affiliation: Weinberg Unit for ALS Research, Farber Institute for Neuroscience, Department of Neuroscience, Thomas Jefferson University 900 Walnut Street, Philadelphia, Pennsylvania, 19107.
authors.forename: Piera
authors.initials: P
authors.lastname: Pasinelli