There are 30,000 cases of ALS at any given time in the United States. Presently there is no cure for ALS and few treatment options. Approximately 95% of cases have unknown etiology, but the remainder have a clear genetic origin. Studying the genetic cases has allowed great insight into the disease, which is applicable to both sporadic and familial cases. Continued work with animal models based on ALS-linked gene mutations and in vitro models of sporadic ALS will continue to increase knowledge of the disorder. The efficacy of CNS therapeutics is affected by limited CNS access, which can result in pharmacoresistance. Preclinical trials with different compounds have failed to cure the mouse model of ALS or even stop the progression of the disease and pharmacoresistance is one possible explanation for these failures. Tight junctions of the blood-brain and blood-spinal cord barriers (BBB/BSCB) physically restrict neural penetration of drugs;in addition, active drug extrusion by ATP-binding cassette (ABC) drug efflux transporters are known to affect the bioavailability and efficacy of multiple drugs. Recently, our laboratory reported a disease-driven increase in P-gp expression levels the spinal cords of SOD1-G93A mice. Furthermore, new data that I generated in the laboratory indicate that BCRP, another ABC transporter, increases in expression and function throughout disease progression in ALS mice, in addition to P-gp. This preliminary data, which was recently published, provides a comprehensive analysis of ABC drug efflux transporter alterations in ALS. A functional assessment of BBB/BSCB permeability throughout progression of ALS will be determined, since this phenomenon along with changes in transporter expression and function would alter the bioavailability of ALS- treating compounds. Finally, identification of the molecular mechanisms leading to drug transporter and blood- brain barrier alterations in ALS will be studied. The goals of this proposal will aid in understanding the obstacle provided by the ABC drug efflux transporters and the BBB/BSCB in developing effective pharmacotherapies for ALS.

Public Health Relevance

Amyotrophic Lateral Sclerosis (ALS) is a fatal, neurodegenerative disease with limited therapeutic strategies available for treatment. The failure of many clinical and preclinical compounds in treating ALS led to the hypothesis that limited drug penetration into the central nervous system is mediating the lack of therapeutic efficacy. ABC drug efflux transporters and blood-brain barrier dysfunction have been implicated in multiple central nervous system diseases. Preliminary data indicates a disease-driven increase in ABC drug efflux transporters in an ALS mouse model throughout disease as well as in ALS patients. Conflicting reports have also indicated altered function of the blood-brain and blood-spinal cord barrier in ALS. The ideas presented here will provide novel insight into the functional alterations of the ABC drug efflux transporters as well as the altered function of the blood-brain and blood-spinal cord barrier throughout disease progression in the ALS.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Predoctoral Individual National Research Service Award (F31)
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Special Emphasis Panel (ZRG1)
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Gubitz, Amelie
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Thomas Jefferson University
Schools of Medicine
United States
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Jablonski, Michael; Miller, David S; Pasinelli, Piera et al. (2015) ABC transporter-driven pharmacoresistance in Amyotrophic Lateral Sclerosis. Brain Res 1607:1-14