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PLoS One. 2014 Dec 19;9(12):e91608. doi: 10.1371/journal.pone.0091608. eCollection 2014.

Dexpramipexole is ineffective in two models of ALS related neurodegeneration.

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ALS Therapy Development Institute, Cambridge, Massachusetts, United States of America.
Gladstone Institute of Neurological Disease, San Francisco, California, United States of America.
Gladstone Institute of Neurological Disease, San Francisco, California, United States of America; Taube-Koret Center for Neurodegenerative Disease Research and the Hellman Family Foundation Alzheimer's Disease Research Program, San Francisco, California, United States of America; Departments of Neurology and Physiology, University of California San Francisco, San Francisco, California, United States of America.


Treatment options for people living with amyotrophic lateral sclerosis (ALS) are limited and ineffective. Recently, dexpramipexole (RPPX) was advanced into human ALS clinical trials. In the current studies, we investigated RPPX in two parallel screening systems: 1) appropriately powered, sibling-matched, gender-balanced survival efficacy screening in high-copy B6-SJL-SOD1G93A/Gur1 mice, and 2) high-content neuronal survival screening in primary rat cortical neurons transfected with wild-type human TDP43 or mutant human TDP43. In both cases, we exposed the test systems to RPPX levels approximating those achieved in human Phase II clinical investigations. In SOD1G93A mice, no effect was observed on neuromotor disease progression or survival. In primary cortical neurons transfected with either mutant or wild-type human TDP43, a marginally significant improvement in a single indicator of neuronal survival was observed, and only at the 10 µM RPPX treatment. These systems reflect both mutant SOD1- and TDP43-mediated forms of neurodegeneration. The systems also reflect both complex non-cell autonomous and neuronal cell autonomous disease mechanisms. The results of these experiments, taken in context with results produced by other molecules tested in both screening systems, do not argue positively for further study of RPPX in ALS.

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