Dexpramipexole is ineffective in two models of ALS related neurodegeneration.

Fernando G Vieira,Beth Levine,Alan Gill,Andy Moreno,Eva Ladow,Steven Perrin,Steven Finkbeiner,Kenneth Thompson,Joshua D Kidd

doi:10.1371/journal.pone.0091608

Abstract

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.

Highlights

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease defined by upper and lower motor neuron failure. [1] Treatment options exist for the management of symptoms and complications relating to ALS, but only riluzole treatment has been approved by regulatory agencies to slow ALS disease progression. [2,3] Riluzole’s efficacy is marginal
We investigated RPPX in two parallel screening systems: 1) appropriately powered, sibling-matched, genderbalanced 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
The best characterized is the high-copy B6-SJL-SOD1G93A/Gur1 mouse, a heterozygous transgenic mouse that ubiquitously expresses more than 20 copies of mutant human Superoxide dismutase 1 (SOD1). [5,6] It recapitulates many of the pathological hallmarks of both human familial and sporadic ALS, including muscle weakness, atrophy, motor neuron death, protein aggregation, and more

Summary

Introduction

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease defined by upper and lower motor neuron failure. [1] Treatment options exist for the management of symptoms and complications relating to ALS, but only riluzole treatment has been approved by regulatory agencies to slow ALS disease progression. [2,3] Riluzole’s efficacy is marginal. [5,6] It recapitulates many of the pathological hallmarks of both human familial and sporadic ALS, including muscle weakness, atrophy, motor neuron death, protein aggregation, and more. The best characterized is the high-copy B6-SJL-SOD1G93A/Gur mouse, a heterozygous transgenic mouse that ubiquitously expresses more than 20 copies of mutant human SOD1. These high-copy B6-SJL-SOD1G93A/Gur mice have been used to better understand ALS pathogenesis and to screen and test potential therapeutics to justify a human ALS clinical trial

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