Amyotrophic lateral sclerosis (ALS) is a catastrophic degeneration of the nervous system with great need for disease-modifying treatments. Stefan Pulst, MD, and his collaborator Daniel Scoles, PhD, were studying a lesser-known but similarly dire condition (spinocerebellar ataxia 2, SCA2) when they identified a gene relevant to both diseases. They generated mice expressing the mutant version of the gene identified as the cause of SCA2 in humans (ataxin-2), and developed an antisense oligonucleotide targeting ataxin-2 to test its effects. The antisense oligonucleotide improved SCA2 in these mice. In humans, ALS is associated with abnormal accumulation of the TDP-43 protein in the brain. ALS mice were therefore generated by inducing increased expression of TDP-43. Deletion of the ataxin-2 gene and administration of the ataxin-2 antisense oligonucleotide each improved survival of these mice, presumably by protecting against TDP-43 toxicity. They recently optimized the ataxin-2 antisense oligonucleotide, which is now being tested in clinical trials. This series of ground-breaking studies offers promise for novel strategies to treat these previously incurable and severely debilitating neurological diseases.
Antisense oligonucleotide therapy for spinocerebellar ataxia type 2. Scoles DR, Meera P, Schneider M, Paul S, Dansithong W, Figueroa KP, Hung G, Rigo F, Bennett CF, Otis TS, Pulst SM.Nature. 2017 April 20;544(7650):362. doi:10.1038/nature22044.
Therapeutic reduction of ataxin 2 extends lifespan and reduces pathology in TDP-43 mice. Becker LA, Huang B, Bieri G, Ma R, Knowles DA, Jafar-Nejad P, Messing J, Kim HJ, Soriano A, Auburger G, Pulst SM, Taylor JP, Rigo F, Gitler AD. Nature. 2017 Apr 20;544(7650):367.