Therapy for ALS

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.