Emerging antisense oligonucleotide and viral therapies for amyotrophic lateral sclerosis

Abstract

Purpose of review: Amyotrophic lateral sclerosis (ALS) is a rapidly fatal disease for which there is currently no effective therapy. The present review describes the current progress of existing molecular therapies in the clinical trial pipeline and highlights promising future antisense oligonucleotide (ASO) and viral therapeutic strategies for treating ALS.

Recent findings: The immense progress in the design of clinical trials and generation of ASO therapies directed towards superoxide dismutase-1 (SOD1) and chromosome 9 open reading frame 72 (C9orf72) repeat expansion related disease have been propelled by fundamental work to identify the genetic underpinnings of familial ALS and develop relevant disease models. Preclinical studies have also identified promising targets for sporadic ALS (sALS). Moreover, encouraging results in adeno-associated virus (AAV)-based therapies for spinal muscular atrophy (SMA) provide a roadmap for continued improvement in delivery and design of molecular therapies for ALS.

Summary: Advances in preclinical and clinical studies of ASO and viral directed approaches to neuromuscular disease, particularly ALS, indicate that these approaches have high specificity and are relatively well tolerated.

Figure 1.. Cycle of gene therapy development

The development of gene therapies for ALS begins with 1) pinpointing promising disease targets which have historically derived from identification of genes in familial ALS and the discovery of aberrant cellular processes in affected patients or animal models. 2) Generation of cellular or animal disease models helps to clarify how gene mutations or pathologic features impact disease. 3) Mechanistic knowledge of disease pathogenesis derived from disease models informs development of a therapeutic strategy. Disease mechanisms governed by gain-of-function (i.e. SOD1-ALS, C9-ALS) may benefit from approaches that enable gene knockdown (i.e. ASOs, AAV-mediated delivery of ASOs, shRNA, or miRNA) while disease caused by loss-of-function could benefit from restoration of the defective gene using AAV. If gene therapies show 4) preclinical efficacy, they may progress to 5) human clinical trials. 6) The cumulative lessons derived from iterations of this cycle will hopefully streamline the process of drug development in ALS.