Spinal muscular atrophy: a timely review

Abstract

Spinal muscular atrophy (SMA) is a neurodegenerative disease characterized by loss of motor neurons in the anterior horn of the spinal cord and resultant weakness. The most common form of SMA, accounting for 95% of cases, is autosomal recessive proximal SMA associated with mutations in the survival of motor neurons (SMN1) gene. Relentless progress during the past 15 years in the understanding of the molecular genetics and pathophysiology of SMA has resulted in a unique opportunity for rational, effective therapeutic trials. The goal of SMA therapy is to increase the expression levels of the SMN protein in the correct cells at the right time. With this target in sight, investigators can now effectively screen potential therapies in vitro, test them in accurate, reliable animal models, move promising agents forward to clinical trials, and accurately diagnose patients at an early or presymptomatic stage of disease. A major challenge for the SMA community will be to prioritize and develop the most promising therapies in an efficient, timely, and safe manner with the guidance of the appropriate regulatory agencies. This review will take a historical perspective to highlight important milestones on the road to developing effective therapies for SMA.

Figure 1

Spinal muscular atrophy (SMA) timeline. Spinal muscular atrophy was first reported by Werdnig in 1891 and then by others who recognized variability of muscle weakness severity. A century later, a consensus classification scheme outlining three SMA types was adopted, and in 2007 a Standard of Care document formalized the clinical treatment of patients with SMA. The SMN gene was identified as the causative gene in SMA in 1995, which has led to the development of SMA animal models and targeted therapeutic approaches to increase SMN protein levels. The increasingly successful preclinical testing of multiple therapeutic approaches during the last 10 years has led to great optimism that an era of successful clinical trials is fast approaching.

Figure 2

Schematic of SMN gene. Schematic diagram of the human SMN1 and SMN2 genes and the resultant pre–messenger RNAs. Patients with spinal muscular atrophy (SMA) have deletions or mutations in both copies of SMN1. The SMN2 gene is expressed, however, most resultant SMN2 pre-mRNA lacks exon 7 because of a C-to-T transition at position 6 of exon 7. The truncated SMN protein is unstable and nonfunctional. A small proportion of full-length messenger RNA containing exon 7 is produced by from the SMN2 pre–messenger RNA, however, resulting in full-length SMN protein, which is functional.