Progress and promise: the current status of spinal muscular atrophy therapeutics

Abstract

Spinal muscular atrophy (SMA) is an inherited neuromuscular disorder that causes degeneration of α-motor neurons. Frequently, muscle weakness is very severe causing affected infants to die before reaching two years of age, but mild forms of the disease can be characterized by relatively static muscle weakness for many years. SMA is caused by recessive mutations of the SMN1 gene, but all patients retain at least one copy of SMN2, a similar gene capable of producing low levels of full-length SMN protein. No treatments currently exist for SMA patients, but the identification of therapeutic targets and the development of suitable animal models for preclinical testing have resulted in increased drug development efforts in the past ten years. Here, we review the current status of many of these programs, including those designed to activate SMN2 gene expression, modulate splicing of SMN2 preRNAs, stabilize SMN protein, replace SMN1, provide neuroprotective support, and transplant neural cells.