The clinical landscape for SMA in a new therapeutic era

Abstract

Despite significant advances in basic research, the treatment of degenerative diseases of the nervous system remains one of the greatest challenges for translational medicine. The childhood onset motor neuron disorder spinal muscular atrophy (SMA) has been viewed as one of the more tractable targets for molecular therapy due to a detailed understanding of the molecular genetic basis of the disease. In SMA, inactivating mutations in the SMN1 gene can be partially compensated for by limited expression of SMN protein from a variable number of copies of the SMN2 gene, which provides both a molecular explanation for phenotypic severity and a target for therapy. The advent of the first tailored molecular therapy for SMA, based on modulating the splicing behaviour of the SMN2 gene provides, for the first time, a treatment which alters the natural history of motor neuron degeneration. Here we consider how this will change the landscape for diagnosis, clinical management and future therapeutic trials in SMA, as well as the implications for the molecular therapy of other neurological diseases.

Figure 1

A continuous spectrum of phenotypes in SMA. Despite genetic confirmation of SMN1 absence or mutations in all patients, SMA presentation ranges from very compromised neonates (type 1A) to adults with minimal manifestations (MM) depending on the number of SMN2 copies and full-length protein produced by each patient and modulated by negative or positive modifiers that influence the final phenotype.

Figure 2

Schematic representation of the mechanism of action of nusinersen (Spinraza). (a) SMN2 intron 7 contains an intronic splicing silencer (termed ISS-N1) with binding sites for negative splicing factors (NSFs), hnRNPA1 and 2. Binding of these NSFs to intron 7 pre-mRNA precludes the interaction of U1 snRNP1 with its specific site at the beginning of the intron and therefore the recognition of exon 7 during the splicing process. (b) The antisense oligonucleotide nusinersen blocks the ISS-N1 site preventing the binding of the NSFs, and allowing U1 snRNP1 to recognise exon 7 of the SMN2 pre-mRNA. As a result, exon 7 is included in the SMN2 mature RNA, and is translated into full-length SMN protein. Based on a bidimensional model by Singh et al.