Spinal muscular atrophy: mechanisms and therapeutic strategies

Abstract

Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disorder and a leading genetic cause of infantile mortality. SMA is caused by mutation or deletion of Survival Motor Neuron-1 (SMN1). The clinical features of the disease are caused by specific degeneration of alpha-motor neurons in the spinal cord, leading to muscle weakness, atrophy and, in the majority of cases, premature death. A highly homologous copy gene (SMN2) is retained in almost all SMA patients but fails to generate adequate levels of SMN protein due to its defective splicing pattern. The severity of the SMA phenotype is inversely correlated with SMN2 copy number and the level of full-length SMN protein produced by SMN2 ( approximately 10-15% compared with SMN1). The natural history of SMA has been altered over the past several decades, primarily through supportive care measures, but an effective treatment does not presently exist. However, the common genetic etiology and recent progress in pre-clinical models suggest that SMA is well-suited for the development of therapeutic regimens. We summarize recent advances in translational research that hold promise for the progression towards clinical trials.

Figure 1.

Schematic of the human SMN locus. The human SMN genes, SMN1 and SMN2, are located in close proximity on chromosome 5. The SMN2 locus is likely derived from a recent duplication event of a genomic region spanning ∼500 kb which contains additional genes and microsatellite markers. The SMN genes comprise nine exons and eight introns and encode an identical protein product. A silent C–T transition in exon 7 of SMN2 alters a critical exonic splice enhancer and results in a strong reduction of exon 7 inclusion during splicing. Consequently, ∼85% of the mature mRNA lacks exon 7 (Δ7), highlighted by the RT–PCR in the bottom panel. The truncated protein is defective in SMN self-association and is degraded rapidly.

Figure 2.

Schematic of the exon 7 region and the factors involved in the inclusion or exclusion of exon 7 within SMN pre-mRNA. Components of the machinery are shown in blue. The positively acting sequences and splicing factors are shown in green. The negatively acting sequences and splicing factors are shown in red. The C–T transition at +6 is indicated.

Figure 3.

(A) Schematic of the exon 7 region and the proposed function of a bifunctional RNA. The bifunctional RNA is illustrated with an antisense-targeting domain specific to 5′ end of exon 7, a short spacer region and a domain comprising three tandem repeats of ESEs shown in green. Positive splicing factors, interacting with the splicing machinery, are shown in yellow. (B) Schematic of trans-splicing in the context of SMN2 pre-mRNA splicing. The antisense domain of the trans-splicing RNA binds to endogenous SMN2 pre-mRNA at the intron 6 region by complementary base-pairing. The SMN1 exon 7 is contained within the trans-splicing RNA and precedes a polyadenylation signal. The product of an interaction between the 5′ ss of intron 6 and the 3′ ss of the trans-splicing RNA is a trans-spliced mRNA that contains SMN1 exon 7. BP, branch point; p(Py), polypyrimidine tract; p(A), polyadenylation signal.