Targeting RNA-splicing for SMA treatment

Abstract

The central dogma of DNA-RNA-protein was established more than 40 years ago. However, important biological processes have been identified since the central dogma was developed. For example, methylation is important in the regulation of transcription. In contrast, proteins, are more complex due to modifications such as phosphorylation, glycosylation, ubiquitination, or cleavage. RNA is the mediator between DNA and protein, but it can also be modulated at several levels. Among the most profound discoveries of RNA regulation is RNA splicing. It has been estimated that 80% of pre-mRNA undergo alternative splicing, which exponentially increases biological information flow in cellular processes. However, an increased number of regulated steps inevitably accompanies an increased number of errors. Abnormal splicing is often found in cells, resulting in protein dysfunction that causes disease. Splicing of the survival motor neuron (SMN) gene has been extensively studied during the last two decades. Accumulating knowledge on SMN splicing has led to speculation and search for spinal muscular atrophy (SMA) treatment by stimulating the inclusion of exon 7 into SMN mRNA. This mini-review summaries the latest progress on SMN splicing research as a potential treatment for SMA disease.

Fig. 1.

Survival motor neuron (SMN) genes and spinal muscular atrophy (SMA) disease. Two inverted SMN genes, SMN1 and SMN2 are located on chromosome 5. SMN1 and SMN2 have nine exons. Exon 7 is alternatively spliced. Under normal conditions (Normal), > 95% of SMN1 mRNA includes exon 7, whereas only 10% of SMN2 mRNA has exon 7. Most patients with SMA have a deletion of the SMN1 gene (SMA: SMN1 deletion). In these patients, 10% of full-length mRNA produced from the SMN2 gene is unable to compensate for the loss of the SMN1 gene. SMA can also be caused by point mutations (SMA: SMN1 mutation). Missense mutations have been identified across the gene (indicated by ^*).

Fig. 2.

Potential therapeutic approaches for spinal muscular atrophy (SMA). (A) Compounds that have been or will be tested in clinical studies. (B) Gene therapy can be achieved by delivering full length SMN1 cDNA into patients with SMA; (C) Trans-splicing can be used to correct exon 7 skipping in the SMN2 gene; (D) A bifunctional oligonucleotide can recruit splicing factors to exon 7, leading to more exon 7 inclusion in SMN2 mRNA; (E) Anti-sense oligonucleotides would block negative elements in SMN splicing, stimulating exon 7 inclusion into SMN2 mRNA.