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.

Impact of EBV Essential Nuclear Protein EBNA-3C on B-Cell Proliferation and Apoptosis

“…Soon after the discovery that Gemin3 is an interacting partner of EBV-encoded latent antigens, Gemin3 has subsequently been shown to interact with a number of transcriptional regulators, such as the orphan nuclear receptor SF-1, Egr2, mitogen Ets repressor and SMN [135]. The SMN complex plays an essential role in the synthesis of small nuclear ribonucleoproteins, pre-mRNA splicing, RNA transport, as well as regulation of gene transcription [136]. Interestingly, both EBNA-2 and EBNA-3C have also been shown to associate with the SMN complex [134].…”

Alternatives Spleißen – Prinzipien, funktionelle Konsequenzen und therapeutische Relevanz

“…Dies 7 im SNM2-Transkript führen, konnte die Lebenserwartung dieser Mäuse dramatisch erhöht werden [15]. Ähnliche Ergebnisse wurden durch die Injektion von membrangängigen MOs in ein Maus-Modell für das Hutchinson-Gilford-Syndrom erzielt [11].…”

Antisense oligonucleotide therapeutics for inherited neurodegenerative diseases

“…Humans also possess the SMN2 gene that is nearly identical to SMN1 and the result of a chromosomal duplication event. However, a silent mutation in exon 7 (C to T) disrupts splicing and leads to exon 7 exclusion in 80-90% of all SMN2 mRNAs, resulting in an unstable protein that is rapidly degraded [68,69]. SMN2 copy number modifies the severity of the SMA phenotype [70], indicating that small amounts of functional SMN are produced from the SMN2 gene and that augmenting the levels of SMN production through ASO-mediated splice modulation may be a feasible strategy for treating SMA.…”