Antisense oligonucleotides (ASOs) are small molecules that can bind to RNA to change how it is spliced. It is a potential therapy for SMA, as customizing ASOs may change the splicing of SMN2 and, therefore, produce more functional SMN protein.
How antisense oligonucleotides work
Antisense oligonucleotides could be a treatment for SMA because they may correct the splicing of the SMN2 gene. ASOs are small single strands of RNA designed to pair with a complementary strand of RNA, and alter or reduce expression of the targeted RNA. By custom designing ASOs in such a way that they will pair with a region in the SMN2 pre-mRNA near exon 7, they can control whether the exon will be included.
A correct binding of the ASO would result in the inclusion of the exon 7 in the mRNA and, therefore, the SMN protein. The inclusion of exon 7 corrects the splicing of the SMN2 gene, producing full-length mRNA and a functional SMN protein, increasing its levels in SMA patients. This therapy can be administered via intrathecal injection.
Antisense oligonucleotides research
RaNA Therapeutics has done some preliminary studies in symptomatic SMA mouse models that suggest that ASOs can positively affect preclinical outcomes.
Current in vivo studies are focused on determining the effect of ASOs on various preclinical phenotypes and on survival in SMA mouse models. Ongoing mechanistic studies are focused on RNA identification and determining ASOs action at the chromatin level.
Data collected so far also suggests a new epigenetic mechanism to increase SMN2 protein that will likely provide a significant therapeutic treatment to people with SMA.
Next steps for Antisense Oligonucleotides
RaNA’s goal is to try to upregulate the transcripts derived from the SMN2 gene, leading to an increase in the functional SMN2 protein and improving SMA symptoms.
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