Antisense oligonucleotides (ASOs) have the potential to treat most diseases that involve altered mRNA expression due to gene mutations, such as spinal muscular atrophy (SMA).

ASOs are small synthetic single-stranded ribonucleic acid (RNA) molecules. They are designed to pair with specific complementary regions on the target premature mRNA (pre-messenger RNA), altering the formation of mature mRNA and the expression of the target gene.

Compared to other small molecule drugs, ASOs are large negatively-charged molecules that must cross cell membranes to have a therapeutic effect.

ASOs bind the target pre-mRNA by Watson-Crick base pairing, which is a common way that two nucleotides stick together across the genome.

SMA is a neurodegenerative disease caused by mutations in the SMN1 (survival motor neuron 1) gene. In about 95 percent of SMA patients, mutations in the SMN1 gene cause the deletion of a segment of the gene called exon 7. As a result, there is a lack of functional SMN protein, which is essential for the maintenance of motor neurons that control movement. Consequently, motor neurons die prematurely.

SMN protein is also expressed in small amounts from another related gene, called SMN2, which is similar to SMN1 except for one nucleotide (or DNA letter) in exon 7. This difference causes alternative splicing of the SMN2 pre-mRNA, resulting in low levels of stable SMN protein and mostly unstable versions of the protein.

Therefore, a specifically tailored ASO, which tilts the splicing of the SMN2 pre-mRNA toward the production of more SMN protein, could serve as a potential SMA therapy.

ASO against SMN2 mRNA

Biogen and Ionis Pharmaceuticals developed an ASO called Spinraza (nusinersen), which binds to the SMN2 pre-mRNA and alters its splicing to allow the inclusion of exon 7 in the mature mRNA, therefore increasing the expression of a stable SMN protein. This drug was shown to be effective in a Phase 3 trial (NCT02193074) in infants with SMA, and was recently approved by the U.S. Food and Drug Administration (FDA) for the treatment of SMA.

Spinraza is injected into the spinal canal by lumbar puncture to allow it to reach the central nervous system (CNS).

ASO against lncRNA

RaNA Therapeutics discovered a new mechanism that regulates SMN2 gene expression. It involves a long non-coding RNA (lncRNA) that recruits a protein called the polycomb repressive complex (PRC2) onto the SMN2 gene to represses its expression. Researchers designed synthetic ASOs that specifically interact with lncRNA at the SMN2 gene, preventing the lncRNA-PRC2 interaction, resulting in increased transcription of the SMN2 gene and expression of functional SMN protein. The effects of the ASO are currently being investigated in preclinical models.

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