A pharmaceutical company develops a splice-switching antisense oligonucleotide (ASO) that corrects aberrant splicing of the SMN2 pre-mRNA to produce full-length SMN protein, used in spinal muscular atrophy (SMA). What is the mechanism of action of this ASO at the molecular level?

• A It base-pairs with SMN2 mRNA in the cytoplasm and recruits RISC to degrade the transcript via siRNA mechanism
• B It binds the SMN2 promoter in the nucleus and recruits CRISPR-Cas9 to correct the DNA sequence
• C It acts as a decoy for the spliceosome to redirect splicing from SMN2 to SMN1
• D It binds a splicing silencer sequence in SMN2 pre-mRNA intron 7, blocking hnRNP A1 binding and promoting exon 7 inclusion ✓

Explanation

Nusinersen (the approved ASO for SMA) binds an intronic splicing silencer element (ISS-N1) in intron 7 of SMN2 pre-mRNA. This silencer normally recruits hnRNP A1/A2 proteins that promote exon 7 skipping, producing a truncated non-functional SMN protein. By blocking ISS-N1, nusinersen prevents hnRNP A1 binding, allowing U1 snRNP and other splicing enhancers to include exon 7, generating full-length functional SMN protein. This is a steric-blocking ASO mechanism, distinct from RNase H-mediated degradation or RNA interference.

Reference: Harper's Illustrated Biochemistry, 32nd ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.