Effective Splicing Correction of SMN2 Gene in SMA Cells after Delivery of RNA Interpolyelectrolyte Complexes

Introduction: Spinal muscular atrophy (SMA) is a genetic disorder caused by mutations in the SMN1 gene, leading to a deficiency of survival motor neuron (SMN) protein. The human genome contains a paralog of the SMN1 gene, SMN2, which, due to a splicing defect, produces insufficient levels of functional SMN protein. Therapeutic strategies aiming to correct this splicing defect in SMN2 are supposed as treatments for SMA. The disadvantage of this therapy is intrathecal administration with associated side effects. Ternary oligonucleotide--peptide complexes coated by anionic polypeptide are designed to overcome the impossibility of systemic delivery antisense RNA oligonucleotide.

Methods: The study involved transfecting SMA fibroblast cell culture with the serum-stable oligonucleotide--peptide complexes, reverse transcription, semiquantitative PCR, and resazurin assay.

Results and Discussion: A significant increase was observed in the proportion of full-length SMN transcripts after therapeutic antisense RNA oligonucleotide delivery. Interpolyelectrolyte oligonucleotide--peptide complexes showed stability in the serum in contrast to cationic peptide complexes. The toxicity of the complexes remained within acceptable levels.

Conclusions: The delivery of antisense RNA oligonucleotides using interpolyelectrolyte complexes represents a promising strategy for the treatment of SMA. This strategy combines the specificity of antisense oligonucleotides with the protective and delivery-enhancing properties of interpolyelectrolyte complexes, potentially offering a more effective and sustained therapeutic option for SMA treatment.