Peptide-assisted systemic delivery of therapeutic antisense oligonucleotides in a spinal muscular atrophy model

Spinal muscular atrophy (SMA) is a neurodegenerative disease caused by homozygous loss of the survival motor neuron 1 (SMN1) gene. It results in progressive atrophy of voluntary muscle groups leading to paralysis and eventually premature infantile death.

Humans have a second, nearly identical copy of the SMN1 gene, SMN2. The 90% majority of SMN2 transcripts lack exon-7, which leads to the production of a truncated SMN protein that is highly unstable. Therefore, increasing the expression of full-length functional SMN protein by forcing SMN2 exon-7 inclusion is a rational therapeutic development for SMA patients.

Antisense oligonucleotides (ASO) targeting SMN2 exon 7 inclusion have been developed, which inhibit binding of small nuclear ribonucleic proteins (snRNPs) and can restore full-length SMN2, leading to the production of functional SMN protein. However, the delivery of ASO to the spinal motor neurons remains a challenge. In this project, we will develop a peptide-based delivery system that can shuttle ASO to the spinal cord using an axonal retrograde transport system.