In Vitro Evaluation of Antisense-Mediated Exon Inclusion for Spinal Muscular Atrophy.

Spinal muscular atrophy (SMA), the most common genetic cause of infantile death caused by mutations in the SMN1 gene, presents a unique case in the field of splice modulation therapy, where a gene (or lack of) is responsible for causing the disease phenotype but treatment is not focused around it. Antisense therapy targeting SMN2, which leads to SMN protein expression, has been at the forefront of research when it comes to developing a feasible therapy for treating SMA. The recent FDA approval of an antisense-based drug with 2'-methoxyethoxy (2'MOE) chemistry, called Nusinersen (Spinraza), brought antisense drugs into the spotlight. The 2'MOE, although effective, has weaknesses, such as the inability to cross the blood-brain barrier and the high cost of treatment. This propelled the research community to investigate new chemistries of antisense oligonucleotides (ASOs) that may be better in both treatment and cost efficiency. Here we will describe two new types of ASOs, phosphorodiamidate morpholino oligomers (PMOs) and locked nucleic acids (LNA)/DNA mixmers, being investigated as potential treatments for SMA, and methods used to test their efficacy in type I SMA patient fibroblast cell lines.