Fig. 2

SMN correcting therapy, mechanism of action. The antisense oligonucleotide (ASO) nusinersen is an intrathecally-delivered splicing modifier that binds to the exon 7 silencer region on SMN2 pre-mRNA (Pre mRNA) (left). By displacing the splicing repressor protein hnRNP, nusinersen promotes inclusion of exon 7 and boosts production of full-length SMN2 mRNA. Functional SMN protein in central nervous system motor neurons is increased. Risdiplam is an orally available, selective small molecule that modifies SMN2 pre-mRNA (Pre mRNA) splicing (center). Risdiplam increases exon 7 inclusion in SMN2 mRNA transcripts and production of full-length SMN protein in the brain. This leads to increased production of functional SMN protein in the brain and throughout peripheral tissues. Onasemnogene abeparvovec-xioi is an adeno-associated virus 9 (AAV9)-based therapy that delivers a fully functional copy of SMN complementary deoxyribonucleic acid (cDNA) (right). Administered intravenously as a single-dose, the SMN transgene passes the blood–brain barrier and is introduced directly into target motor neuron cells throughout the CNS. Transduced cells produce full-length SMN mRNA transcripts, which enable continuous production of SMN protein in motor neurons and peripheral tissue over time [43,44,45,46]. Figure property of Scholar Rock, Inc