Nusinersen for spinal muscular atrophy

Spinal muscular atrophy (SMA) is a monogenic anterior horn disease caused by mutations in the SMN1 gene leading to lack of SMN protein necessary for motor neuron functioning and survival. Phenotypic severity is modulated primarily by the amount of SMN protein produced by the paralogue SMN2 gene that differs from SMN1 by a critical single-nucleotide polymorphism in exon 7 (C to T) resulting in only 10%–15% of full-length functioning SMN protein. The phenotypes include subgroups with different age at onset, severity, and rate of progression: babies with type 1 SMA have onset of weakness before 6 months, are never able to sit, and have 8% survival at 20 months; babies with type 2 have symptoms onset after 6 months, they reach the ability to sit but never walk; children and teenagers with type 3 are able to walk, become progressively weaker, and eventually lose the ability to walk; the ultra-rare type 4 with adult onset has a very slow progression of lower extremity weakness. Nusinersen is an antisense oligonucleotide that corrects pre-mRNA splicing to promote inclusion of exon 7 in the SMN2 mRNA transcript, resulting in increased production of full-length functioning SMN protein.