Nusinersen in the Treatment of Spinal Muscular Atrophy

Methods Mol Biol. 2018:1828:69-76. doi: 10.1007/978-1-4939-8651-4_4.

Abstract

Spinal muscular atrophy (SMA) is one of the most common genetic causes of infantile death arising due to mutations in the SMN1 gene and the subsequent loss of motor neurons. With the discovery of the intronic splicing silencer N1 (ISS-N1) as a potential target for antisense therapy, several antisense oligonucleotides (ASOs) are being developed to include exon 7 in the final mRNA transcript of the SMN2 gene and thereby increasing the production of spinal motor neuron (SMN) proteins. Nusinersen (spinraza), a modified 2'-O-methoxyethyl (MOE) antisense oligonucleotide is the first drug to be approved by Food and Drug Agency (FDA) in December of 2016. Here we briefly review the pharmacological relevance of the drug, clinical trials, toxicity, and future directions following the approval of nusinersen.

Keywords: Antisense oligonucleotides (ASOs); Exon inclusion; Food and drug agency (FDA); Intronic splicing silencer (ISS-N1); Nusinersen (Spinraza); SMN2; Spinal muscular atrophy (SMA); Survival of motor neuron (SMN); Werdnig–Hoffmann disease; 2'-O-methoxyethyl (MOE).

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Drug Development
  • Exons
  • Genetic Therapy* / adverse effects
  • Genetic Therapy* / methods
  • Humans
  • Introns
  • Muscular Atrophy, Spinal / genetics*
  • Muscular Atrophy, Spinal / therapy*
  • Mutation
  • Oligonucleotides / administration & dosage*
  • Oligonucleotides / chemistry
  • Oligonucleotides / genetics*
  • Oligonucleotides / pharmacokinetics
  • Oligonucleotides, Antisense
  • Survival of Motor Neuron 1 Protein / genetics

Substances

  • Oligonucleotides
  • Oligonucleotides, Antisense
  • Survival of Motor Neuron 1 Protein
  • nusinersen

Grants and funding