Biodistribution of onasemnogene abeparvovec DNA, mRNA and SMN protein in human tissue

Nat Med. 2021 Oct;27(10):1701-1711. doi: 10.1038/s41591-021-01483-7. Epub 2021 Oct 4.


Spinal muscular atrophy type 1 (SMA1) is a debilitating neurodegenerative disease resulting from survival motor neuron 1 gene (SMN1) deletion/mutation. Onasemnogene abeparvovec (formerly AVXS-101) is a gene therapy that restores SMN production via one-time systemic administration. The present study demonstrates widespread biodistribution of vector genomes and transgenes throughout the central nervous system (CNS) and peripheral organs, after intravenous administration of an AAV9-mediated gene therapy. Two symptomatic infants with SMA1 enrolled in phase III studies received onasemnogene abeparvovec. Both patients died of respiratory complications unrelated to onasemnogene abeparvovec. One patient had improved motor function and the other died shortly after administration before appreciable clinical benefit could be observed. In both patients, onasemnogene abeparvovec DNA and messenger RNA distribution were widespread among peripheral organs and in the CNS. The greatest concentration of vector genomes was detected in the liver, with an increase over that detected in CNS tissues of 300-1,000-fold. SMN protein, which was low in an untreated SMA1 control, was clearly detectable in motor neurons, brain, skeletal muscle and multiple peripheral organs in treated patients. These data support the fact that onasemnogene abeparvovec has effective distribution, transduction and expression throughout the CNS after intravenous administration and restores SMN expression in humans.

Publication types

  • Clinical Trial, Phase I
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Autopsy
  • Biological Products / administration & dosage
  • Biological Products / adverse effects*
  • DNA / genetics
  • Female
  • Genetic Therapy / adverse effects*
  • Genetic Vectors / administration & dosage
  • Genetic Vectors / adverse effects
  • Genetic Vectors / genetics
  • Humans
  • Infant
  • Infant, Newborn
  • Male
  • Motor Neurons / drug effects
  • Motor Neurons / pathology
  • RNA, Messenger / genetics
  • Recombinant Fusion Proteins / administration & dosage
  • Recombinant Fusion Proteins / adverse effects*
  • Recombinant Fusion Proteins / genetics
  • Spinal Muscular Atrophies of Childhood / genetics
  • Spinal Muscular Atrophies of Childhood / mortality
  • Spinal Muscular Atrophies of Childhood / pathology
  • Spinal Muscular Atrophies of Childhood / therapy*
  • Survival of Motor Neuron 1 Protein / genetics*
  • Tissue Distribution / drug effects


  • Biological Products
  • RNA, Messenger
  • Recombinant Fusion Proteins
  • SMN1 protein, human
  • Survival of Motor Neuron 1 Protein
  • Zolgensma
  • DNA