Artificial microRNA suppresses C9ORF72 variants and decreases toxic dipeptide repeat proteins in vivo

Gene Ther. 2024 Mar;31(3-4):105-118. doi: 10.1038/s41434-023-00418-w. Epub 2023 Sep 26.

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that affects motor neurons, causing progressive muscle weakness and respiratory failure. The presence of an expanded hexanucleotide repeat in chromosome 9 open reading frame 72 (C9ORF72) is the most frequent mutation causing familial ALS and frontotemporal dementia (FTD). To determine if suppressing expression of C9ORF72 gene products can reduce toxicity, we designed a set of artificial microRNAs (amiRNA) targeting the human C9ORF72 gene. Here we report that an AAV9-mediated amiRNA significantly suppresses expression of the C9ORF72 mRNA, protein, and toxic dipeptide repeat proteins generated by the expanded repeat in the brain and spinal cord of C9ORF72 transgenic mice.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Amyotrophic Lateral Sclerosis* / genetics
  • Amyotrophic Lateral Sclerosis* / therapy
  • Animals
  • C9orf72 Protein / genetics
  • C9orf72 Protein / metabolism
  • DNA Repeat Expansion / genetics
  • Dipeptides / genetics
  • Dipeptides / metabolism
  • Humans
  • Mice
  • Mice, Transgenic
  • MicroRNAs* / genetics
  • Neurodegenerative Diseases*
  • Proteins / genetics
  • Proteins / metabolism

Substances

  • C9orf72 Protein
  • Dipeptides
  • MicroRNAs
  • Proteins
  • C9orf72 protein, human