In vivo gene editing via homology-independent targeted integration for adrenoleukodystrophy treatment

Mol Ther. 2022 Jan 5;30(1):119-129. doi: 10.1016/j.ymthe.2021.05.022. Epub 2021 May 29.

Abstract

Adrenoleukodystrophy (ALD) is caused by various pathogenic mutations in the X-linked ABCD1 gene, which lead to metabolically abnormal accumulations of very long-chain fatty acids in many organs. However, curative treatment of ALD has not yet been achieved. To treat ALD, we applied two different gene-editing strategies, base editing and homology-independent targeted integration (HITI), in ALD patient-derived fibroblasts. Next, we performed in vivo HITI-mediated gene editing using AAV9 vectors delivered via intravenous administration in the ALD model mice. We found that the ABCD1 mRNA level was significantly increased in HITI-treated mice, and the plasma levels of C24:0-LysoPC (lysophosphatidylcholine) and C26:0-LysoPC, sensitive diagnostic markers for ALD, were significantly reduced. These results suggest that HITI-mediated mutant gene rescue could be a promising therapeutic strategy for human ALD treatment.

Keywords: ABCD1; CRISPR; adrenoleukodystrophy; base editing; gene therapy; genome editing; homology-independent targeted integration; very long-chain fatty acid.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily D, Member 1 / genetics
  • ATP-Binding Cassette Transporters / genetics
  • Adrenoleukodystrophy* / diagnosis
  • Adrenoleukodystrophy* / genetics
  • Adrenoleukodystrophy* / therapy
  • Animals
  • Fatty Acids
  • Gene Editing
  • Genetic Therapy
  • Humans
  • Mice

Substances

  • ATP Binding Cassette Transporter, Subfamily D, Member 1
  • ATP-Binding Cassette Transporters
  • Abcd1 protein, mouse
  • Fatty Acids