One-year follow-up of transgene expression by integrase-defective lentiviral vectors and their therapeutic potential in spinocerebellar ataxia model mice

Gene Ther. 2014 Sep;21(9):820-7. doi: 10.1038/gt.2014.60. Epub 2014 Jul 3.


We examined integrase-defective lentiviral vectors (IDLVs) with a mutant (D64V) integrase in terms of their residual integration capability, the levels and duration of transgene expression and their therapeutic potential in comparison to wild-type lentiviral vectors (WTLVs) with a wild-type integrase gene. Compared with WTLVs, the IDLV-mediated proviral integration into host-cell chromosomes was approximately 1/3850 in HeLa cells and approximately 1/111 in mouse cerebellar neurons in vivo. At 2 months, transgene expression by IDLVs in the mouse cerebellum was comparable to that by WTLVs, but then significantly decreased. The mRNA levels at 6 and 12 months after injection in IDLV-infected cerebella were approximately 26% and 5%, respectively, of the mRNA levels in WTLV-injected cerebella. To examine the therapeutic potential, IDLVs or WTLVs expressing a molecule that enhances the ubiquitin-proteasome pathway were injected into the cerebella of spinocerebellar ataxia type 3 model mice (SCA3 mice). IDLV-injected SCA3 mice showed a significantly improved rotarod performance even at 1 year after-injection. Immunohistochemistry at 1 year after injection showed a drastic reduction of mutant aggregates in Purkinje cellsfrom IDLV-injected, as well as WTLV-injected, SCA3 mice. Our results suggest that because of the substantially reduced risk of insertional mutagenesis, IDLVs are safer and potentially effective as gene therapy vectors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cerebellum / metabolism*
  • Cerebellum / virology
  • Disease Models, Animal
  • Follow-Up Studies
  • GTP Phosphohydrolases / genetics
  • GTP Phosphohydrolases / metabolism
  • Genetic Vectors / administration & dosage
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Integrases / genetics*
  • Integrases / metabolism
  • Lentivirus / genetics*
  • Mice
  • Mutation
  • Rotarod Performance Test
  • Signal Transduction
  • Spinocerebellar Ataxias / therapy*
  • Transgenes


  • Integrases
  • CRAG protein, mouse
  • GTP Phosphohydrolases