Gene therapy restores vision and delays degeneration in the CNGB1(-/-) mouse model of retinitis pigmentosa

Hum Mol Genet. 2012 Oct 15;21(20):4486-96. doi: 10.1093/hmg/dds290. Epub 2012 Jul 16.

Abstract

Retinitis pigmentosa (RP) is a group of genetically heterogeneous, severe retinal diseases commonly leading to legal blindness. Mutations in the CNGB1a subunit of the rod cyclic nucleotide-gated (CNG) channel have been found to cause RP in patients. Here, we demonstrate the efficacy of gene therapy as a potential treatment for RP by means of recombinant adeno-associated viral (AAV) vectors in the CNGB1 knockout (CNGB1(-/-)) mouse model. To enable efficient packaging and rod-specific expression of the relatively large CNGB1a cDNA (~4 kb), we used an AAV expression cassette with a short rod-specific promoter and short regulatory elements. After injection of therapeutic AAVs into the subretinal space of 2-week-old CNGB1(-/-) mice, we assessed the restoration of the visual system by analyzing (i) CNG channel expression and localization, (ii) retinal function and morphology and (iii) vision-guided behavior. We found that the treatment not only led to expression of full-length CNGB1a, but also restored normal levels of the previously degraded CNGA1 subunit of the rod CNG channel. Both proteins co-localized in rod outer segments and formed regular CNG channel complexes within the treated area of the CNGB1(-/-) retina, leading to significant morphological preservation and a delay of retinal degeneration. In the electroretinographic analysis, we also observed restoration of rod-driven light responses. Finally, treated CNGB1(-/-) mice performed significantly better than untreated mice in a rod-dependent vision-guided behavior test. In summary, this work provides a proof-of-concept for the treatment of rod channelopathy-associated RP by AAV-mediated gene replacement.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cyclic Nucleotide-Gated Cation Channels / genetics*
  • Cyclic Nucleotide-Gated Cation Channels / metabolism
  • DNA, Complementary / genetics
  • DNA, Complementary / metabolism
  • Dependovirus / genetics
  • Dependovirus / metabolism
  • Disease Models, Animal
  • Electroretinography
  • Genetic Therapy
  • Genetic Vectors / genetics
  • Genetic Vectors / metabolism
  • Mice
  • Mice, Knockout
  • Nerve Tissue Proteins / genetics*
  • Nerve Tissue Proteins / metabolism
  • Retinal Degeneration / genetics
  • Retinal Degeneration / therapy
  • Retinitis Pigmentosa / genetics*
  • Retinitis Pigmentosa / metabolism
  • Retinitis Pigmentosa / therapy*
  • Rhodopsin / genetics
  • Rhodopsin / metabolism
  • Rod Cell Outer Segment / metabolism

Substances

  • Cngb1 protein, mouse
  • Cyclic Nucleotide-Gated Cation Channels
  • DNA, Complementary
  • Nerve Tissue Proteins
  • Rhodopsin