Long-term and age-dependent restoration of visual function in a mouse model of CNGB3-associated achromatopsia following gene therapy

Hum Mol Genet. 2011 Aug 15;20(16):3161-75. doi: 10.1093/hmg/ddr218. Epub 2011 May 15.

Abstract

Mutations in the CNGB3 gene account for >50% of all known cases of achromatopsia. Although of early onset, its stationary character and the potential for rapid assessment of restoration of retinal function following therapy renders achromatopsia a very attractive candidate for gene therapy. Here we tested the efficacy of an rAAV2/8 vector containing a human cone arrestin promoter and a human CNGB3 cDNA in CNGB3 deficient mice. Following subretinal delivery of the vector, CNGB3 was detected in both M- and S-cones and resulted in increased levels of CNGA3, increased cone density and survival, improved cone outer segment structure and normal subcellular compartmentalization of cone opsins. Therapy also resulted in long-term improvement of retinal function, with restoration of cone ERG amplitudes of up to 90% of wild-type and a significant improvement in visual acuity. Remarkably, successful restoration of cone function was observed even when treatment was initiated at 6 months of age; however, restoration of normal visual acuity was only possible in younger animals (e.g. 2-4 weeks old). This study represents achievement of the most substantial restoration of visual function reported to date in an animal model of achromatopsia using a human gene construct, which has the potential to be utilized in clinical trials.

Publication types

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

MeSH terms

  • Aging / pathology*
  • Animals
  • Arrestins / genetics
  • Cell Survival
  • Color Vision Defects / pathology
  • Color Vision Defects / physiopathology*
  • Color Vision Defects / therapy*
  • Cyclic Nucleotide-Gated Cation Channels / deficiency
  • Cyclic Nucleotide-Gated Cation Channels / genetics*
  • Cyclic Nucleotide-Gated Cation Channels / metabolism
  • Cyclic Nucleotide-Gated Cation Channels / therapeutic use*
  • Disease Models, Animal
  • Gene Transfer Techniques
  • Genetic Therapy*
  • Genetic Vectors / genetics
  • Humans
  • Injections
  • Mice
  • Mice, Transgenic
  • Opsins / metabolism
  • Organ Specificity
  • Promoter Regions, Genetic / genetics
  • Protein Transport
  • Retina / metabolism
  • Retina / pathology
  • Retinal Cone Photoreceptor Cells / pathology
  • Retinal Cone Photoreceptor Cells / ultrastructure
  • Time Factors
  • Vision, Ocular / physiology*
  • Visual Acuity / physiology

Substances

  • Arrestins
  • CNGB3 protein, human
  • CNGB3 protein, mouse
  • Cyclic Nucleotide-Gated Cation Channels
  • Opsins