Restoration of photoreceptor ultrastructure and function in retinal degeneration slow mice by gene therapy

Nat Genet. 2000 Jul;25(3):306-10. doi: 10.1038/77068.


The gene Prph2 encodes a photoreceptor-specific membrane glycoprotein, peripherin-2 (also known as peripherin/rds), which is inserted into the rims of photoreceptor outer segment discs in a complex with rom-1 (ref. 2). The complex is necessary for the stabilization of the discs, which are renewed constantly throughout life, and which contain the visual pigments necessary for photon capture. Mutations in Prph2 have been shown to result in a variety of photoreceptor dystrophies, including autosomal dominant retinitis pigmentosa and macular dystrophy. A common feature of these diseases is the loss of photoreceptor function, also seen in the retinal degeneration slow (rds or Prph2 Rd2/Rd2) mouse, which is homozygous for a null mutation in Prph2. It is characterized by a complete failure to develop photoreceptor discs and outer segments, downregulation of rhodopsin and apoptotic loss of photoreceptor cells. The electroretinograms (ERGs) of Prph2Rd2/Rd2 mice have greatly diminished a-wave and b-wave amplitudes, which decline to virtually undetectable concentrations by two months. Subretinal injection of recombinant adeno-associated virus (AAV) encoding a Prph2 transgene results in stable generation of outer segment structures and formation of new stacks of discs containing both perpherin-2 and rhodopsin, which in many cases are morphologically similar to normal outer segments. Moreover, the re-establishment of the structural integrity of the photoreceptor layer also results in electrophysiological correction. These studies demonstrate for the first time that a complex ultrastructural cell defect can be corrected both morphologically and functionally by in vivo gene transfer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Cricetinae
  • Disease Models, Animal
  • Genetic Therapy* / methods
  • Intermediate Filament Proteins / genetics
  • Intermediate Filament Proteins / physiology*
  • Membrane Glycoproteins*
  • Mice
  • Mice, Inbred CBA
  • Mice, Transgenic
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / physiology*
  • Peripherins
  • Retinal Cone Photoreceptor Cells / metabolism
  • Retinal Cone Photoreceptor Cells / physiopathology*
  • Retinal Cone Photoreceptor Cells / ultrastructure
  • Retinal Rod Photoreceptor Cells / metabolism
  • Retinal Rod Photoreceptor Cells / physiopathology*
  • Retinal Rod Photoreceptor Cells / ultrastructure
  • Retinitis Pigmentosa / genetics
  • Retinitis Pigmentosa / metabolism
  • Retinitis Pigmentosa / physiopathology*
  • Retinitis Pigmentosa / therapy*
  • Rhodopsin / metabolism


  • Intermediate Filament Proteins
  • Membrane Glycoproteins
  • Nerve Tissue Proteins
  • Peripherins
  • Prph2 protein, mouse
  • Rhodopsin