Restoration of photoreceptor ultrastructure and function in retinal degeneration slow mice by gene therapy
| Autor: | MB Reichel, G.–M. Sarra, Mahesh de Alwis, Sascha Fauser, Peter M. G. Munro, Adrian J. Thrasher, James W B Bainbridge, Shomi S. Bhattacharya, Christine Kinnon, Robin R. Ali, C Stephens, David M. Hunt |
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| Rok vydání: | 2000 |
| Předmět: |
Retinal degeneration
Rhodopsin genetic structures Peripherins Mice Transgenic Nerve Tissue Proteins Cell Line Mice Intermediate Filament Proteins Retinal Rod Photoreceptor Cells Cricetinae Retinitis pigmentosa Genetics medicine Animals Peripherin 2 Membrane Glycoproteins biology Genetic transfer Peripherin Genetic Therapy medicine.disease Null allele Photoreceptor outer segment eye diseases Cell biology Disease Models Animal Mice Inbred CBA Retinal Cone Photoreceptor Cells biology.protein sense organs Retinitis Pigmentosa |
| Zdroj: | Nature Genetics. 25:306-310 |
| ISSN: | 1546-1718 1061-4036 |
| DOI: | 10.1038/77068 |
| Popis: | The gene Prph2 encodes a photoreceptor-specific membrane glycoprotein1, 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 capture3. Mutations in Prph2 have been shown to result in a variety of photoreceptor dystrophies, including autosomal dominant retinitis pigmentosa and macular dystrophy4. 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 segments5, downregulation of rhodopsin6,7 and apoptotic loss of photoreceptor cells8,9. The electroretinograms (ERGs) of Prph2Rd2/Rd2 mice have greatly diminished a-wave and b-wave amplitudes, which decline to virtually undetectable concentrations by two months10. 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. |
| Databáze: | OpenAIRE |
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