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

The gene Prph2 encodes a photoreceptor-specific membrane glycoprotein(1), p eripherin-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 necessar y for photon capture(3). Mutations in Prph2 have been shown to result in a variety of photoreceptor dystrophies, including autosomal dominant retiniti s pigmentosa and macular dystrophy(4). A common feature of these diseases i s the loss of photoreceptor function, also seen in the retinal degeneration slow (rds or prph2(Rd2/Rd2)) mouse, which is homozygous for a null mutatio n in Prph2. It is characterized by a complete failure to develop photorecep tor discs and outer segments(5), downregulation of rhodopsin(6,7) and apopt otic loss of photoreceptor cells(8,9). The electroretinograms (ERGs) of Prp h2(Rd2/Rd2) mice have greatly diminished a-wave and b-wave amplitudes, whic h decline to virtually undetectable concentrations by two months(10). Subre tinal injection of recombinant adeno-associated virus (AAV) encoding a Prph 2 transgene results in stable generation of outer segment structures and fo rmation of new stacks of discs containing both perpherin-2 and rhodopsin, w hich in many cases are morphologically similar to normal outer segments. Mo reover, the re-establishment of the structural integrity of the photorecept or layer also results in electrophysiological correction. These studies dem onstrate for the first time that a complex ultrastructural cell defect can be corrected both morphologically and functionally by in vivo gene transfer .