Functional rescue of P23H rhodopsin photoreceptors by gene delivery

Academic Article


  • The mechanism of autosomal dominant retinitis pigmentosa (ADRP) caused by the P23H mutation in rhodopsin is tightly associated with misfolded rhodopsin (RHO) which causes endoplasmic reticulum overload (ER stress), activates the unfolded protein response (UPR), and triggers apoptosis. In efforts to create a therapy for ADRP caused by the P23H mutation, we have explored different approaches leading to survival of photoreceptor (PR) cells. The direct approach involves the modulation of the level of wild-type RHO, while the indirect approach involves reprogramming the UPR and increasing the expression of heat shock proteins (HSPs). Taking the direct approach, we found that overexpression of wild-type RHO rescues scotopic ERG responses partially. However, greater therapeutic effects were obtained by manipulation of the UPR in P23H RHO rat PRs treated with the endoplasmic reticulum protein BiP/Grp78. In vitro study revealed that the prosurvival effect of Bip gene was not associated with its function as a molecular chaperone, but rather with its regulation of the UPR. Another indirect approach was the overexpression of the Hsf-1 gene, a transcriptional regulator of the heat shock response. AAV-delivery of Hsf-1 resulted in an increase of scotopic ERG amplitudes by over 35%. Taken together, these data suggest viable therapeutic treatments for ADRP. © 2012 Springer Science+Business Media, LLC.
  • Authors

    Digital Object Identifier (doi)

    Author List

  • Gorbatyuk MS; Gorbatyuk OS; LaVail MM; Lin JH; Hauswirth WW; Lewin AS
  • Start Page

  • 191
  • End Page

  • 197
  • Volume

  • 723