Functional Rescue of P23H Rhodopsin Photoreceptors by Gene Delivery

  • Marina S. GorbatyukEmail author
  • Oleg S. Gorbatyuk
  • Matthew M. LaVail
  • Jonathan H. Lin
  • William W. Hauswirth
  • Alfred S. Lewin
Conference paper
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 723)


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.


Gene delivery Gene therapy ER stress P23H rhodopsin ERG siRNA BiP/Grp78 Transgenic rats Folding 



This study was supported by FFB: TA-GT-4090-0479-UFL, TA-GT-0507-0384, by C-NP-0706-0353-UCSF, by NIH: EY020905, EY11123, EY08571, EY02162, EY01919, EY06842, EY018313, and EY020846.


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Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Marina S. Gorbatyuk
    • 1
    Email author
  • Oleg S. Gorbatyuk
    • 2
  • Matthew M. LaVail
    • 3
  • Jonathan H. Lin
    • 4
  • William W. Hauswirth
    • 5
  • Alfred S. Lewin
    • 2
  1. 1.Department of Cell Biology and AnatomyUniversity of North Texas Health Science CenterFort WorthUSA
  2. 2.Department of Molecular Genetics and MicrobiologyUniversity of FloridaGainesvilleUSA
  3. 3.Beckman Vision CenterUniversity of CaliforniaSan FranciscoUSA
  4. 4.Department of PathologyUniversity of California at San DiegoLa JollaUSA
  5. 5.Department of OphthalmologyUniversity of FloridaGainesvilleUSA

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