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. 2012:723:191-7.
doi: 10.1007/978-1-4614-0631-0_26.

Functional rescue of P23H rhodopsin photoreceptors by gene delivery

Marina S Gorbatyuk  1 , Oleg S Gorbatyuk, Matthew M LaVail, Jonathan H Lin, William W Hauswirth, Alfred S Lewin
Affiliations

Functional rescue of P23H rhodopsin photoreceptors by gene delivery

Marina S Gorbatyuk et al. Adv Exp Med Biol. 2012.

Abstract

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 over-expression 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 pro-survival 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 over-expression 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.

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Figures

Fig. XX.1
Fig. XX.1
Over-expression of mouse RHO301 leads to functional preservation of P23H RHO-3 photoreceptors.
Fig. XX.2
Fig. XX.2
Over-expression of human BiP/GRP78 protein leads to steady therapeutic effect over 6 months measured A: by scotopic ERG and B: by Histological analysis.
Fig. XX.3
Fig. XX.3
Immunostaining of HeLa cells co-transfected with wild-type RHO, P23H RHO, and BiP-Flag. A: Immunostaining analysis demonstrated the localization of wild-type RHO to the cell membrane and B: P23H RHO retained within the ER (green). C: Over-expression of BiP-Flag (red) did not affect the trafficking of WT RHO and D: did not promote the distribution of P23H RHO to the cytoplasm.
Fig. XX.4
Fig. XX.4
Over-expression of HSF1 in P23H RHO-3 photoreceptors leads to sustained preservation of a- and b-wave amplitudes of the scotopic ERG.
See this image and copyright information in PMC

References

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