XIAP Protection of Photoreceptors in Animal Models of Retinitis Pigmentosa

Abstract

BackgroundRetinitis pigmentosa (RP) is a blinding genetic disorder that is caused by the death of photoreceptors in the outer nuclear layer of the retina. To date, 39 different genetic loci have been associated with the disease, and 28 mutated genes have been identified. Despite the complexity of the underlying genetic basis for RP, the final common pathway is photoreceptor cell death via apoptosis.Methodology/Principal FindingsIn this study, P23H and S334ter rhodopsin transgenic rat models of RP were used to test the neuroprotective effects of anti-apoptotic gene therapy. Adeno-associated viruses (AAV) carrying the X-linked inhibitor of apoptosis (XIAP) or green fluorescent protein (GFP) were delivered subretinally into the eye of transgenic rat pups. Histological and functional measures were used to assess neuroprotection. XIAP is known to block apoptosis by inhibiting the action of caspases-3, -7 and -9. The results show that XIAP gene therapy provides long-term neuroprotection of photoreceptors at both structural and functional levels.Conclusions/SignificanceOur gene therapy strategy targets the apoptotic cascade, which is the final common pathway in all forms of retinitis pigmentosa. This strategy holds great promise for the treatment of RP, as it allows for the broad protection of photoreceptors, regardless of the initial disease causing mutation.

MAPK1 is required for establishing the pattern of cell proliferation and for cell survival during lens development

“…4G,H), which could be responsible for the increased apoptosis in this region in Mapk1 CKO lenses. Other apoptosis-regulatory proteins, such as p53 (TRP53 -Mouse Genome Informatics) (Pan and Griep, 1995) and the anti-apoptotic protein XIAP (XAF1 -Mouse Genome Informatics) (Leonard et al, 2007), were also examined, but their expression patterns were not discernably altered in Mapk1 CKO lenses (supplementary material Fig. S3A-D).…”

Restoration of visual function in P23H rhodopsin transgenic rats by gene delivery of BiP/Grp78

“…In cultured cells, P23H opsin is retained in the endoplasmic reticulum (ER) unlike wild-type rhodopsin, which is glycosylated and transported to the plasma membrane (7). The ER-retention of P23H opsin can induce the unfolded protein response (UPR) and later apoptosis (3,(8)(9)(10). However, P23H opsin is subject to degradation by the ubiquitin-proteosome system (UPS).…”

XIAP inhibition of β-cell apoptosis reduces the number of islets required to restore euglycemia in a syngeneic islet transplantation model

“…While our findings point to the therapeutic potential of XIAP to enhance islet transplant success, our data also emphasize the importance of focusing on less toxic means of gene and protein delivery. Potential alternatives include adeno-associated viral vectors and protein-based therapy as, for example, in the subretinal delivery of XIAP using an AAV to protect photoreceptors in models of retinitis pigmentosa, 34 or the delivery of XIAP using proteintransduction domains, which has been shown to be effective in a model of ischemic cell death of neurons. 18 with 100 XIAP-transduced islets per recipient maintained euglycemia until the study was terminated at up to ten weeks posttransplantation, indicating that prolonged glucose homeostasis can be obtained with a suboptimal islet dose.…”