Brydon Elizabeth M, Bronstein Revital, Buskin Adriana, Lako Majlinda, Pierce Eric A, Fernandez-Godino Rosario
Department of Ophthalmology, Ocular Genomics Institute, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA.
Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK.
Mol Ther Methods Clin Dev. 2019 Nov 11;15:392-402. doi: 10.1016/j.omtm.2019.10.014. eCollection 2019 Dec 13.
Retinitis pigmentosa (RP) is the most common form of inherited vision loss and is characterized by degeneration of retinal photoreceptor cells and the retinal pigment epithelium (RPE). Mutations in pre-mRNA processing factor 31 () cause dominant RP via haploinsufficiency with incomplete penetrance. There is good evidence that the diverse severity of this disease is a result of differing levels of expression of the wild-type allele among patients. Thus, we hypothesize that -related RP will be amenable to treatment by adeno-associated virus (AAV)-mediated gene augmentation therapy. To test this hypothesis, we used induced pluripotent stem cells (iPSCs) with mutations in and differentiated them into RPE cells. The mutant iPSC-RPE cells recapitulate the cellular phenotype associated with the PRPF31 pathology, including defective cell structure, diminished phagocytic function, defects in ciliogenesis, and compromised barrier function. Treatment of the mutant iPSC-RPE cells with AAV- restored normal phagocytosis and cilia formation, and it partially restored structure and barrier function. These results suggest that AAV-based gene therapy targeting RPE cells holds therapeutic promise for patients with -related RP.
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