Gene therapy induces pigmentation in induced pluripotent stem cell-derived retinal pigment epithelium of OCA1A patients and albino rat eye

Oculocutaneous albinism type 1A (OCA1A), the most severe and prevalent form of albinism, is caused by recessive mutations in the TYROSINASE gene. We provide proof-of-principle of an effective gene therapy-based strategy for future human application in OCA1A patients. Here, we show that an AAV-based TYROSINASE gene delivery under the control of human BESTROPHIN promoter VMD2 can successfully induce pigmentation in human retinal pigment epithelium (RPE) monolayer tissue, derived from OCA1A patients, via induced pluripotent stem cells. Pigmentation was induced without significantly compromising the RPE monolayer tissue integrity, apical-basal polarization, cellular morphology, or functionally relevant gene expression patterns. This human RPE-specific construct was able to induce pigmentation in albino rat RPE and choroid when delivered into eyes via suprachoroidal injection. Our strategy can be potentially employed to not only induce pigmentation but also efficiently deliver other target genes, without significantly compromising monolayer tissue integrity and viability of human RPE, a prime gene therapy target tissue for many degenerative disorders affecting vision.