Autologous transplantation of genetically modified induced pluripotent stem cells for rescue of autosomal dominant retinal disorders

The National Eye Institute, part of the Department of Health and Human Services National Institutes of Health, awarded The Trustees of Columbia University in the City of New York $100,228 on December 1, 2026, under the Vision Research program (CFDA 93.867).

The recipient will conduct preclinical research on autologous transplantation of genetically modified induced pluripotent stem cells (iPSCs) to treat autosomal dominant retinal disorders, specifically RPE65 D477G mutations causing retinitis pigmentosa. Work includes CRISPR-based in vitro repair of patient-derived iPSC-derived retinal pigment epithelium (IRPE), validation of functional repair and genomic integrity through whole-genome sequencing, assessment of transplanted IRPE integration and vision rescue in a retinitis pigmentosa mouse model, and safety and tumorigenicity evaluation through long-term analysis. The research addresses a gap in therapeutic strategies for autosomal dominant disorders, which require removal of gain-of-function alleles through precise genomic repair rather than gene supplementation approaches already tested in FDA-approved trials for autosomal recessive conditions.

Performance runs through April 29, 2029, with work conducted in New York, New York.

Abstract

Gene therapy for the treatment of autosomal recessive disorders by supplementation with wild-type (WT) copies of the affected gene has been tested in FDA-approved trials. However, strategies for treating autosomal dominant (ad) disorders, which require the removal of a gain-of-function allele through precise genomic repair, have been tested preclinically but have not been evaluated in human subjects. In this proposal, we aim to overcome long standing obstacles to the treatment of RPE65 D477G dominant disorders using autologous induced pluripotent stem cell (ipsc) transplantation. The central hypothesis is that patient-derived ipsc RPE (irpe) grafts repaired by crispr in vitro are a therapeutic option to treat RPE disorders. We will use allele- specific crispr-edited RPE65 D477G irpe to confirm functional repair and differentiation in aim 1A, and the genomic integrity will be validated via WGS in aim 1B. The therapeutic potential of irpe transplantation will be assessed when transplanted into a retinitis pigmentosa preclinical mouse model, RPE65RD12; prdcscid. By comparing phenotypes induced by transplantation of repaired irpe VS. Control RPE lines, we will assess whether in vitro crispr-repaired irpe halts disease development in the context of an ad disorder. Our objective is to identify ways to leverage patient stem cells as a tissue source for regenerative medicine. Aim 2 will determine whether patient irpe repaired in vitro functionally integrate into the retinal circuitry of live mice and rescue vision. Lastly, aim 3 will determine whether transplanted irpe is safe and nontumorigenic through long-term analysis.