Developing autologous cell therapy for macular degeneration: From bench‐to‐bedside

Abstract

AbstractInduced pluripotent stem cells (iPSCs) can provide autologous and allogeneic replacement tissues, potentially for all degenerative diseases. Autologous tissues have the advantage of not requiring immune‐suppressive drugs that have deleterious side‐effects. The safety and feasibility of autologous iPSC‐based therapies has not been established. Here, we developed an autologous iPSC‐based therapy for age‐related macular degeneration (AMD), a blinding eye disease that affects over 30 million people world‐wide. AMD is caused by the progressive degeneration of retinal pigment epithelium (RPE), a monolayer tissue that maintains photoreceptor function and survival. We tissue engineered a clinical‐grade iPSC‐RPE‐patch on a biodegradable scaffold using autologous cells from AMD patients. Preclinical investigational new drug (IND)‐enabling studies performed on iRPE‐patch derived from multiple AMD patients demonstrated reproducible manufacturing, validating our manufacturing process – a key requirement for an autologous phase I trial. Functional validation of clinical‐grade iRPE‐patches allowed determination of tissue barrier resistance, purity of RPE cells, and RPE cell shape metrics as key critical quality attributes now used as clinical product release criteria. Preclinical animal studies performed in immune‐compromised rats confirmed safety of the auto‐iRPE‐patch and efficacy studies performed in a porcine laser‐induced RPE injury model that mimics AMD‐like eye conditions demonstrated integration and functionality of RPE patches. A phase I/IIa IND‐application for an auto‐iRPE‐patch to treat AMD was recently cleared by the FDA. This Phase I/IIa clinical trial will test safety, feasibility, and integration of an auto‐iRPE‐patch in twelve advanced AMD patients. The trial is currently being run as a single site study at the NIH and targets patient enrollment in two cohorts – with visual acuity between 20/100 to 20/500 and between 20/80 to 20/500.