Translational development of human retinal progenitor cells for treatment of retinitis pigmentosa

Abstract

Purpose: Retinitis pigmentosa (RP) is an incurable blinding disease that is genetic in nature and due to the sequential degeneration of rod and then cone photoreceptors. Although RP is rare, the onset is earlier and phenotype more severe than is the case in the more prevalent condition of age-related macular degeneration (AMD). The ultimate goal of this project is transplantation of allogeneic retinal progenitor cells (RPCs) of human fetal origin to the vitreal cavity of patients with RP in order to improve visual outcome.

Methods: Human donor tissue was obtained from an approved distributor under a GTP protocol and maternal blood was screened for adventitious agents. Human RPCs were expanded and banked under GMP conditions using serum-free, xeno-free media previously developed for CNS progenitors of this type. The resulting cellular product was subjected to a wide range of tests including sterility, karyotype analysis, marker expression, freeze-thaw viability, in vitro and in vivo tumorigenesis assays, biodistribution, and in vivo dose range studies. Proof-of-concept studies were performed in immunosuppressed RCS rats.

Results: hRPCs manufactured under GMP conditions met established phenotypic and safety criteria for cells of this type. The therapeutic mechanism of action of RPCs appears to involve trophic-mediated neuroprotection of host photoreceptors. Efficacy has been demonstrated in dystrophic RCS rats at the anatomical level, as well as behaviorally and electrophysiologically. The product has been designated as an orphan drug by the FDA for treatment of RP.

Conclusions: There is much to recommend this approach, including simplicity, safety, and most of all the potential for a striking degree of stem cell-mediated efficacy in an untreatable blinding disease. Ongoing work is directed towards the completion of all IND-enabling preclinical studies and the initiation of clinical trials in RP.

Keywords: 695 retinal degenerations: cell biology • 741 transplantation • 688 retina