Retinitis pigmentosa therapy with human embryonic stem cell- and induced pluripotent stem cell-derived photoreceptor progenitors

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 DESCRIPTION (provided by applicant): Advanced Cell Technology, Inc., (ACT) is a clinical stage biotechnology company focused on the development and commercialization of regenerative medicine and cell therapy technology. The company's most advanced products are in pioneering clinical trials for the treatment of a variety of eye-related debilitating diseases. he overall objective of this SBIR Phase I application is to extend previous studies and provide proof-of-concept that human pluripotent stem cell (PSC)-derived photoreceptor progenitors (PSC-PhRPs) are able to prevent progression of retinitis pigmentosa (RP) by transplantation of PhRPs derived from human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs) using a rat model of RP. Investigations will determine whether these grafted PSC-PhRPs will promote survival of host photoreceptors and differentiate into mature photoreceptors, maintain retinal connections, preserve vision, and rationalize further development of PhRP cell-based approaches for RP therapy. Retinal degenerative diseases such as RP, age-related macular degeneration, and rod/con dystrophies are characterized by loss of photoreceptor cells resulting in permanent loss of vision and often blindness; currently no curative therapy exists. These conditions exert extensive societal burdens on quality-of-life, productivity, and health- care costs, and thus an urgent need exists to develop strategies for retinal survival, repair, and replacement to combat RP and other degenerative diseases of the retina. Recent animal studies have shown that photoreceptor cell replacement is a promising therapeutic strategy for retinal degeneration, although robust cell integration and recovery of visual function has yet to be achieved. Impediments to progress in the field include a limited supply of donor cells and questionable cell purity. In order to overcome these barriers ACT has developed a unique method for robust differentiation of human PSCs into pure, renewable populations of retinal photoreceptor cells, successfully using multiple hESC and iPSC lines as starting material. In initial studies ACT has demonstrated that these PSC-PhRPs are able to further differentiate in vitro and form mature photoreceptors expressing rhodopsin and opsin and when transplanted into the vitreous of RCS rats differentiate into mature rod photoreceptors expressing rhodopsin and recoverin. Additional preliminary studies in end-stage retinal degenerated mice demonstrated that PSC-PhRPs migrated and integrated into the outer nuclear layer and were therapeutically active in improving optokinetic responses. In this proposal these promising studies will be extended to determine whether ACT's human PSC-PhRPs when grafted into retinas of RP rats are able to protect and rescue photoreceptors at an early stage of disease to limit progression of degeneration and whether they are also able to replace degenerated photoreceptors in late stage disease to restore visual function. If successful, IND-enabling studies will initiate in a Phase II program toward eventual clinical trial.