Human Embryonic Stem Cells Could Safely Treat Eye Diseases, Research Suggests

Two important early potential hESC applications are the use of RPE for the treatment of age-related macular degeneration and Stargardt disease, an untreatable form of eye disease that leads to early-onset blindness.

The research, which appears online ahead of print in the journal Stem Cells, shows long-term functional rescue using hESC-derived cells in both the RCS rat and Elov14 mouse, animal models of retinal degeneration and Stargardt, respectively. The cells survived transplantation for prolonged periods (>220 days) and sustained visual function without tumor formation or untoward pathological reactions. Near-normal functional rescue was also achieved in the 'Stargardt' mouse. To further address safety concerns, a study was carried out in the NIH III immune deficient mouse model. Long-term data (spanning the life of the animals) revealed no evidence of tumor formation after transplantation.

"We're delighted with these results," said Robert Lanza, Chief Scientific Officer at ACT, and co-senior author of the study. "Everything looks great so far. Based on these and other studies, we're on schedule to file an IND with the FDA to begin human clinical trials sometime in the next 3 or 4 months. Barring any surprises, Stargardt disease and macular degeneration are likely to be the next two clinical applications of ES technology.

Since their discovery over a decade ago, hESCs have been considered a promising source of replacement cells for clinical studies. However, problems continue to plague clinical translation, including the risk of teratoma formation and the need for powerful drugs to overcome the problem of immune rejection. Until induced pluripotent stem (iPS) cell technology is further developed, hESC-derived therapies are likely to be limited to immunoprivileged sites such as the central nervous system and the eye. In the retina, compromised RPE function can lead to deteriorated vision and photoreceptor loss in both age-related macular degeneration and other forms of degenerative eye disease. In this study, the cell manufacturing and documentation process complied with the guidelines set forth by the FDA, collectively referred to as Good Manufacturing (GMP) and Good Tissue Practices.

The cells were prepared for clinical application and tested for safety and efficacy in several different in vitro and animal models in collaboration with researchers at the Casey Eye Institute at Oregon Health and Science University (OHSU) headed by Dr. Raymond Lund. Dr. Lund, co-senior author of the paper, is widely considered one of the world's foremost experts in retinal cell physiology and vision restoration. RPE from different hESC lines were tested in the RCS rat, an animal in which vision deteriorates over several months due to an RPE functional defect.

The studies focused on longevity of effect, dosing effect, and evidence of untoward pathology. After three months, the treated retina had 5-6 layers of photoreceptors, whereas the untreated animals only had a single layer of cells remaining (they were essentially blind). Based on these data, a cell batch was chosen for a GLP safety study using the NIH III mouse model, an immune deficient animal model. Importantly, we also showed that vision can be rescued in a mouse model of Stargardt's disease, which is a form of early-onset macular dystrophy that leads to blindness despite an intact Bruch's membrane (critical for RPE cell attachment and potential clinical efficacy).

"We have worked with Dr. Lund and his team for over three years investigating the safety and efficacy of our RPE cell therapy," stated William M. Caldwell IV, Chairman and CEO of ACTC. "We are now completing the finishing touches to seek FDA approval to conduct human clinical trials with a cell therapy that may be able to address many of the 200 plus known retinal diseases."

The researchers of the paper from Advanced Cell Technology, collaborated with scientists from Casey Eye Institute at the Oregon Health & Science University, Portland, Oregon. The paper's other authors are Bin Lu (co-equal first author), Shaomei Wang (co-equal first author), Sergej Girman, and Peter Francis at OHSU; and Christopher Malcuit (co-equal first author) and Linda Lemieux of ACT.