Interim analysis of two ongoing phase 1/2 trials of human embryonic stem cell (hESC) grafting into the subretinal space provides the first human use data on the medium- to long-term safety, graft survival, and biological activity of tissue derived from pluripotent stem cells.1
One trial included nine patients with atrophic age-related macular degeneration (dry AMD) and the other, nine patients with Stargardt macular dystrophy. Each patient received a transplant, in the worse eye, of hESC-derived retinal pigment epithelium placed between the compromised central macular tissue and fairly normal peripheral tissue. At baseline, all patients had very limited vision due to advanced disease.
Treatment appears safe. After 37 months, none of the concerns commonly raised about use of hESCs— tumor formation, immune reactions, or cell differentiation into unwanted cell types—materialized in these trials, and no serious safety events related to the transplanted cells occurred.
Of the 18 total patients in both groups, 13 showed favorable increases in subretinal pigmentation, the area of which increased in density and size over time.
Surprise visual benefits. Though no improvement was expected in the phase 1 patients, visual acuity and function were tested as part of the safety evaluation. Surprisingly, more than half of the treated eyes—but none of the untreated eyes—showed improved vision. Eight patients’ visual acuity increased by at least 15 letters within one year of surgery. Participants also noted improvement in their general vision, near and distance activities, and peripheral vision as measured with the National Eye Institute Visual Function Questionnaire 25 subscales.
“We need to take these results with a grain of salt,” said coauthor Carl D. Regillo, MD, “as it’s very difficult to accurately assess visual function in patients who have such limited vision. Still, evidence of any improvement is encouraging.” Dr. Regillo is leading the trials at Wills Eye Hospital, where he is director of the retina service.
Looking ahead. “We used four different cell doses in the phase 1 trials,” he said. “In phase 2 we’ll push the dose a bit higher and implant cells in eyes with less advanced disease in hopes of seeing a more definitive favorable visual effect.”
At the time of transplant, hESC-derived RPE cells are somewhat immature, and Dr. Regillo noted that their potential ability to mature within the retina may offer vital advantages. For instance, the tissue may be less immunogenic and more likely to survive and function than mature tissue. There may be other benefits, as well: Cell differentiation can be controlled to ensure optimum tissue safety and functionality before transplantation; cell lines can be tested to eliminate disease-associated genetic abnormalities; and since hESC proliferate continuously, they offer a virtually unlimited supply of “starter” cells.
Positive RPE trial safety results bolster the hope that hESC could be used in other diseased tissues, for example, to regenerate heart cells after myocardial infarction, replace islet cell in patients with diabetes, or replace neural cells in ischemic stroke, Parkinson disease, or Alzheimer disease.
1 Schwartz SD et al. Lancet. Published online Oct.15, 2014. doi:10.1016/S01406736(14)61376-3.
Dr. Regillo receives research funding from Ocata Therapeutics.
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