Subretinal Transplantation of Embryonic Stem Cell–Derived Retinal Pigment Epithelium for the Treatment of Macular Degeneration: An Assessment at 4 Years

Abstract

Advanced macular degeneration is an important cause of vision loss in the United States with over 2 million people affected by the disease. Despite substantial progress in the development of new therapies for wet AMD, the severe visual impairment associated with geographic atrophy in dry AMD or Stargardt disease remains untreatable. Recently, two phase I/II studies involving 18 patients with these diseases have demonstrated that it is possible to safely implant human embryonic stem cell-derived RPE (hESC-RPE) in an attempt to rescue photoreceptors and visual function. The anatomical and functional results are encouraging, with more than half of treated patients experiencing sustained improvements in visual acuity and demonstrating evidence of possible cellular engraftment. However, any conclusions remain tempered by the relatively short follow-up time, lack of a formal control group, poor initial visual acuity, and small number of patients. Aside from an instance of postoperative infectious endophthalmitis, no adverse events related to the cell therapy, such as hyperproliferation, tumorigenicity, or rejection-related inflammation were noted in this initial cohort of 18 patients. These first-in-human safety studies have opened the door to future studies enrolling patients with less advanced disease, treating other diseases that result in RPE loss, employing shorter immunosuppressive regimens, and using alternative strategies for RPE transplantation such as sheets of cells with or without scaffolding to mimic Bruch's membrane. The ultimate goal of these initial safety studies is to promote continued translation of complex biological therapies into meaningful treatment strategies that may address unmet medical needs.

Integration of Subretinal Suspension Transplants of Human Embryonic Stem Cell-Derived Retinal Pigment Epithelial Cells in a Large-Eyed Model of Geographic Atrophy

“…In agreement, preliminary data from the first clinical trial on hESC-RPE showed presence of pigmented tissue at the border of the atrophic area in GA patients. 1,29 Therefore, for the suspension approach to be functionally effective, it will most likely be crucial to choose patients diagnosed in an early stage of the disease, with a relatively conserved outer retina. The large-eyed GA model presented in this study should be a valuable tool for further understanding if and when hESC-RPE-based treatments may succeed in a clinical setting.…”

Subretinal Injection: A Review on the Novel Route of Therapeutic Delivery for Vitreoretinal Diseases

“…Schwartz et al [85] reported the possibility of hESC-RPE to treat patients with Stargardt's macular dystrophy and dry AMD and provided preliminary data. Recently, 2 phase I/II studies with a length of 4 years, involving 18 patients with dry AMD or Stargardt's disease, demonstrated the possibility of safe implantation of hESC-RPE subretinally in an attempt to rescue photoreceptors and vision [86] .…”

“…In the clinical procedures described above, the subretinal injections of the hESC-RPE reported by Schwartz et al [85,86] were preformed along the site of a pars plana vitrectomy, and the injection sites were carefully chosen on the basis of optical coherence tomography results. Sites with native, albeit compromised, RPE and similarly compromised overlaying photoreceptors were thought to be the optimal injection spots for transplantation.…”

Potential of Induced Pluripotent Stem Cells (iPSCs) for Treating Age-Related Macular Degeneration (AMD)

“…The RPE is important for photoreceptor survival and function, and loss of this cell type is involved in the pathophysiology of atrophy in AMD [65]. The rationale for transplantation of RPE cells is clear and the potential for cell-based therapy has been investigated in both animals and humans [66,67,68]. …”