Stem cell implant study

Human stem-cell-derived RPE transplants show good safety with hints of functional improvement

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Early analysis from a study of human embryonic stem cell (hESC)-derived retinal pigmented epithelium (RPE) implantation suggests the procedure is well tolerated in patients with dry AMD, with some indication of structural retinal improvement, according to Eyal Banin MD, PhD, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. Dr Banin’s group, in collaboration with Dr Benjamin Reubinoff from Hadassah, developed a xeno-free, directed differentiation protocol for derivation of RPE cells from hESCs in-vitro. The proprietary product, called OpRegen, was further developed and carried through the translational phases by CellCure, Ltd., (a subsidiary of BioTime, Inc.) and is now being tested in an FDA-approved Phase I/IIa clinical trial in Israel and in the USA (NCT02286089). Dr Banin presented information from the first nine patients with advanced dry AMD and geographic atrophy (GA) who received a subretinal injection of Opregen cells in suspension at the Association for Research in Vision and Ophthalmology 2018 Annual Meeting, in Honolulu, Hawaii. All patients had dry AMD with geographic atrophy and best-corrected acuity of worse than 20/200 at the time of enrolment. Patients received from 50k to 200k cells delivered in a balanced saline suspension. The cells were delivered by subretinal injection following conventional 23- or 25-gauge vitrectomy. Patients received systemic immunosuppression one week prior to treatment until up to one year after. The procedure appears to have been well tolerated, with no serious systemic treatment-related adverse effects noted. With up to two years of follow-up, best-corrected acuity has remained stable in treated eyes. Best-corrected acuity has also remained stable in untreated eyes. Improvement noted in one treated eye could probably be attributed to clearing of the vitreous and posterior capsule opacity during surgery, Dr Banin noted. IMAGING STUDIES The researchers performed retinal function and structure assessment throughout the study. In addition to best-corrected acuity they used colour fundus photography, optical coherence tomography (OCT) and fundus autofluorescence imaging techniques. Imaging studies showed the creation of subretinal blebs during surgery followed by absorption of the subretinal fluid within 48 hours and healing of the injection site within a few weeks. Imaging also showed signs of subretinal pigmentation in the treated areas accompanied by hypo- and hyperfluorescent spots on fundus autofluorescence imaging that developed over the first one-to-three months postoperatively. Particularly interesting was the appearance of irregular subretinal hyperfluorescence on OCT imaging of treated areas, and taken together, the imaging results suggest potential engraftment of the transplanted cells. These findings persisted throughout follow-up for up to two years in the first-treated patients, although slow loss of cells could be occurring. STRUCTURAL IMPROVEMENT  In a few patients, there were signs of altered or reduced drusen in the treated areas, and possible restoration of the RPE layer. Potential structural improvement was seen in the photoreceptor layer and ellipsoid zone where the cells were injected. Surgery-related adverse events included conjunctival haemorrhage, worsening of cataract and epiretinal membrane formation. Seven of nine patients developed new or worsening epiretinal membranes. Four of these were considered to be mild, and three were more advanced. None of these cases required intervention. Some of these cases may have been associated with incomplete vitrectomy or efflux of RPE cells, he noted. No unexpected ocular adverse events occurred. The phase I/II study is ongoing. A new cohort will involve 12 patients with less advanced disease (visual acuity of 20/100 or worse), and smaller areas of geographic atrophy. OpRegen cells are created using a proprietary process that drives the differentiation of human pluripotent stem cells to generate high-purity RPE cells (Idelson et al., Cell Stem Cell, 2009 2;5(4):396-408). The cells generated with the system are ‘xeno free’, are derived from an NIH-approved hESC line produced under GMP conditions and underwent extensive safety testing prior to being approved by the US FDA for the current clinical trial. Prior to testing the stem cell-derived RPE cells in humans, researchers conducted animal studies. Upon being injected in rats, the RPE cells formed monolayers, polarised and began to function. Both structural and functional improvements were observed (McGill et al., Transl Vis Sci Technol;6(3):17). The current study also compared findings observed in pig eyes and human study participants. In vivo OCT studies conducted following transplantation showed similar findings in the form of irregular subretinal hyper-reflectance in the area of transplantation. In the pig eyes, following enucleation, subretinal layering of the human hESC-RPE transplanted cells was evident and proven by immunohistochemical staining using a human-specific marker. The researchers thus believe that the hyper-reflectance on OCT also seen in the human patients correlates with the presence of the transplanted cells. More than a dozen research groups around the world are working on other approaches to stem cell-based RPE cell transplantation for dry AMD. One group recently reported promising phase I results with a clinical-grade retinal implant made of hESC-derived RPE grown on a synthetic substrate. The implants were well tolerated and one patient showed improvement in visual function (AH Kashani, Science Translational Medicine, Vol. 10, Issue 435, eaao4097).
Tags: ARVO, stem cells