Dataset Information

Transplantation of human embryonic stem cell-derived retinal pigment epithelial cells (MA09-hRPE) in macular degeneration.

ABSTRACT: The use of human embryonic stem cell (hESC)-derived Retinal Pigment Epithelium (RPE) transplants has advanced dramatically in different forms for clinical application in macular degeneration. This review focuses on the first generation of hESC-RPE cell line, named as "MA09-hRPE" by Astellas Institute of Regenerative Medicine (AIRM), and its therapeutic application in human, which evaluated the safety and efficacy of MA09-hRPE cell line transplanted in patients with macular degeneration. This project marks the first milestone in overcoming ethical hurdles and oncogenic safety concerns associated with the use of an embryonic stem cell-derived line. Through in-depth, evidence-based analysis of the MA09-hRPE cell line, along with other hESC-RPE cell lines, this review aims to draw attention to the key technical challenges pertinent to the generation of a biologically competent hESC-RPE cell line and distill the four key prognostic factors residing in the host retina, which concurrently determine the outcomes of clinical efficacy and visual benefits. Given that the technology is still at its infancy for human use, a new clinical regulatory path could aid in cell line validation through small cohort, adaptive clinical trials to accelerate product development toward commercialization. These strategic insights will be invaluable to help both academia and industry, collaboratively shorten the steep learning curve, and reduce large development expenditures spent on unnecessary lengthy clinical trials.

SUBMITTER: Qiu TG

PROVIDER: S-EPMC6712006 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Transplantation of human embryonic stem cell-derived retinal pigment epithelial cells (MA09-hRPE) in macular degeneration.

Qiu Tina Guanting TG

NPJ Regenerative medicine 20190827

The use of human embryonic stem cell (hESC)-derived Retinal Pigment Epithelium (RPE) transplants has advanced dramatically in different forms for clinical application in macular degeneration. This review focuses on the first generation of hESC-RPE cell line, named as "MA09-hRPE" by Astellas Institute of Regenerative Medicine (AIRM), and its therapeutic application in human, which evaluated the safety and efficacy of MA09-hRPE cell line transplanted in patients with macular degeneration. This pro ...[more]

PMID: 31482011

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Project description:PURPOSE:Transplantation of human embryonic stem cell (hESC)-derived retinal pigment epithelial (RPE) cells offers the potential for benefit in macular degeneration. Previous trials have reported improved visual acuity (VA), but lacked detailed analysis of retinal structure and function in the treated area. DESIGN:Phase 1/2 open-label dose-escalation trial to evaluate safety and potential efficacy (clinicaltrials.gov identifier, NCT01469832). PARTICIPANTS:Twelve participants with advanced Stargardt disease (STGD1), the most common cause of macular degeneration in children and young adults. METHODS:Subretinal transplantation of up to 200?000 hESC-derived RPE cells with systemic immunosuppressive therapy for 13 weeks. MAIN OUTCOME MEASURES:The primary end points were the safety and tolerability of hESC-derived RPE cell administration. We also investigated evidence of the survival of transplanted cells and measured retinal structure and function using microperimetry and spectral-domain OCT. RESULTS:Focal areas of subretinal hyperpigmentation developed in all participants in a dose-dependent manner in the recipient retina and persisted after withdrawal of systemic immunosuppression. We found no evidence of uncontrolled proliferation or inflammatory responses. Borderline improvements in best-corrected VA in 4 participants either were unsustained or were matched by a similar improvement in the untreated contralateral eye. Microperimetry demonstrated no evidence of benefit at 12 months in the 12 participants. In one instance at the highest dose, localized retinal thinning and reduced sensitivity in the area of hyperpigmentation suggested the potential for harm. Participant-reported quality of life using the 25-item National Eye Institute Visual Function Questionnaire indicated no significant change. CONCLUSIONS:Subretinal hyperpigmentation is consistent with the survival of viable transplanted hESC-derived RPE cells, but may reflect released pigment in their absence. The findings demonstrate the value of detailed analysis of spatial correlation of retinal structure and function in determining with appropriate sensitivity the impact of cell transplantation and suggest that intervention in early stage of disease should be approached with caution. Given the slow rate of progressive degeneration at this advanced stage of disease, any protection against further deterioration may be evident only after a more extended period of observation.

Project description:Background: Different sources of retinal pigment epithelial cells (RPE) were transplanted to treat Age-related Macular Degeneration. But the mechanisms of therapeutic effect are unclear till now, and GMP level fetal RPE (fRPE) need further evaluation for treatment. Methods: Modified GMP fRPE primary culture system was founded. These RPE were tested on Mer-/- mice and sodium iodate induced retinopathy primate model for safety and feasibility. Five dry-AMD patients and one Stargardt’s Disease patient were enrolled, and received sub retinal transplantation of hfRPE with three dosage cohorts(1×105，2×105，5×105). ETDRS, optic coherent tomographic imaging (OCT), color fundus (CF), fluorescent angiography (FFA), autofluorescence, microperimetry examination were conducted before surgery, and during follow-up period. The studies are registered with ClinicalTrials.gov, numbers NCT02868424. Findings: GMP level fRPE from modified primary culture system has good proliferative capacity and full functions of RPE in vitro. Human fetal RPE can survive long period in sub-retinal space in mice and monkey models of RPE degeneration, and showed therapeutic effect on Mer-/- mice. During our nine-months follow-up of six clinical cases, no endophthalmitis, no vitreous hemorrhage, no proliferative vitreoretinopathy was observed, and epiretinal memrbrane was the only complication. Among the patients, four of them achieved increase in ETDRS visual acuity (VA), of which the greatest improvement was 18 letters, and one kept steady while the other had 9 letters decreased VA. Color fundus photos and OCT demonstrated the existence of the fRPE cells, and improved retinal sensitivity as well as the changes observed in auto fluorescence also can tell the situation of grafted cells to some extent. Interpretation: GMP level fRPE from modified culture system exhibited satisfactory results on in vitro and preclinical experiments. Preliminary clinical trial proved safety of the fRPE subretinal transplantation, and substantiated it a promising therapy for dry AMD including the converted from exudative AMD.

Dataset Information

Transplantation of human embryonic stem cell-derived retinal pigment epithelial cells (MA09-hRPE) in macular degeneration.

Publications

Transplantation of human embryonic stem cell-derived retinal pigment epithelial cells (MA09-hRPE) in macular degeneration.

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