Cell Therapy for Retinal Dystrophies: From Cell Suspension Formulation to Complex Retinal Tissue Bioengineering

Abstract

Retinal degeneration is an irreversible phenomenon caused by various disease conditions including age-related macular degeneration (AMD) and retinitis pigmentosa (RP). During the course of these diseases, photoreceptors (PRs) are susceptible to degeneration due to their malfunctions or to a primary dysfunction of the retinal pigment epithelium (RPE). Once lost, these cells could not be endogenously regenerated in humans, and cell therapy to replace the lost cells is one of the promising strategies to recover vision. Depending on the nature of the primary defect and the stage of the disease, RPE cells, PRs, or both might be transplanted to achieve therapeutic effects. We describe in this review the current knowledge and recent progress to develop such approaches. The different cell sources proposed for cell therapy including human pluripotent stem cells are presented with their advantages and limits. Another critical aspect described herein is the pharmaceutical formulation of the end product to be delivered into the eye of patients. Finally, we also outline the future research directions in order to develop a complex multilayered retinal tissue for end-stage patients.

Automation of human pluripotent stem cell differentiation toward retinal pigment epithelial cells for large-scale productions

“…The use of cell suspension formulation considerably simplifies the logistical and surgical procedures but several studies made in animal models, including our own, suggest that the survival of the RPE cells and the visual benefits for the animal are improved when the cells are grafted as an epithelial tissue rather than a cell suspension 13,44 . In human, these two approaches have shown both satisfactory safety results and promising efficacy results, even if the extent and the causes of visual improvement in transplant recipients remain ambiguous 16 . Nevertheless, considering that 1 × 10 5 hESC-RPE cells are currently used to graft a human eye with the both methods 14,15,43 , the automated process presented here should allow to produce enough cells to treat several thousands of patients with retinal degeneration even if some steps of the production, such as the simultaneous banking of a huge numbers of cryovials, remains challenging.…”

“…The distinctive cobblestone morphology of RPE cells as well as their pigmentation allow to manually collect pigmented areas that appear upon differentiation of hPSCs to obtain a pure population of hPSC-RPE cells. Such approach of RPE cell production is used as cell replacement material in on going and planned clinical trials 12–16 . However, this spontaneous method remains fastidious, inefficient and time consuming (8 to 12 weeks of hPSCs differentiation) making it incompatible with the industrial large-scale production which is required to treat the potential millions of patients.…”

The primate model for understanding and restoring vision

“…However, determination of the most appropriate surgical approach; the application of treatment in eyes of size and structure similar to the human eye, including the presence of a macula; and a thorough understanding of the immunological considerations for graft survival and the consequences of grafted rejection can only be assessed in transplantation studies conducted with NHPs. Promising therapies, such as those based on transplantation of iPSC-derived retinal sheets (15,16) or RPE (123,124), conducted in acute outer retinal degeneration models in NHPs, contributed greatly to their clinical translation. Indeed, the first-in-human safety and tolerability clinical trial to evaluate subretinal injection of human ESC-derived RPE cells into patients with dry AMD and Stargardt disease is ongoing (125).…”

Stem Cell Therapy

“…Retinitis pigmentosa is a group of heterogeneous inherited conditions with a prevalence of 1:4000. Since the PR and the RPE cannot be endogenously regenerated, stem cell therapy is a promising therapeutic alternative for treating these retinal degeneration conditions (Ben M'Barek and Monville 2019).…”

“…There are currently three ongoing clinical trials using iPSC-derived RPEs, with more expected to be approved. The results from these trials will help to optimize the best formulation strategy to combat retinal degeneration (Ben M'Barek and Monville 2019;Schwartz et al 2015).…”