Multilayered control of retinal stem/progenitor cell fate in the single-cell and organoid era: Developmental blueprints and regenerative opportunities

Table 5 Clinical pathway + endpoint stack + chemistry, manufacturing, and controls interface for cell-replacement therapy

Clinical modality	Delivery plane/format	Biological trade-off	Recommended endpoint stack (early phase)	CMC release criteria anchor (identity/purity/potency)	Major confounders to control	Evidence level framing in your text
RPE - cell suspension	Subretinal injection	Scalable + simpler surgery; risks non-uniform monolayer	OCT graft coverage; FAF atrophy expansion; microperimetry/dark adaptation	Identity: Polarity markers; purity: Residual pluripotency; potency: Phagocytosis + TEER	Bruch’s membrane integrity; atrophic niche variability	Level II-III feasibility; signals not definitive
RPE - patch/scaffold	Sheet/patch implant	Pre-polarized monolayer; higher surgical complexity	Same stack + implant positioning stability	Same axes + mechanical integrity (implant)	PVR/retinal detachment; immune response modulation by scaffold	Durability-oriented but complication-prone
RPE - strip (hybrid)	“Strip” transplantation	Balances handling vs structure	Same stack; add uniformity metrics	Same axes	Surgical learning curve; comparability issues	Emerging modality
Photoreceptor precursors	Subretinal; precursor “Goldilocks” maturity	Requires synaptic integration; risk of material transfer illusion	Structural survival + layer targeting; function with integration-sensitive assays	Potency: Light-response surrogates + integration proxies	Disease stage; host residual photoreceptors	First-in-human transition; mechanism-of-benefit controversy
Immunology-as-engineering adjunct	Immunosuppression; scaffold immune barrier; hypoimmune iPSC	Enable durable allografts; must avoid immune escape	Safety surveillance; inflammation markers; imaging	Purity + proliferation markers; in vivo tumor surveillance	Immune privilege is relative	“Universal donor” direction but needs safeguards

CMC: Chemistry, manufacturing, and controls; RPE: Retinal pigment epithelium; OCT: Optical coherence tomography; FAF: Fundus autofluorescence; TEER: Transepithelial electrical resistance; PVR: Proliferative vitreoretinopathy; iPSC: Induced pluripotent stem cell.