Cellular Reprogramming Strategies for Age-Related Macular Degeneration From iPSCs to In Vivo Therapy

Abstract

Age-related macular degeneration (AMD) remains one of the leading, and most stubborn, causes of irreversible central vision loss in older adults, and for a long time clinicians could do little more than slow its march. That picture has begun to change. This review traces how cellular reprogramming technologies — from induced pluripotent stem cell (iPSC)-derived retinal pigment epithelium (RPE) transplantation to direct lineage transdifferentiation and, more recently, in vivo partial epigenetic reprogramming — are reshaping what regenerative ophthalmology can offer. Background: since Takahashi and Yamanaka's original demonstration that four transcription factors can reset adult somatic cells to pluripotency, the field has moved from single-patient autologous grafts toward banked, HLA-matched allogeneic lines and, in parallel, toward strategies that bypass pluripotency altogether. Methods: we conducted a structured, PubMed-oriented narrative synthesis of peer-reviewed literature, clinical trial registries, and preprint sources addressing stem cell platforms, reprogramming delivery systems, direct transdifferentiation, and partial in vivo rejuvenation relevant to retinal degeneration, screened for relevance and synthesized thematically rather than through formal meta-analysis. Results: autologous iPSC-RPE sheets demonstrated long-term graft survival without systemic immunosuppression, while allogeneic HLA-banked lines improved scalability at some immunological cost; non-integrating delivery platforms (Sendai virus, AAV, modified mRNA) meaningfully reduced insertional mutagenesis risk relative to integrating vectors; and OSK-based partial reprogramming reversed markers of retinal ganglion cell aging in preclinical models, now advancing to early-phase human trials. Conclusion: cellular reprogramming has moved from proof-of-concept to an increasingly diversified therapeutic toolkit for AMD, though genomic stability, manufacturing cost, and regulatory clarity remain unresolved before these approaches can be considered routine care.