Critical manufacturing challenges are analyzed, including GMP scalability, quality assurance, and ethical considerations in donor material sourcing in donor material sourcing.
Abstract
Abstract Retinal degenerations, comprising a heterogeneous group of disorders culminating in neuroretinal dysfunction, such as inherited retinal dystrophies (IRDs) and age-related retinal degeneration, are among the leading causes of irreversible vision loss worldwide. Restoring visual function through cell replacement therapy represents an attractive, yet challenging, strategy. Candidate retinal cell sources include retinal progenitor cells (RPCs), Müller glia, human neuroretinal stem-like cells (hNRSCs), and pluripotent stem cells (PSCs). In this review, we discuss their translational advantages and limitations, which in turn influence clinical implementation. We analyze critical manufacturing challenges, including GMP scalability, quality assurance, and ethical considerations in donor material sourcing. Experimental criteria for assessing cellular products’ integration into host circuitry and their capacity to restore visual function in preclinical retinal degeneration models must account for donor maturity, host retina architecture, and immune modulation, which determine survival, synapse connectivity, and delivery requirements. Ongoing clinical trials highlight the diversity of cell replacement strategies—from fetal-derived and allogenic progenitor suspensions to laminated PSC-derived retinal sheets—with each approach presenting distinct implications for survival, true integration, and logistical complexity.
Vision restoration is a vital yet challenging objective in ophthalmology, as traditional therapies cannot reverse irreversible retinal damage. This issue is of significant concern, considering that millions globally are afflicted by untreatable degenerative conditions such as retinitis pigmentosa (RP) and age-related macular degeneration. Stem cell treatments and retinal organoid (RO) technology have emerged as revolutionary methodologies. ROs derived from pluripotent stem cells (PSCs) autonomously form three-dimensional (3D) laminar structures that mimic the natural human retina, providing exceptional platforms for disease modeling, pharmacological screening, and cellular replacement. Clinical studies indicate that retinal pigment epithelium (RPE) transplantation enhances visual function. In contrast, PSC-derived mesenchymal stem cells (MSCs), retinal progenitor cells (RPCs), and RPE grafts have neuroprotective and regenerative capabilities in preclinical and early-phase trials. Notwithstanding this advancement, several challenges remain, including suboptimal cell survival, insufficient functional synaptic integration, immunological rejection, tumorigenic potential, and the absence of standardized production processes. This article presents three unique contributions, diverging from previous reviews that focus solely on positive outcomes: (1) a comprehensive assessment of advancements and challenges in PSCs, MSCs, RPCs, and RPE; (2) a methodical examination of the disparity between structural engraftment and genuine functional integration; and (3) a cohesive discourse on innovative strategies such as optogenetics, 3D bioprinting, and extracellular vesicle-based therapies. We consolidate recent clinical discoveries, highlight persistent obstacles, and provide a roadmap for the future. Growing evidence suggests that, despite significant obstacles, effective retinal regeneration is gradually becoming a reality.
B. Jaber, M. Abd, S. Younis et al.· International Immunopharmaco...· 0 citations
Inherited retinal disorders (IRDs) are a group of ophthalmic conditions that are characterized by progressive degeneration of photoreceptors and/or retinal pigment epithelium (RPE), leading to irreversible vision loss. IRDs are a promising target for stem cell therapies, which have largely aimed to restore vision by either replacement of degenerated photoreceptors or retinal pigment epithelial cells via transplantation of stem cells or preservation of cells through expression of neuroprotective factors. Several therapies have recently moved into early clinical trials, demonstrating that stem cell therapies can be safely administered through different routes of administration including intravitreal, sub-retinal, and suprachoroidal injection. However, further larger-scale studies are needed to demonstrate efficacy of these treatments for the prevention or reversal of vision loss from photoreceptor or RPE degeneration.
Anupam K. Garg, Ishrat Ahmed· American journal of ophthalm...· 0 citations
Age-related macular degeneration (AMD) remains a leading cause of irreversible blindness worldwide, characterized by the progressive breakdown of the outer blood-retinal barrier, accumulation of protein and lipid deposits in the subretinal space, and the consequential degeneration of macular photoreceptors. Geographic atrophy (GA) is one of the blinding end points of AMD. While current pharmaceutical interventions can slow lesion expansion or counter choroidal neovascularization, they fail to address the most significant clinical unmet need: regeneration of damaged retinal tissue to restore vision. Regenerative medicine via stem cell transplantation offers a definitive curative approach by replacing the structural and immune framework of the outer retina. This review synthesizes current advancements in human embryonic and pluripotent stem cells platforms engineered for outer retinal reconstruction. We evaluate the differentiation, culturing, and quality validation required to generate clinical-grade, polarized RPE monolayers and homeostatic microglia-like cells. Structurally, single-cell suspensions are contrasted against bioengineered patches, scaffold-free cell sheets, and advanced cell strips, analyzing how graft configuration dictates post-transplantation integration and visual recovery while balancing procedural adverse events like cell reflux and epiretinal membrane formation. Furthermore, this review addresses the microenvironmental challenges of transplanting allogeneic constructs into an inflamed, senescent host niche. We examine CRISPR-Cas9 genome editing paradigms, including cytosine base and prime editing, designed to rectify cell-intrinsic genetic vulnerabilities such as the complement factor H (CFH) risk variant. We highlight translational applications, such as knocking out the Class II transactivator to eliminate major histocompatibility complex class II (MHC-II) expression, which successfully circumvents host T-cell immune surveillance and prevents graft rejection in non-human primates. Additionally, we analyze how engineering an inhibitor-resistant colony-stimulating factor 1 receptor (CSF1R) point mutation enables exogenously administered microglia to robustly outcompete and replace maladaptive, pro-inflammatory host microglia under selective small-molecule pressure. Finally, we discuss future directions, emphasizing multi-lineage bilayered co-transplantation models that combine genome-edited RPE patches with homeostatic microglia or retinal organoids to achieve durable synaptic repair, alongside automated artificial intelligence manufacturing pipelines. Together, these combined structural, molecular, and immune-modulating strategies represent the next clinical frontier in restoring clear central vision and achieving permanent neurovascular rescue in advanced macular degeneration.
Nuntachai Surawatsatien, Rajvir Mukesh Solanky, Robert P. van de Werken et al.· American journal of ophthalm...· 0 citations
Müller glia (MG) are the predominant non-neuronal cells of the vertebrate retina, playing an integral role in retinal homeostasis and photopic signal transmission. In lower vertebrates, MG retain robust regenerative potential, acting as a source of neuronal progenitors following injury. In contrast, mammalian MG primarily responds to damage with gliosis, a process that provides initial neuroprotection but ultimately restricts their neurogenic capacity. This limitation is especially consequential in humans, where genetic disorders and age-related diseases such as diabetic retinopathy, glaucoma, and macular degeneration lead to retinal neuron death and irreversible visual loss. One promising therapeutic strategy is to reprogram MG in vivo into stem-like progenitor cells capable of replacing lost neurons, with the expectation that these new cells can form functional synaptic circuits, replace lost neurons, and restore retinal function. Recent studies have reviewed integrated regulatory network, encompassing signaling pathways including Notch, Wnt/β-catenin, MAPK/ERK, PI3K/AKT, SMADs, and Hippo-YAP, alongside key transcription factors and epigenetic mechanisms, that collectively govern MG cell cycle reentry and neurogenesis in mammals. This review synthesizes current knowledge of this integrated regulatory network, mainly focusing on the role of signaling pathways in MG regeneration, highlighting strategies to harness the intrinsic neurogenic potential of MG for retinal repair, underscoring their promise as cellular targets for curing degenerative retinal diseases from intrinsic cellular sources.
Lu Huang, Ethan Yao, Menglu Yang et al.· American Journal of Patholog...· 0 citations
Advanced degenerative retinal diseases [e.g., retinitis pigmentosa (RP) and age-related macular degeneration (AMD)] are characterized by irreversible photoreceptor loss, and conventional interventions rarely prevent progression to profound vision loss at advanced stages. Retinal prostheses and optogenetic therapies are two leading bionic strategies to bypass absent photoreceptors, yet both are limited by a shared “encoding–biointerface” bottleneck: converting external scenes into interpretable neural activity in surviving retinal circuits with adequate selectivity, safety margins, and long-term stability. This review critically compares the two approaches in spatial resolution, neural adaptation, and biosafety, while explicitly distinguishing clinical evidence from preclinical and proof-of-concept studies. Retinal prostheses provide near-term light perception and limited form vision but are constrained by current spread, non-selective pathway/axon recruitment, interface reactions, and cortical decoding burden. Optogenetic restoration offers cell-type–biased reactivation and potentially more physiological processing, but currently remains coupled to external light-delivery hardware and is limited by scattering, heterogeneous transduction, safety-limited irradiance, restricted dynamic range, and adeno-associated virus (AAV)–related inflammatory risk. We highlight emerging integrative directions, including opto-electronic hybrid interfaces, adaptive encoding, broadband subretinal nanomaterial-based photovoltaic nanoprostheses, and experimental acoustic modalities (e.g., focused ultrasound and sonogenetics), alongside ethical and accessibility considerations for translation.
Na Long, Meng Si, Yingxian Jiang et al.· Frontiers in Medical Technol...· 0 citations
Cerebrovascular and neurodegenerative diseases rank among the leading causes of death worldwide and represent an increasing socioeconomic burden, particularly in aging populations. Pluripotent stem cell (PSC)-based therapies have emerged as promising strategies for replacing lost neurons and restoring neural circuits in disorders of the central nervous system (CNS). However, major barriers remain, including poor survival, limited integration, and variable functional maturation of transplanted cells. These challenges currently limit the reproducibility and clinical translation of PSC-based therapies. Here, we examine these barriers with a particular focus on ischemic stroke and Parkinson's disease, two conditions that represent complementary models of acute and chronic neuronal loss and are among the most advanced indications for PSC-based transplantation. We discuss how programmed cell death signaling contributes not only to neuronal loss in these disorders but also to the limited survival of transplanted PSC-derived grafts. Building on this mechanistic framework, we highlight strategies that may improve graft survival and functional integration. Specifically, we propose an integrated approach that combines modulation of programmed cell death pathways, targeted activation of RAS signaling, optimization of mitochondrial health, and use of biocompatible scaffolds to support neuronal maturation and network integration. Together, these strategies provide a conceptual framework for improving the reliability and therapeutic efficacy of PSC-based cell transplantation therapies and accelerating their translation toward clinical application.Overview of strategies to enhance PSC-derived neural graft survival and integration through modulation of cell death pathways, RAS signaling, mitochondrial function, and extracellular scaffolds. Created in BioRender. Raudzus, F. (2026) https://BioRender.com/blr0ycj.
O. Chen, Kelvin K Hui, Fabian Raudzus et al.· Cell Death and Disease· 0 citations
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