Abstract
BackgroundAge-related macular degeneration (AMD) is a result of degeneration/damage of the retinal pigment epithelium (RPE) while retinitis pigmentosa (RP), an inherited early-onset disease, results from premature loss of photoreceptors. A promising therapeutic approach for both is the replacement of lost/damaged cells with human induced pluripotent stem cell (hiPSC)-derived retinal cells.MethodsThe aim of this study was to investigate the in vivo functionality of RPE and photoreceptor progenitor (PRP) cells derived from a clinical-grade hiPSC line through a unified protocol. De novo-generated RPE and PRP were characterized extensively to validate their identity, purity, and potency.ResultsRPE expressed tight junction proteins, showed pigmentation and ciliation, and secreted polarization-related factors vascular endothelial growth factor (VEGF) and pigment epithelium-derived factor (PEDF). PRP expressed neural retina proteins and cone and rod markers, and responded to KCl-induced polarization. Transcriptomic analysis demonstrated an increase in the expression of mature retinal tissue-specific genes coupled with concomitant downregulation of genes from undesired lineages. RPE transplantation rescued visual function in RCS rats shown via optokinetic tracking and photoreceptor rescue. PRP transplantation improved light perception in NOD.SCID-rd1 mice, and positive electroretinography signals indicated functional photoreceptor activity in the host’s outer nuclear layer. Graft survival and integration were confirmed using immunohistochemistry, and no animals showed teratoma formation or any kind of ectopic growth in the eye.ConclusionsTo our knowledge, this is the first demonstration of a unified, scalable, and GMP-adaptable protocol indicating strong animal efficacy and safety data with hiPSC-derived RPE and PRP cells. These findings provide robust proof-of-principle results for IND-enabling studies to test these potential regenerative cell therapies in patients.
Highlights
Age-related macular degeneration (AMD) is a result of degeneration/damage of the retinal pigment epithelium (RPE) while retinitis pigmentosa (RP), an inherited early-onset disease, results from premature loss of photoreceptors
Wet AMD presents with choroidal neovascularization, where new blood vessels grow into the retina and leak blood and fluid leading to the destruction of the RPE and photoreceptors [1, 4]
embryoid bodies (EBs) treatment with small molecules promotes eye-field induction The differentiation process used here requires the sequential addition of growth factors and small molecule cocktails, resulting in three major steps that recapitulate in vivo retinal development (Fig. 1) to obtain RPE and photoreceptor progenitor (PRP)
Summary
Age-related macular degeneration (AMD) is a result of degeneration/damage of the retinal pigment epithelium (RPE) while retinitis pigmentosa (RP), an inherited early-onset disease, results from premature loss of photoreceptors. Age-related macular degeneration (AMD) is the primary cause of blindness in developed countries and the third leading cause of blindness globally [1]. AMD is characterized by the loss of retinal pigment epithelium (RPE) and accumulation of extracellular aggregates, called drusen, that accumulate between Bruch’s membrane and the RPE layer [4]. The late stage is characterized by geographic atrophy, with degeneration of RPE and loss of photoreceptors that rely on RPE for trophic support. Wet AMD presents with choroidal neovascularization, where new blood vessels grow into the retina and leak blood and fluid leading to the destruction of the RPE and photoreceptors [1, 4]. While inhibiting vascular endothelial growth factor (VEGF) has shown promise in the treatment of wet AMD, there are currently no treatment modalities for atrophic AMD
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