Transplantation of human embryonic stem cell-derived retinal pigment epithelial cells (MA09-hRPE) in macular degeneration

Qiu, Tina Guanting

doi:10.1038/s41536-019-0081-8

Cited by 25 publications

(16 citation statements)

References 33 publications

(79 reference statements)

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“…Differentiated RPE cells are post-mitotic and fully committed to the RPE lineage, in large part due to their cell–cell contact inhibition [53] , [54] . The expression of the proliferation marker MKI67 and of other genes associated with proliferation ( TOP2A , TPX2 , PTTG1 , PCLAF , and RRM2 ) was examined to assess whether some progenitor populations remain with proliferative potentials, and whether these vary over time in culture.…”

Section: Resultsmentioning

confidence: 99%

Transcriptomic Profiling of Human Pluripotent Stem Cell-Derived Retinal Pigment Epithelium over Time

Lidgerwood

Senabouth

Smith-Anttila

et al. 2020

Genomics, Proteomics &Amp; Bioinformatics

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Human pluripotent stem cell (hPSC)-derived progenies are immature versions of cells, presenting a potential limitation to the accurate modelling of diseases associated with maturity or age. Hence, it is important to characterise how closely cells used in culture resemble their native counterparts. In order to select appropriate time points of retinal pigment epithelium (RPE) cultures that reflect native counterparts, we characterised the transcriptomic profiles of the hPSC-derived RPE cells from 1- and 12-month cultures. We differentiated the human embryonic stem cell line H9 into RPE cells, performed single-cell RNA-sequencing of a total of 16,576 cells to assess the molecular changes of the RPE cells across these two culture time points. Our results indicate the stability of the RPE transcriptomic signature, with no evidence of an epithelial–mesenchymal transition, and with the maturing populations of the RPE observed with time in culture. Assessment of Gene Ontology pathways revealed that as the cultures age, RPE cells upregulate expression of genes involved in metal binding and antioxidant functions. This might reflect an increased ability to handle oxidative stress as cells mature. Comparison with native human RPE data confirms a maturing transcriptional profile of RPE cells in culture. These results suggest that long-term in vitro culture of RPE cells allows the modelling of specific phenotypes observed in native mature tissues. Our work highlights the transcriptional landscape of hPSC-derived RPE cells as they age in culture, which provides a reference for native and patient samples to be benchmarked against.

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Section: Resultsmentioning

confidence: 99%

Transcriptomic Profiling of Human Pluripotent Stem Cell-Derived Retinal Pigment Epithelium over Time

Lidgerwood

Senabouth

Smith-Anttila

et al. 2020

Genomics, Proteomics &Amp; Bioinformatics

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“…MA09-hRPE (Astellas Pharma) is hESC-derived Retinal Pigment Epithelium (hESC-RPE). The phases 1/2 clinical trial results confirmed that hESC-derived cells could serve as a potentially safe new source for regenerative medicine [21][22][23].…”

Section: Cell-based Therapiesmentioning

confidence: 78%

New Drugs in the Pipeline for the Management of AMD

Marta¹,

Pessoa²

2022

Recent Advances and New Perspectives in Managing Macular Degeneration

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Anti-vascular endothelial growth factor (anti-VEGF) therapies have revolutionized the care of patients with retinal diseases. In the 1990s, it was observed that anti-VEGF antibodies reduced tumor angiogenesis, and consequently, these antibodies started to be used off-label in the exudative form of age-related macular degeneration (AMD). In the 2000s, research was directed towards the development of anti-VEGF therapies for retinal disease management. Several anti-VEGF therapies were approved: pegaptanib, an RNA aptamer, in 2004; ranibizumab, an anti-VEGF Fab, in 2008; aflibercept, a humanized IgG Fc, in 2011; and brolucizumab, an scFv, in 2019. Currently, new therapeutic options are emerging, and approval is expected soon. These new therapies aim to increase treatment durability and thus reduce treatment burden and improve real-world outcomes. In this chapter, the mechanisms of action and the preliminary trial results of these potential new therapies will be described.

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“…The interactions between RPE and cells of the neuroretina is crucial for optimal functioning of either cell type. Derivation of pure single cell type populations does not necessarily ensure complete functionality [ 43 ]. We propose that a cocktail of cells might better imitate the in vivo interactions.…”

Section: Discussionmentioning

confidence: 99%

Transplantation of retinal pigment epithelium and photoreceptors generated concomitantly via small molecule-mediated differentiation rescues visual function in rodent models of retinal degeneration

Surendran

Nandakumar

et al. 2021

Stem Cell Res Ther

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Background 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. A promising therapeutic approach for both is the replacement of lost/damaged cells with human induced pluripotent stem cell (hiPSC)-derived retinal cells. Methods The 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. Results RPE 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. Conclusions To 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.

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Transplantation of human embryonic stem cell-derived retinal pigment epithelial cells (MA09-hRPE) in macular degeneration

Cited by 25 publications

References 33 publications

Transcriptomic Profiling of Human Pluripotent Stem Cell-Derived Retinal Pigment Epithelium over Time

Transcriptomic Profiling of Human Pluripotent Stem Cell-Derived Retinal Pigment Epithelium over Time

New Drugs in the Pipeline for the Management of AMD

Transplantation of retinal pigment epithelium and photoreceptors generated concomitantly via small molecule-mediated differentiation rescues visual function in rodent models of retinal degeneration

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