Clinical-grade stem cell–derived retinal pigment epithelium patch rescues retinal degeneration in rodents and pigs

Sharma, Ruchi; Khristov, Vladimir; Rising, Aaron; Jha, Balendu Shekhar; Dejene, Roba; Hotaling, Nathan; Li, Yichao; Stoddard, Jonathan; Stankewicz, Casey; Wan, Qin; Zhang, Connie; Campos, Mercedes; Miyagishima, Kiyoharu; McGaughey, David; Villasmil, Rafael; Mattapallil, Mary J.; Stanzel, Boris V.; Qian, Haohua; Wong, Wai T; Chase, Lucas G.; Charles, Steve; McGill, Trevor J.; Miller, Sheldon S.; Maminishkis, Arvydas; Amaral, Juan; Bharti, Kapil

doi:10.1126/scitranslmed.aat5580

Cited by 232 publications

(224 citation statements)

References 54 publications

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“…Twenty-six studies reported ERG data. Fourteen [46,[52][53][54][55][56][57][58][59][60][61][62][63][64] of them were excluded from meta-analysis since they did not report quantitative data or only showed single representative ERG traces.…”

Section: A-wave and B-wave Amplitudes Extracted From Erg Datamentioning

confidence: 99%

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A Systematic Review on Transplantation Studies of the Retinal Pigment Epithelium in Animal Models

Koster

Wever

Wagstaff

et al. 2020

IJMS

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The retinal pigment epithelium (RPE) and the adjacent light-sensitive photoreceptors form a single functional unit lining the back of the eye. Both cell layers are essential for normal vision. RPE degeneration is usually followed by photoreceptor degeneration and vice versa. There are currently almost no effective therapies available for RPE disorders such as Stargardt disease, specific types of retinitis pigmentosa, and age-related macular degeneration. RPE replacement for these disorders, especially in later stages of the disease, may be one of the most promising future therapies. There is, however, no consensus regarding the optimal RPE source, delivery strategy, or the optimal experimental host in which to test RPE replacement therapy. Multiple RPE sources, delivery methods, and recipient animal models have been investigated, with variable results. So far, a systematic evaluation of the (variables influencing) efficacy of experimental RPE replacement parameters is lacking. Here we investigate the effect of RPE transplantation on vision and vision-based behavior in animal models of retinal degenerated diseases. In addition, we aim to explore the effect of RPE source used for transplantation, the method of intervention, and the animal model which is used. Methods: In this study, we systematically identified all publications concerning transplantation of RPE in experimental animal models targeting the improvement of vision (e.g., outcome measurements related to the morphology or function of the eye). A variety of characteristics, such as species, gender, and age of the animals but also cell type, number of cells, and other intervention characteristics were extracted from all studies. A risk of bias analysis was performed as well. Subsequently, all references describing one of the following outcomes were analyzed in depth in this systematic review: a-, b-, and c-wave amplitudes, vision-based, thickness analyses based on optical coherence tomography (OCT) data, and transplant survival based on scanning laser ophthalmoscopy (SLO) data. Meta-analyses were performed on the a-and b-wave amplitudes from electroretinography (ERG) data as well as data from vision-based behavioral assays. Results: original research articles met the inclusion criteria after two screening rounds. Overall, most studies were categorized as unclear regarding the risk of bias, because many experimental details were poorly reported. Twenty-three studies reporting one or more of the outcome measures of interest were eligible for either descriptive (thickness analyses based on OCT data; n = 2) or meta-analyses. RPE transplantation significantly increased ERG a-wave Int.(Hedges' g 1.181 (0.471-1.892), n = 6) and b-wave (Hedges' g 1.734 (1.295-2.172), n = 42) amplitudes and improved vision-based behavior (Hedges' g 1.018 (0.826-1.209), n = 96). Subgroup analyses revealed a significantly increased effect of the use of young and adolescent animals compared to adult animals. Moreover, transplanting more cells (in the range of 10 5 versus in the range o...

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Section: A-wave and B-wave Amplitudes Extracted From Erg Datamentioning

confidence: 99%

“…and additional statistics data (individual Hedges' g, lower-and upper limits) can be found in Table S6. Sixteen studies [26][27][28]31,[34][35][36][37][38][39][41][42][43][46][47][48] reporting 96 experiments were included in the meta-analysis. Ninety-one studies were performed in rats and five in mice.…”

Section: Behavioral Assaysmentioning

confidence: 99%

A Systematic Review on Transplantation Studies of the Retinal Pigment Epithelium in Animal Models

Koster

Wever

Wagstaff

et al. 2020

IJMS

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“…Several studies have also examined the tumorigenic risk at the clinical site (Table 1). 10,15,17,27,28,30,51 Analysis of 26 rabbit eyes transplanted with the clinical dose subretinally (50 000 cells in 50uL)…”

Section: Nontumorigenic Growth After Hesc-rpe Injectionmentioning

confidence: 99%

Preclinical safety studies of human embryonic stem cell-derived retinal pigment epithelial cells for the treatment of age-related macular degeneration

Petrus‐Reurer

Kumar

Sánchez

et al. 2020

Stem Cells Translational Medicine

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As pluripotent stem cell (PSC)-based reparative cell therapies are reaching the bedside, there is a growing need for the standardization of studies concerning safety of the derived products. Clinical trials using these promising strategies are in development, and treatment for age-related macular degeneration is one of the first that has reached patients. We have previously established a xeno-free and defined differentiation protocol to generate functional human embryonic stem cells (hESCs)derived retinal pigment epithelial (RPE) cells. In this study, we perform preclinical safety studies including karyotype and whole-genome sequencing to assess genome stability, single cell RNA sequencing to ensure cell purity, and biodistribution and tumorigenicity analysis to rule out potential migratory or tumorigenic properties of these cells. Whole-genome sequencing analysis illustrates that existing germline variants load is higher than the introduced variants acquired through in vitro culture or differentiation, and enforces the importance to examine the genome integrity at a deeper level than just karyotype. Altogether, we provide a strategy for preclinical evaluation of PSC-based therapies and the data support safety of the hESC-RPE cells generated through our in vitro differentiation methodology.Sandra Petrus-Reurer, Pankaj Kumar, and Sara Padrell Sánchez are co-first authors.

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“…To determine the downstream impact of an epigenetic state with an apparently lower barrier for vascular lineage activation, we investigated the epigenetic configurations of vascular-lineage specific gene promoters in differentiated DVP by ChIP-PCR. We selected the promoters of downstream genes regulated by the PRC2-regulated factor GATA2, which promotes expression of genes of endothelialspecific identity and function (e.g., CD31, vWF, endothelin-1, and ICAM2) 10 . We also selected promoters of genes known to be activated by chemical EZH2 and histone deacetylases (HDAC) de-repression in human endothelial progenitor cells (EPC) (e.g., CXCR4, DLL1, and FZD7) 44 .…”

Section: N-dvp Possessed Vascular Lineage Epigenetic De-repression Anmentioning

confidence: 99%

Vascular Progenitors Generated from Tankyrase Inhibitor-Regulated Naïve Diabetic Human iPSC Potentiate Efficient Revascularization of Ischemic Retina

Park¹,

Zimmerlin²,

Evans-Moses³

et al. 2019

Preprint

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Vascular regenerative therapies with conventional human induced pluripotent stem cells (hiPSC) currently remain limited by high interline variability of differentiation and poor efficiency for generating functionally transplantable vascular progenitors (VP). Here, we report the advantage of tankyrase inhibitor-regulated naïve hiPSC (N-hiPSC) for significantly improving vascular cell therapies. Conventional hiPSC reprogrammed from type-1 diabetic donor fibroblasts (DhiPSC) were stably reverted to naïve epiblast-like state with high functional pluripotency with a cocktail of LIF and three small molecules inhibiting the tankyrase, MEK, and GSK3b signaling pathways (LIF-3i). Naïve diabetic VP (N-DVP) differentiated from naïve DhiPSC (N-DhiPSC) expanded more efficiently, possessed higher proliferation, possessed more stable genomic integrity and displayed higher in vitro vascular functionality than primed diabetic VP (DVP) generated from isogenic conventional DhiPSC.Moreover, N-DVP survived, migrated, and engrafted in vivo into the deep vasculature of the neural retinal layers with significantly higher efficiencies than isogenic primed DVP in a murine model of ischemic retinopathy. Epigenetic analyses of CpG DNA methylation and histone configurations at developmental promoters of N-hiPSC revealed tight regulation of lineage-specific gene expression and a de-repressed naïve epiblast-like epigenetic state that was highly poised for multi-lineage transcriptional activation. We propose that reprogramming of patient donor cells to a tankyrase inhibitor-regulated N-hiPSC may more effectively erase epigenetic aberrations sustained from chronic diseases such as diabetes for subsequent regenerative therapies. More broadly, tankyrase inhibitor-regulated N-hiPSC represent a new class of human stem cells with high epigenetic plasticity, improved multilineage functionality, and potentially high impact for regenerative medicine.

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Clinical-grade stem cell–derived retinal pigment epithelium patch rescues retinal degeneration in rodents and pigs

Cited by 232 publications

References 54 publications

A Systematic Review on Transplantation Studies of the Retinal Pigment Epithelium in Animal Models

A Systematic Review on Transplantation Studies of the Retinal Pigment Epithelium in Animal Models

Preclinical safety studies of human embryonic stem cell-derived retinal pigment epithelial cells for the treatment of age-related macular degeneration

Vascular Progenitors Generated from Tankyrase Inhibitor-Regulated Naïve Diabetic Human iPSC Potentiate Efficient Revascularization of Ischemic Retina

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