Allogenic iPSC-derived RPE cell transplants induce immune response in pigs: a pilot study

Sohn, Elliott H.; Jiao, Chunhua; Kaalberg, Emily E.; Cranston, Cathryn M.; Mullins, Robert F.; Stone, Edwin M.; Tucker, Budd A.

doi:10.1038/srep11791

Cited by 53 publications

(47 citation statements)

References 51 publications

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“…In larger eyed animals, such as rabbits, pigs, and monkeys, the lens:vitreuscavity ratio is much smaller and more space is available to insert instruments. RPE sheets are usually placed using forceps or custom-made delivery tools [81][82][83]. Before placement of the graft, a complete vitrectomy is mostly performed, which is impossible in rodent eyes so far.…”

Section: Small Eyes Big Eyesmentioning

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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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: Small Eyes Big Eyesmentioning

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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“…Allogeneic porcine iPSC-RPE were delivered by subretinal injection into Yucatan mini pigs, and while no tumor formation was detected, there was an innate immune response, suggesting that immunologically matched cells may need to be used (Sohn et al, 2015). Similarly, transplant rejection was detected in allogeneic iPSC-RPE sheet transplantation into nonhuman primates, which was not detected in autologous nonhuman primate injections (Kamao et al, 2014).…”

Section: Cell-based Therapeutic Strategies For Rddsmentioning

confidence: 99%

Cell-based therapeutic strategies for replacement and preservation in retinal degenerative diseases

Jones

Lü

Girman

et al. 2017

Progress in Retinal and Eye Research

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Cell-based therapeutics offer diverse options for treating retinal degenerative diseases, such as age-related macular degeneration (AMD) and retinitis pigmentosa (RP). AMD is characterized by both genetic and environmental risks factors, whereas RP is mainly a monogenic disorder. Though treatments exist for some patients with neovascular AMD, a majority of retinal degenerative patients have no effective therapeutics, thus indicating a need for universal therapies to target diverse patient populations. Two main cell-based mechanistic approaches are being tested in clinical trials. Replacement therapies utilize cell-derived retinal pigment epithelial (RPE) cells to supplant lost or defective host RPE cells. These cells are similar in morphology and function to native RPE cells and can potentially supplant the responsibilities of RPE in vivo. Preservation therapies utilize supportive cells to aid in visual function and photoreceptor preservation partially by neurotrophic mechanisms. The goal of preservation strategies is to halt or slow the progression of disease and maintain remaining visual function. A number of clinical trials are testing the safety of replacement and preservation cell therapies in patients; however, measures of efficacy will need to be further evaluated. In addition, a number of prevailing concerns with regards to the immune-related response, longevity, and functionality of the grafted cells will need to be addressed in future trials. This review will summarize the current status of cell-based preclinical and clinical studies with a focus on replacement and preservation strategies and the obstacles that remain regarding these types of treatments.

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“…Although extensive data exist to demonstrate that iPSC‐derived retinal cells have the ability to integrate with the remaining host retina , different strategies for retinal cell replacement have resulted in variable success. For instance, nonautologous iPSC‐derived RPE cell transplants can result in minimal clinical adverse effects, but elicit an immune response at the cellular level in various animal models . On the other hand, autologous RPE transplantation studies in humans have resulted in retinal detachment, ocular inflammation, proliferative vitreoretinopathy, and/or hemorrhage post‐transplantation .…”

Section: Introductionmentioning

confidence: 99%

“…Supplementing our understanding through animal experimentation, several trials have focused on transplantation of ES‐derived and iPSC‐derived RPE cells for the treatment of AMD . A unifying theme of these trials has been that delivery of stem cell‐derived RPE cells in suspension is inferior to transplantation of RPE cells as an organized sheet (RPE cell graft) .…”

Section: Introductionmentioning

confidence: 99%

“…We and others have previously demonstrated the ability to (a) identify the specific genetic mutations responsible for causing various inherited eye diseases in our patients ; (b) generate patient‐derived iPSCs and correct their disease causing mutations using the CRISPR‐Cas9 system ; (c) differentiate iPSCs into retinal cells using good manufacturing practices (GMP) ; and (d) transplant allogenic iPSC‐derived photoreceptor or RPE cells into a large animal model using pars plana vitrectomy and subretinal injections . The goals of this study were twofold: first, we sought to optimize our donor cell dissociation methods in an attempt to isolate the maximum number of healthy RPCs from three‐dimensional (3D) retinal organoids that could be delivered for seeding of retinal cell grafts; second, we sought to characterize and optimize the subretinal injection parameters used for creating a subretinal bleb prior to retinal graft transplantation.…”

Section: Introductionmentioning

confidence: 99%

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Optimizing Donor Cellular Dissociation and Subretinal Injection Parameters for Stem Cell-Based Treatments

Scruggs

Jiao

Cranston

et al. 2019

Stem Cells Translational Medicine

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Subretinal delivery of stem cell‐derived retinal cells as a strategy to treat retinal degenerative blindness holds great promise. Currently, two clinical trials are underway in which human fetal retinal progenitor cells (RPCs) are being delivered to patients by intravitreal or subretinal injection to preserve or restore vision, respectively. With the advent of the induced pluripotent stem cell (iPSC), and in turn three‐dimensional derivation of retinal tissue, it is now possible to generate autologous RPCs for cell replacement. The purpose of this study was to evaluate the effect of commonly used cell isolation and surgical manipulation strategies on donor cell viability. iPSC‐RPCs were subjected to various conditions, including different dissociation and isolation methods, injection cannula sizes, and preinjection storage temperatures and times. The effects of commonly used surgical techniques on both host and donor cell viability were evaluated in Yucatan mini‐pigs (n = 61 eyes). We found a significant increase in cell viability when papain was used for RPC isolation. In addition, a significant decrease in cell viability was detected when using the 41G cannula compared with 31G and at storage times of 4 hours compared with 30 minutes. Although 96.4% of all eyes demonstrated spontaneous retinal reattachment following injection, retinal pigment epithelium (RPE) abnormalities were seen more frequently in eyes receiving injections via a 31G cannula; interestingly, eyes that received cell suspensions were relatively protected against such RPE changes. These findings indicate that optimization of donor cell isolation and delivery parameters should be considered when developing a subretinal cell replacement strategy. Stem Cells Translational Medicine 2019;8:797&809

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Allogenic iPSC-derived RPE cell transplants induce immune response in pigs: a pilot study

Cited by 53 publications

References 51 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

Cell-based therapeutic strategies for replacement and preservation in retinal degenerative diseases

Optimizing Donor Cellular Dissociation and Subretinal Injection Parameters for Stem Cell-Based Treatments

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