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. 2023 Aug;13(8):a041308. doi: 10.1101/cshperspect.a041308

iPSC-RPE in Retinal Degeneration: Recent Advancements and Future Perspectives

Tadao Maeda 1,2,3, Masayo Takahashi 1,2,3,✉
PMCID: PMC10411862  PMID: 36690464

Abstract

Regenerative medicine is a great hope for patients suffering from diseases for which no effective treatment is available. With the creation of induced pluripotent stem cells (iPSCs) in 2006, research and development has accelerated expeditiously, reaching a practical stage worldwide. The iPSC-regenerative medicine in ophthalmology is one of the pioneers, which has kicked off clinical application ahead of other fields owing to its advantages. The clinical safety issues of iPSC-derived retinal pigment epithelial (iPSC-RPE) transplantation for exudative age-related macular degeneration have been addressed to a certain extent. Preparations are being made for the next clinical study based on the improvement of its therapeutic effects and expansion of indications globally. Steady progress toward the practical applications of regenerative medicine for the treatment of retinal disorders is expected in the future while strengthening global cooperation amid various research areas, clinical fields, and regulations.

Regenerative medicine, which overcomes intractable and serious diseases by replacing tissues and organs using stem cells to regain lost physical function, is a promising treatment to be used worldwide. Since the mid-1990s, following the dramatic progress of neural stem cells, embryonic stem (ES) cells, and induced pluripotent stem cells (iPSCs) in basic science, regenerative treatment of several diseases by cell transplantation of various tissues has recently commenced, including the diseases of the central nervous system. In the last 10 years, there has been a remarkable progress in research related to regenerative medicine of the eye, including clinical studies on bullous keratopathy using cultured human corneal endothelial cells, age-related macular degeneration, retinitis pigmentosa, and corneal stem cell deficiency using iPSCs. This has been possible because the world's first iPSC-RPE transplantation has obtained promising results well within safety limits. In Japan alone, a total of 11 clinical studies using iPSCs were started. Furthermore, until recently, gene therapy for retinitis pigmentosa and related diseases, for which there existed no cure, has been started in Japan and some other countries of the world. In this study, we describe future prospects, issues, and limitations from the viewpoint of practical treatment with a focus on iPSC-based retinal regenerative medicine.

iPSCs AS A RESOURCE IN REGENERATIVE MEDICINE

Stem cells such as ES cells, iPSCs, and somatic stem cells are characterized by self-renewability and multipotency. ES cells are stem cells that are separated and established from the cell mass inside the blastocyst after fertilization and are capable of differentiating into almost all types of cells/tissues. In 2006, iPSCs designed as ES cell–like pluripotent stem cells were induced from mouse fibroblasts by Professor Shinya Yamanaka at Kyoto University using four transcription factors (Oct3/4, Flk1, Sox2, and c-Myc). Further on, in 2007, the same group succeeded in creating human iPSCs for applications in regenerative medicine, drug discovery support, and in basic research for elucidating the mechanisms of cell differentiation, rejuvenation, and aging processes. Adult somatic stem cells are present in niches in living tissues that maintain a special local microenvironment. They are thought to be responsible for tissue regeneration by replenishing cells lost, owing to developmental processes and tissue damage.

iPSCs used in regenerative medicine can be broadly divided into autologous and allogeneic cells (Fig. 1). Autologous transplantation is a treatment method in which cells are collected from a patient, cultured, processed, and returned to the patient. The risk of immune rejection and infection due to incompatibility of donor cells is reduced, as the patient's own cells are reintroduced into his/her body. Since cells need to be cultured and processed from somatic cells, the time and cost required for such treatment per patient is quite high. In addition, it requires a high level of skill/high efficiency to maintain the same quality of the final product due to differences in cell properties among individuals. On the other hand, in allogeneic transplantation cells collected from selected healthy donors, that meet certain quality standards are used as raw materials, but there is always a risk of immune rejection. In many cases, it is possible to store the cultured and processed cells as intermediates (cell stock) for a long period using methods such as cryopreservation. By such techniques, it is possible to decrease the time and cost required for allogeneic treatment compared to autologous treatment, and also to suppress variations in the quality of the cultured cells making them more suitable for practical use. The pioneer in preparing this material for allogeneic transplantation is the iPS Cell Stock Project for Regenerative Medicine, which has been underway since 2013 at the Center for iPS Cell Research and Application, Kyoto University, Japan (www.cira.kyoto-u.ac.jp/e/research/stock.html). In this project, it was estimated that more than 80% of the Japanese people can be treated with less immune rejection by collecting 75 types of iPSCs using healthy volunteers’ cells with human leukocyte antigens (HLAs) in a homozygous combination at 6 loci. Most recently, to further improve its practical application, the group has started to provide research-grade iPSCs by knocking out the part of HLA that caused rejection, by using gene editing. If this technology is put into practical use, it is expected that only seven types of HLA class C-KO cell lines will be able to cover 95% of the Japanese population in the future (Xu et al. 2019). In addition, several other iPSC lines that can be used in clinical trials are being prepared globally for practical applications in regenerative medicine (commonfund.nih.gov/stemcells/lines; ct.catapult.org.uk/clinical-grade-iPS-cell-line).

Figure 1.

Figure 1.

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Concept of induced pluripotent stem cell retinal pigment epithelial (iPSC-RPE) preparation as regenerative medicine. Transfection of somatic cells with the four Yamanaka factors, including OCT4, SOX2, KLF4, and CMYC (OSKM), results in iPSCs. iPSCs differentiate into RPE cells and are used for autologous or allogeneic transplantation. In the case of allogeneic transplantation, human leucocyte antigen (HLA) matching between donor and host is assessed to determine the protocols of immunosuppressant administration and monitoring of immune rejection against transplanted iPSC-RPE cells. Allogeneic iPSCs with partial HLA gene editing were tested to avoid unfavorable immune rejection against transplanted RPE cells and to minimize immunosuppressant administration. (KO) Knockout, (LGIR) lymphocyte graft immune reaction.

CONCEPT OF STEM CELL–BASED THERAPIES FOR RETINAL DEGENERATION

According to some recent reports, the prevalence of retinal degeneration, such as age-related macular degeneration (AMD) and retinitis pigmentosa (RP), is the leading cause of blindness in the working age group of 15–64 yr, especially in developed countries (Buch et al. 2001; Al-Merjan et al. 2005; Morizane et al. 2019; GBD 2019 Blindness and Vision Impairment Collaborators 2021). However, there is no established treatment for patients with RP or AMD with photoreceptor cell and/or RPE degeneration to date (Scholl et al. 2016; Fleckenstein et al. 2018; Maeda et al. 2021). Stem cell–based therapies are drawing worldwide attention as ES/iPSC-RPE cell studies have evaluated safety and efficacy to a certain extent (Scholl et al. 2016; Maeda et al. 2019, 2021).

Retinal degeneration is an ideal target for stem cell–based therapies because fewer stem cells are required for the human eye compared to other organs owing to its anatomical characteristics (Fig. 2A). Furthermore, high-resolution in vivo retinal imaging systems, such as spectral domain optical coherence tomography (SD-OCT), and adaptive optics scanning laser ophthalmoscopy (AO-SLO) (Fig. 2A), enable precise clinical observation of the retina and allow for close follow-up of stem cell–based therapies. Currently, these therapies are being applied for retinal diseases affecting the outer retinal layers including photoreceptors and RPE, such as AMD (Maeda et al. 2021) and RP with RPE-related gene mutation (Fig. 3). RPE cell products have been used for AMD to halt disease progression via reconstruction of the RPE layer and to restore partial visual function in RP with RPE-related gene mutations (Fig. 1B). Two types of formulations have been in use for the administration of iPSC-RPE at our institute: cell sheets without scaffolds and cell suspensions for patients with wet AMD (Mandai et al. 2017; Sugita et al. 2020). Due to the greater extent of surgical invasiveness involving a wider incision site and occasional removal of choroidal neovascularization (CNV) before RPE sheet transplantation, the risk of surgical complications following RPE sheet transplantation is generally higher than that following RPE cell suspension. Several adverse events associated with surgery such as retinal hemorrhage and edema have been reported in some clinical trials of ES-RPE cell transplantation (da Cruz et al. 2018; Kashani et al. 2018, 2021). However, survival and integration of grafted RPE cells can be improved significantly compared to cell suspension. In fact, in a promising approach, clinical trials of autologous iPSC-RPE on a biodegradable scaffold have been initiated (NCT04627428). It has been reported that long-term outcomes may be affected by the use of non-biodegradable scaffolds in RPE sheet formulation (da Cruz et al. 2018; Kashani et al. 2018, 2021). Although there are several reports on both improvement as well as maintenance of visual acuity to various extents after RPE cell sheet transplantation, several cases of adverse events related to surgery have also been reported (Mandai et al. 2017; da Cruz et al. 2018; Kashani et al. 2018, 2021; Takagi et al. 2019).

Figure 2.

Figure 2.

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Characteristics of the human eye as a target of regenerative medicine: Anatomical structure of the human eye. The anatomical structures of the human eye can be observed using spectral domain optical coherence tomography (SD-OCT) (A) and a fundus camera (B). SD-OCT provides a cross-sectional image of retinal laminar structures consisting of different types of neural structures at micrometer resolution (A, right panel). The positions of the photoreceptor cells and the retinal pigment epithelium (RPE) are indicated in the OCT images. The fundus camera provides an en face image of the retina at various magnifications; for example, a color fundus image shows a wide-angled macro image, and an adaptive optics scanning laser ophthalmoscopy (AO-SLO) image shows the cellular structure of the outer segment of a photoreceptor and RPE at high resolution. (C) Clinical characteristics of retinal degeneration: Retinal degeneration is characterized by various clinical features, which can be observed in ophthalmological examinations and fundus images of retinitis pigmentosa (RP), healthy eyes, wet-type age-related macular degeneration (AMD), and dry-type AMD. In cases of RP with RPE-related gene mutations, degeneration of the outer retina starts from the peripheral retinal region and the macular region is relatively secure. In AMD with either wet- or dry-type features, the macular region is damaged by exudative changes caused by choroidal neovascularization (CNV) formation or geographic atrophy (GA) of the outer retina.

Figure 3.

Figure 3.

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Formulation type for induced pluripotent stem cell retinal pigment epithelium (iPSC-RPE) cell transplantation for retinal degeneration. Formulation of iPSC-RPE cells (A). iPSC-RPE cells prepared from iPSCs were stored as a frozen stock/intermediate product. The frozen stock was defrosted, and RPE cells were cultivated for 2 weeks to recover their functions. iPSC-RPE cells can be formulated into three different types: cell sheets, strips, or suspensions. These formulations can be used for wet-type age-related macular degeneration (AMD) according to the pathological condition and size of exudative lesions to maximize the advantage of each formulation (B). In the case of RPE-impaired disease, including dry-type AMD, RPE cell suspension or cell strips could be used to cover pathological lesions enough to predict the efficacy of RPE cell therapy (C). (VEGF) Vascular endothelial growth factor, (CNV) choroidal neovascularization.

On the other hand, clinical trials that used ES or iPSC-RPE cells have reported that RPE cell suspension transplantation is less invasive than that with an RPE sheet because a small-gauge cannula with a soft tip (38G) is used in the former procedure (Schwartz et al. 2015; Song et al. 2015; Mehat et al. 2018; Sugita et al. 2020). Similar reports exist on adverse events in the epiretinal membrane both for ES and iPSC-RPE associated with suspension, most likely due to leakage of cells from the transplanted lesions (Schwartz et al. 2015; Song et al. 2015; Mehat et al. 2018; Sugita et al. 2020). Although some cases showed retinal sensitivity improvement in these areas, there was no significant improvement in visual function, including visual acuity, or quality-of-life assessment (Schwartz et al. 2015; Song et al. 2015; Mehat et al. 2018; Sugita et al. 2020).

To improve the efficacy and safety of RPE cell transplantation, a new formulation using RPE strips has been reported (Nishida et al. 2021) and preparation for clinical research is underway (jRCTa050210178). RPE strips have the advantage of both cell sheets and cell suspensions and can be prepared in 2 d. RPE strips are expected to be a useful alternative to the other two formulations because of their ability to expand into a monolayer sheet in the subretinal space after transplantation from a small retinal hole (Fig. 3A,B).

Furthermore, clinical research on iPSC retinal sheets for RP with photoreceptor degeneration has just begun to find ways to restore the functional and anatomical integrity of the neural retina (jRCTa050200027). In the future, a combination of cell products with RPE and retinal sheets might be a viable option for the treatment of advanced AMD with both photoreceptor and RPE degeneration, as well as for RP with similar pathology (jRCTa050190084). The clinical studies on iPSC-RPE cell transplantation are summarized in Table 1.

Table 1.

Clinical studies on stem cell–based therapies for retinal degeneration

No. Study title Sponsor/collaborators Study design Intervention Age Ph No. of subject Period Status Study ID
1 A study of transplantation of autologous- induced pluripotent stem cell (iPSC)-derived retinal pigment epithelium (RPE) cell sheet in subjects with exudative age-related macular degeneration The Laboratory for Retinal Regeneration, RIKEN Center for Developmental Biology Intervention model: single group assignment;
masking: none (open label);
primary purpose: safety		 Autologous human iPSC (hiPSC)-derived RPE cell sheet 50 yr and older P1 1 Oct. 2013/Sept. 2018 Completed UMIN000011929
2 Autologous transplantation of iPSC-derived RPE for geographic atrophy associated with age-related macular degeneration National Institutes of Health Clinical Center, Bethesda, Maryland, USA Intervention model: single group assignment;
masking: none (open label);
primary purpose: treatment		 Combination product: hiPSC-derived RPE/ polylactic-co-glycolic acid (PLGA) scaffold 55 yr and older P1/II 20 July 2020/Mar. 2029 Recruiting NCT04339764
3 A study of transplantation of allogeneic iPSC- derived RPE cell suspension in subjects with neovascular age- related macular degeneration The Laboratory for Retinal Regeneration, RIKEN Center for Developmental Biology, Kobe, Japan/Kobe City Medical Center General Hospital, Kobe, Japan Intervention model: single group assignment;
masking: none (open label);
primary purpose: safety		 Subretinal transplantation of allogeneic hiPSC-derived RPE cells 50 yr to 85 yr P1 5 Feb. 2017/Oct. 2021 Active, not recruiting UMIN000026003
4 Clinical research of allogeneic iPSC-RPE cell strips transplantation for RPE impaired disease Kobe Eye Hospital Intervention model: single group assignment;
masking: none (open label);
primary purpose: treatment		 Allogeneic iPSC-RPE cell strips 20 yr and older P1/2 50 Feb. 2022/Feb. 2032 Recruiting jRCTa050210178
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Referenced clinical trials are either registered with clinicaltrials.gov or jrct.niph.go.jp.

CLINICAL RESEARCH ON iPSC-RPE TRANSPLANTATION FOR AMD

AMD is a leading cause of severe central vision loss in the elderly worldwide. AMD is induced via sequential damage to the RPE, Bruch's membrane, the choroidal membrane, and photoreceptors due to pathological changes with age. The global prevalence of AMD is 8.7%, and it is estimated to affect approximately 288 million individuals globally by 2040 (Wong et al. 2014). Advanced stages of AMD are categorized into two forms: non-neovascular (dry, nonexudative, or geographic atrophy [GA]), and neovascular (wet or exudative). Dry AMD is characterized by GA of the outer retina, including the RPE, photoreceptors, and choriocapillaris, which results in gradual retinal cell loss and decreased visual acuity. In wet-type AMD, CNV causes exudative changes involving subretinal leakage of blood, lipids, and fluids, and the formation of fibrous scars. In wet-type AMD, anti-vascular endothelial growth factor (VEGF) antibodies are used as a standard treatment to improve visual function in many cases. However, some patients are resistant to anti-VEGF antibody treatment. In addition, cases of RPE atrophy or RPE tear due to the long-term administration of anti-VEGF antibody treatment have been reported (Nagiel et al. 2013; Young et al. 2014; Kuroda et al. 2015, 2016; Daniel et al. 2020). Furthermore, they only suppressed the proliferation of CNV and did not ameliorate RPE atrophy. Since no cure for RPE degeneration exists to date, reconstruction and functional recovery of RPE by cell transplantation are needed to maintain or restore visual function (Fig. 1). Research on RPE cell transplantation began to attract attention in the late 1980s. Transplanting human RPE cells into the subretinal space of monkeys showed engraftment on Bruch's membrane (Gouras et al. 1985). Since then, several reports have been published on the protective effect of RPE cell transplantation on neural retinas in animal models (Singh et al. 2020). These studies demonstrated the proof-of-concept (POC) of cell therapy with RPE for diseases of the outer retinal layer.

Peyman et al. (1991) first reported RPE transplantation in humans with AMD in 1991. In the first case, autologous cell transplantation was performed after removing proliferative tissue under the macula. The nearby RPE was transplanted into the macula to improve visual acuity. In the second case, the RPE was exfoliated from the donor's eye as a sheet and transplanted, but no visual acuity improvement was observed. In another study, the CNV of AMD was removed and a cell sheet obtained by culturing fetal-derived RPE was transplanted into a sheet (Algvere et al. 1994, 1997); however, immune rejection occurred after the operation. Weisz et al. also reported that when fetal RPE was injected as a cell suspension, no improvement in visual acuity or graft fibrosis was observed (Weisz et al. 1999). Del Priore et al. (2001) transplanted a donor RPE sheet after CNV removal, but engraftment was poor and visual acuity did not improve. In this way, almost all transplants using allografts in eyes that have destroyed the blood–retinal barrier by CNV removal showed rejection and deterioration in visual acuity.

Autologous transplantation is ideal to avoid rejection and RPE collected from the peripheral area is frequently transplanted (Joussen et al. 2006; Maaijwee et al. 2007; MacLaren et al. 2007). Reports suggest that although some patients had improved visual acuity, it is difficult to collect sufficient autologous RPE cells with stable quality, and serious adverse events frequently occur due to surgical intervention. Furthermore, when peripheral RPE patches with choroid were transplanted, some of the patients obtained good visual acuity. However, surgery had a higher risk of cutting out patches and the choroid could act as a fibrous tissue if it was not connected to the host choroidal vessels.

As a countermeasure against these problems, we reviewed the cell source of the transplant and suggested that RPE cells derived from ES-RPE and iPSC-RPE are promising candidates as graft cells (Haruta et al. 2004; Hirami et al. 2009; Osakada et al. 2009). It has been observed that both ES-RPE and iPSC-RPE have the same functions as those derived from living organisms, such as the formation of cell sheets with a collection of hexagonal cells with tight junctions. These cells, which can be prepared more easily than primary cultured RPE cells, have led to dramatic developments in cell therapy for AMD. Recent advances in RPE cell transplantation research among various pluripotent stem cells can be attributed to the fact that ES-RPE/iPSC-RPE have all the following conditions suitable for their clinical application: (1) they have the required cell functions (quality), (2) the retina requires a small number of cells so that enough cells can be manufactured for transplantation (amount), (3) cells with certified quality for clinical use can always be obtained (reproducibility), and (4) their purity is satisfactory (safety). Furthermore, subretinal surgeries such as CNV removal has already been performed. Thus, the field of ophthalmology, as described above, has contributed significantly to the area of clinical application of iPSCs.

Autologous iPSC-RPE Cell Sheet Transplantation

In August 2013, we initiated clinical research on autologous iPSC-RPE cell sheet transplantation through joint research with RIKEN, the Institute of Biomedical Research and Innovation Hospital, and Kobe City Medical Center General Hospital (UMIN000011929). The skin of the patient was collected in November 2013, and CNV removal and RPE sheet transplant surgery were performed in September 2014. In September 2015, 12 mo after transplant surgery, safety and effectiveness were evaluated as the primary and secondary end points, respectively (Mandai et al. 2017). The 4-yr report has already been published (Takagi et al. 2019), and the 5-yr follow-up has been completed (Fig. 2). No intraoperative complications, tumorigenesis, engraftment failure, rejection, or other serious complications of transplanted cells, which were the primary end points, were observed 5 yr after surgery. No recurrence of CNV was observed in patients in the absence of additional anti-VEGF antibody treatment. Corrected visual acuity was maintained at 0.09 preoperatively. When comparing the preoperative and final observations, the foveal retinal thickness decreased from 0.298 mm before transplantation to 0.170 mm 1 yr after transplantation. However, it increased to 0.569 mm, 5 yr after transplantation due to the development of macular edema, although macular edema was dramatically decreased by topical steroid treatment (Fig. 2B). Regarding the graft, the major axis, minor axis, and thickness observed were 2.667 mm, 0.623 mm, and 0.33 mm, respectively, 3 d after transplantation. Six months later, the major and minor axis increased to 3.261 mm and 1.635 mm, respectively, and a further increase to 3.366 mm and 2.232 mm, respectively, was observed 5 yr later. The area of the graft was 1.521 mm2 3 d after transplantation and a threefold increase to 5.471 mm2 was seen 1 yr after transplantation. The size of the RPE sheet was relatively stable, with an area of 6.532 mm2 at 3 yr and 5.769 mm2 at 5 yr after transplantation. The choroidal volume was relatively stable from 0.56 mm3 before transplantation to 0.43 mm3 5 yr after transplantation immediately below the transplantation site but decreased from 2.31 mm3 to 1.40 mm3 around the transplantation site. In addition, according to the National Eye Institute (NEI), evaluation of the safety and feasibility of subretinal transplantation of iPSC-RPE that is grown as a monolayer on a biodegradable polylactic-co-glycolic acid (PLGA) scaffold, as a potential autologous cell-based therapy for GA preparations associated with AMD, is underway.

Allogeneic iPSC-RPE Cell Suspension Transplantation

The world's first autologous iPSC-RPE cell transplantation was carefully studied, and the results suggested that autologous iPSC-RPE transplantation is safe and effective (Mandai et al. 2017). Our next aim was to study allogeneic transplantation. First, we established a test system that can evaluate and manage immune rejection for allogeneic RPE transplantation, called the lymphocyte graft immune reaction (LGIR) test (Fig. 4). We also established a test to detect grafted RPE-specific antibodies (donor-specific antibodies [DSAs]) (Sugita et al. 2020).

Figure 4.

Figure 4.

Figure 4.

Figure 4.

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Monitoring immune rejection against allogeneic-induced pluripotent stem cell retinal pigment epithelial (iPSC-RPE) after transplantation. A lymphocyte graft immune reaction (LGIR) test was developed and used to detect the immune response of the transplanted RPE cells (A). Peripheral blood mononuclear cells (PBMCs) were collected and incubated with irradiated iPSC-RPE cells. The immune response of PBMCs against irradiated iPSC-RPE cells was monitored by flow cytometry. The LGIR results and findings of the fundus and optical coherence tomography (OCT) images of a patient with wet-type age-related macular degeneration in clinical research on allogeneic iPSC-RPE cell suspension transplantation are shown after transplantation. Mild immune rejection was suspected 5 wk after transplantation according to an increase in the activated PBMC population (red frame in B), and exudative changes in fundus images (white arrows in C and D), and OCT images (yellow arrow in E). (Legend continues on following page.) Immune rejection was ameliorated at 8 wk after transplantation due to a decrease in the activated PBMC population (F, red frame), and attenuated exudative changes in fundus images (white arrows in G and H), and OCT images (yellow arrow in I) by treatment with subcapsular injection of triamcinolone. (T) T cell, (B) B cell, (DC) dendritic cell. (Panels B–E reprinted from Maeda et al. 2021 because original article was published under an open access Creative Common CC BY license.)

In our preclinical studies (Sugita et al. 2016a,b; Fujii et al. 2020), we confirmed the reliability of the LGIR test in determining immune rejection after RPE cell transplantation. Thereafter, a local steroid administration protocol, a clinical study of allogeneic iPSC-RPE suspension transplantation (UMIN000026003), was conducted in collaboration with RIKEN, Center for iPS Cell Research and Application, Kyoto University (CiRA), Osaka University, and Kobe City Medical Center General Hospital in Japan. This study aimed to investigate the safety of six HLA loci-matched allogeneic cell transplantations under local steroids only, to develop/establish future standard cell therapy with iPSC-RPE (Sugita et al. 2020).

In the period of March to September 2017, transplantation was performed on five patients with exudative AMD who had the same HLA haplotype as allogeneic iPSC-RPE. Twelve months after transplantation surgery, safety and efficacy were evaluated as primary and secondary end points, respectively. The following are the notable points taken from that study: (1) The raw material was established from an HLA 6-locus homozygote donor manufactured by CiRA, Kyoto University; (2) Dosage of a cell suspension that is easy to store and transport and is considered less invasive by transplantation was selected; (3) A frozen stock of RPE cells was created as an intermediate, which was thawed as per requirement on the date of transplantation. Recovery culture was performed for 2 weeks, and the cell suspension was prepared using a dedicated transplant medium; (4) At the time of transplantation, the procedure for removal of neovascularization was not performed in autologous RPE transplantation, and a commercially available ophthalmic cannula (PolyTip cannula 25 g/38 g; MedOne, Sarasota, FL) was used as a dedicated transplantation device for the cell suspension; and (5) Immune rejection after transplantation was evaluated using a test system (LGIR and DSA) that assessed the immune response of the participant's peripheral lymphocytes to the transplanted cells in vitro, RPE-specific antibody, and OCT imaging to detect any exudative findings at the RPE-transplanted lesion.

There were no intraoperative complications, and the RPE cell suspension was implanted in the subretinal space as planned in all five cases. According to the protocol, anti-VEGF antibodies and topical ocular steroids were administered at the time of transplantation to treat the underlying disease and suppress rejection. In a follow-up examination after transplantation, only one out of five cases were suspected of having mild immune rejection from OCT findings. LGIR was found to be slightly positive, indicating subtle immune rejection. In this case, administration of additional sub-Tenon topical steroids resulted in successful management. However, no noticeable rejection of transplanted cells was observed during the observation period. In case of any occurrence of rejection, it can be managed with topical ocular steroids. Among the three cases in which a positive reaction was observed in LGIR, only one case showed clinical findings suggestive of rejection of transplanted cells, whereas none of the cases showed damage to photoreceptor cells directly above the transplanted cells. The epiretinal membrane was observed in all cases, whereas macular edema resistant to anti-VEGF antibody treatment was observed only in one case and vitreous surgery was performed for its removal. The study concluded that grafted RPE cells survived in all five cases for more than 2 yr and further suggests that the instances of immune rejection and complications that occurred during this study could be managed appropriately (Fig. 5; Sugita et al. 2020).

Figure 5.

Figure 5.

Figure 5.

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Clinical findings of induced pluripotent stem cell retinal pigment epithelial (iPSC-RPE) transplantation to wet-type age-related macular degeneration (AMD) patients. Survival of the autologous iPSC-RPE sheet was observed stably for 5 yr in subretinal transplanted lesions while maintaining pigmentation and a slight increase in graft size (A, green arrows). Changes in the retinal structure before and after surgery were monitored using optical coherence tomography (OCT) (B). The outer nuclear layer (*) and inner and outer segment (IS/OS) junction lines were recognized at the RPE sheet-transplanted lesion (above the orange arrow), whereas the retinal structure was disrupted before surgery (b′). The corrected visual acuity of the patient was stably maintained for 5 yr without significant changes, and anti-VEGF antibody treatment was completely discontinued after surgery (C). Quantitative assessment of transplanted iPSC-RPE cells in a representative case of the clinical research on iPSC-RPE cell suspension transplantation. Color fundus photographs and early-phase fluorescein angiography (FA) images were obtained during pretreatment (C) and 1 yr after treatment (D). (E) Window defect (WD) shown by binary image processing of the FA images at pretreatment. The FA image was processed using binary imaging (E, left panel), and the vessel images were manually removed (E, right panel). Overlays of WD binary images for pretreatment FA (F) and FA at 1 yr after treatment (G). The WD area is displayed in pixels. (H) Automated measurement of the WD area with soft tissue was performed using deep learning. The decrease in the WD area due to RPE engraftment is indicated by the score (pixel). Polarization-sensitive OCT showed that the presence of pigmented RPE cells indicated that the high-entropy area was above the RPE basement membrane and that there was a time-dependent decrease in the low-entropy area within the fovea-centered 3-mm-diameter circle. The low-entropy areas at 1, 7, and 12 mo after transplantation are shown in black on the entropy map for each time point with the percentage of the black area within the red circle. Low-entropy areas for each time point were aligned with the retinal vessels and are shown in the right panel to demonstrate consistency in the pattern (H). Time course of a representative section view at the white line on the left color fundus image, which shows the continuity of the presumably melanin-containing RPE cells covering the surface of the fibrous tissue 12 mo after transplantation. (Panels A and B reprinted from Maeda et al. 2021 because original article was published under an open access Creative Common CC BY license.) (See facing page for legend.)

REGENERATIVE MEDICINE-RELATED LAWS: TOWARD THE REALIZATION OF SAFE AND HIGH-QUALITY MEDICAL CARE

The Regenerative Medicine Promotion Act was enacted in April 2014 to quickly and safely promote the practical applications of regenerative medicine. The basic philosophy of the Act includes comprehensive efforts aimed at the realization of safe research development, and the spread of treatments based on the consideration of bioethics associated with treatments using human cells. Therefore, it is permitted to outsource the cultivation and processing of cells and tissues, used for regenerative medicine, to a certified corporate factory outside the medical institution to promote industrialization and commercialization. Furthermore, apart from its promotion, it is stipulated that the basic policy should be reviewed at least every 3 years if required.

In connection with this law, the Act on the Safety of Regenerative Medicine was enacted in 2014, which sets regulations for all clinical studies and treatments led by hospitals using cells or genes. According to this law, depending on the cell type applied to humans, first-, second-, and third-class tiers of regenerative medicine were defined. The first class is for pluripotent stem cells and other allogeneic cell therapies. The criteria for determining which category each medical technology falls into will be reviewed in accordance with technological progress and changes over time. Of note, in the United States, the 21st Century Cures Act was enacted at the end of 2016 and progress is being made toward the establishment of a system similar to the conditional and time-limited approval system in Japan. In particular, the same section defines a new category of “regenerative medicine advanced therapy” (RMAT) and stipulates that the above-mentioned accelerated approval system can be applied to products that meet its requirements (www.fda.gov/regulatory-information/selected-amendments-fdc-act/21st-century-cures-act#:~:text=The%2021st%20Century%20Cures%20Act, them%20faster%20and%20more%20efficiently).

DEVELOPMENT OF REGENERATIVE MEDICINE: FROM MANUFACTURING TO CLINICAL APPLICATIONS

Unlike small molecule compounds, regenerative medicines should use cells that are heterogeneous and changeable at any time. They undergo a quality control test and a highly controlled manufacturing process (induction of differentiation if derived from iPSCs); however, cells are not yet homogeneous. They may change characteristics even after transplantation according to the host environment. Furthermore, when the final product forms a tissue, transplantation to a diseased site is a prerequisite, and it may be necessary to prepare a transplantation device for this purpose and study the transplantation techniques. The safety and efficacy of regenerative medicine products in these developmental stages are verified through nonclinical animal tests, and after being evaluated in accordance with the criteria described later, clinical studies and trials are conducted. For those cells that exist in the body, the clinical efficacy will be determined by surgical techniques and the retaining ability of the host tissue. However, it is difficult to speculate on the treatment effect only by randomized controlled trials (RCTs), or in other words, RCT results cannot be applied to every surgery. Therefore, suitable regulations are required for such new fields of medicine.

FUTURE PROSPECTS AND CHALLENGES IN RETINAL REGENERATIVE MEDICINE

New Category of Disease Group and Medication for Retinal Degeneration

While RPE is responsible for maintaining retinal homeostasis (Boulton and Dayhaw-Barker 2001; Sparrow et al. 2010; Palczewski 2014), it has been suggested that functional deterioration of RPE may be a major cause of some hereditary and nonhereditary retinal degenerative diseases, such as AMD (Hageman et al. 2001; Sparrow et al. 2010; Ach et al. 2014). RPE is a layer of pigment epithelial cells that exists in the outer layer of the retina and plays an important role in maintaining homeostasis of the retina such as stress relief in the photo response of retinal photoreceptor cells and maintenance of photoreceptor function. Retinal disease, which is included in the hereditary disease group, is caused by age-related pathological changes such as genetic abnormalities expressed in RPE, oxidative stress associated with aging, and abnormal accumulation of waste products. It has been suggested that it can be a major cause of RP and AMD, which have been the target diseases of clinical studies using RPE transplantation. There are several other retinal degenerative diseases mainly caused by RPE deficiency and are grouped into one disease group called RPE-impaired diseases. These rare diseases include RP, diseases related to RP, and RP with RPE-related gene abnormalities (those with abnormalities in genes such as RPE65, RDH5, and MERTK). This group also includes AMD, which is a common cause of blindness in the elderly, and is recognized as one of the intractable diseases of the eye. Although the pathogenesis of these diseases is different, RPE cell dysfunction and degeneration are common, and a standard treatment for RPE cell dysfunction and degeneration has not been established to date. Cell transplantation may be effective, but this requires further research. Therefore, retinal degenerative disease, a common pathological condition for which this treatment method has not been established yet, was targeted as a disease group called RPE-impaired disease. Clinical research is being conducted on corneal epithelial stem cell exhaustion as a target disease for regenerative medicine of the corneal epithelium, which has been proposed under the same concept as RPE-impaired disease.

Objective Evaluation of RPE Transplantation for Retinal Degeneration

Because of the variation in disease types in RPE-impaired diseases, setting a primary end point that can be objectively evaluated among these multiple diseases and incorporating various visual function tests as secondary end points is indispensable for performing clinical studies efficiently. This evaluation will enable the identification of diseases for which RPE cell transplantation can be effective. To address issues related to RPE-impaired diseases, evaluation methods using a window defect (WD) and clinical findings of fluorescein angiography (FA), which is an imaging test used in general ophthalmic practice, were designed. Since the WD shows an RPE abnormal region in the FA as a lesion with hyperfluorescence, measurement of the decrease in WD after RPE transplantation is suggested to represent engraftment of transplanted cells. This method was successfully used to quantify the engrafted area in a previous study (Sugita et al. 2020) and the quality of analyses was improved using automated measurement software driven by deep learning (Motozawa et al. 2022). It is possible to develop a treatment method for rare diseases by collectively evaluating the efficacy using this concept. In fact, as in a past case, it is indicated for patients with severe myopia who have decreased visual acuity due to CNV, as well as in exudative AMD, even though an anti-VEGF drug was likely to be effective. Since it took 7 years to be approved, it may be useful to conduct clinical trials on a group of diseases to examine the safety and efficacy of diseases with common pathological conditions. From these observations, proper treatments can be provided according to the stage of the disease in retinal degeneration with categorized medicines in combination with other types of treatments (Fig. 6).

Figure 6.

Figure 6.

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Treatment strategy with categorized medicine for retinal degeneration. Categorized medicine is a therapeutic strategy based on the pathology of the retina, rather than on a disease-by-disease basis. In the early stage of retinal degeneration, the photoreceptor cells and retinal pigment epithelial cells to be treated are intact; therefore, gene therapy or drug therapy with neuroprotective factors for these cells is indicated. Gene therapy or cell transplantation is indicated at the stage of severe dysfunction or degeneration of the retinal cells. Cell transplantation is indicated when retinal degeneration progresses and photoreceptor cells and retinal pigment epithelial cells disappear. Optogenetic or artificial retinas are indicated in the final stages of damage to the inner retina. (Figure based on data in Scholl et al. 2016.)

Improvement of Formulation for Better Efficacy

In the allogeneic iPSC-RPE cell suspension transplantation performed so far for wet-type AMD, the formation of an anterior retinal membrane, which is thought to be caused by cell leakage from the transplantation site, is frequently observed (Sugita et al. 2020). This has also been reported in clinical trials of RPE cell suspensions derived from ES cells by another group (Maeda et al. 2021). No direct adverse events have occurred due to anterior retinal membrane formation itself, and it can be dealt with by vitreous surgery performed in general medical care. However, the effects of cell transplantation treatment are the reconstruction and functional recovery of the RPE layer on the premise of engraftment of transplanted cells, the effect on visual function due to anterior retinal membrane formation, and the risk of vitreous surgery as a countermeasure. Based on the above, it is desirable to improve the transplantation technique for prompt engraftment of transplanted cells at the subretinal transplantation site, thereby suppressing the leakage of nonadherent cells. Several nonclinical studies have confirmed that transplanting cells with a simple aggregated strip provides shape, facilitates observation of the transplanted cells, and suppresses the risk of postoperative leakage (Nishida et al. 2021). Preparations for clinical research using this technique are currently in progress (Table 1).

Other Technical Improvements in Retinal Regenerative Medicine

A strategy to consistently establish manufacturing and treatment methods is important for the practical application of retinal regenerative medicine. For example, cost reduction can be expected by reviewing the cells used as raw materials and the manufacturing method in a timely manner. In fact, for research purposes, the Kyoto iPS Cell Research Institute, Japan has started to provide iPSCs that are partially KO HLA. Since these cells are less likely to be rejected even by recipients with different HLA haplotypes, there is a possibility that the cost of cell raw materials can be reduced if they are put into practical use. Furthermore, in currently planned retinal cell transplantations, the number of transplanted cells and the transplantation site are limited; thus, significant improvements in visual acuity and visual field cannot be expected. Therefore, it is important to evaluate the anatomical recovery and normalization of the retinal structure at the transplantation site. Polarization-sensitive OCT (PS-OCT) and AO are new diagnostic imaging techniques for this problem (Fig. 5). Since PS-OCT can visualize melanin pigment that is abundant in healthy RPE cells, it is possible to distinguish normal RPE sites from abnormal ones where RPE is deficient or dysfunctional. In addition, AO enables retinal observations at the cellular level (Fig. 5). Using these techniques, a more precise evaluation can be attained if cells are engrafted at an abnormal RPE site and normalization of the retinal structure is seen.

CONCLUDING REMARKS

Cell therapies with iPSC-RPE have significant potential as curative treatments for retinal degeneration because of the distinct advantages of retinal characteristics, and such diseases are an attractive target for applications/implementations of regenerative medicine. However, several important issues remain yet to be addressed, and the relevant basic research areas must continue to solve these practical problems. It is expected that advances in the clinical applications of stem cell–derived retinal cells will be made with the help of various technologies from several/diverse/disparate fields, and cooperation with regulatory systems to design more suitable clinical studies for regenerative medicine. In the future, comprehensive therapeutic strategies should be developed and made available for the pharmacological treatment of retinal degeneration, along/together with other therapies/remedial treatments (e.g., gene therapy).

ACKNOWLEDGMENTS

We would like to thank Dr. Yasuo Kurimoto, Dr. Michiko Mandai, Dr. Sunao Sugita, Dr. Yasuhiko Hirami, and Dr. Akiko Maeda (Kobe Eye Center Hospital) for their valuable comments and support.

Footnotes

Editors: Eyal Banin, Jean Bennett, Jacque L. Duncan, Botond Roska, and José-Alain Sahel

Additional Perspectives on Retinal Disorders: Genetic Approaches to Diagnosis and Treatment available at www.perspectivesinmedicine.org

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