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Irreversible visual impairment is mainly caused by retinal degenerative diseases such as age-related macular degeneration and retinitis pigmentosa. Stem cell research has experienced rapid progress in recent years, and researchers and clinical ophthalmologists are trying to implement this promising technology to treat retinal degeneration. There is currently no surgical or pharmacological solution to regenerate an injured or degenerative retina, and the only approach ophthalmologists can take is to slow the progress of the loss of vision. In the last decade, many efforts have been made to take advantage of the promising properties of the stem cell technology and apply them to retinal degenerative diseases.
The first level of search using “Stem cell transplant AND retina” keywords produced 1229 publications indexed in PubMed. By using the filter “Human” authors excluded 459 of the studies. Two additional filters were subsequently applied in order to ensure that the aim of the studies focused on patient intervention and excluded in vitro or animal experimental procedures. Authors used the “Adult: 19+ years” PubMed filter followed by “Child: birth-18 years”, which resulted in a data set of 121 studies. Authors then identified 12 review articles and 12 clinical trials by activating the corresponding filters in PubMed. Two of the clinical trials were not related to retinal treatments and were excluded from the study. A summary of the conclusions of the 10 papers containing results from clinical trials and published between 2014 and 2021 [1][2][3][4][5][6][7][8][9][10] is presented in Table 1.
Table 1. Summary of the results of the articles linked to clinical trials using stem cells to treat human retinal diseases.
Title |
Disease |
Intervention |
Results |
Human embryonic stem cell (hESC)-derived retinal pigment epithelium in patients with age-related macular degeneration and Stargardt macular dystrophy: follow-up of two open-label phase 1/2 studies (NCT01345006 and NCT01344993) [5] |
Stargardt macular dystrophy. |
Subretinal transplantation of hESC-derived retinal pigment epithelium |
Evidence of the medium-term to long-term safety, graft survival, and possible biological activity of pluripotent stem cell progeny in individuals with any disease. |
Atrophic age-related macular degeneration. |
|
|
|
Phase 1 clinical study of an embryonic stem cell-derived retinal pigment epithelium patch in age-related macular degeneration (NCT01691261) [1] |
Severe exudative AMD. |
Subretinal implant of engineered human embryonic stem cell (hESC)-derived RPE patch. |
Successful delivery and survival of the RPE patch. |
|
data |
Visual acuity gain of 29 and 21 letters. |
|
Transplantation of Human Embryonic Stem Cell-Derived Retinal Pigment Epithelial Cells in Macular Degeneration (NCT01469832) [6] |
Stargardt disease (STGD1). |
Subretinal transplantation of up to 200,000 hESC-derived RPE cells with systemic immunosuppressive therapy for 13 weeks |
Survival of viable transplanted hESC-derived RPE cells. |
Long-term safety and tolerability of subretinal transplantation of embryonic stem cell-derived retinal pigment epithelium in Asian Stargardt disease patients (NCT01625559) [7] |
Stargardt macular dystrophy (SMD). |
Subretinal transplantation of hESC-retinal pigment epithelium (RPE) cells |
No serious adverse events. Long-term safety, tolerability and feasibility. |
|
|
Favorable functional and anatomical results. |
|
Surgical Method for Implantation of a Biosynthetic Retinal Pigment Epithelium Monolayer for Geographic Atrophy: Experience from a Phase 1/2a Study (NCT02590692) [2] |
Advanced non-neovascular age-related macular degeneration (NNAMD). |
Subretinal implantation of a human embryonic stem cell-derived retinal pigment epithelium (RPE) monolayer seeded on a synthetic substrate. |
No unanticipated serious adverse events related to the implant or surgery were reported. |
|
|
Surgical implantation of CPCB-RPE1 targeted to the area of GA in subjects with advanced NNAMD is feasible in an outpatient setting. |
|
Subretinal adipose tissue-derived mesenchymal stem cell implantation in advanced stage retinitis pigmentosa: a phase I clinical safety study (Ministry of Health of Turkey approval: 56733164/203) [8] |
Retinitis pigmentosa. |
Subretinal adipose tissue-derived mesenchymal stem cell (ADMSC) implantation. |
Ocular complications. |
|
|
Evidence of the short-term safety of ADMSCs in humans |
|
Treatment of macular degeneration using embryonic stem cell-derived retinal pigment epithelium: preliminary results in Asian patients (NCT01625559 and NCT01674829) [4] |
Dry age-related macular degeneration. |
Subretinal transplantation of human embryonic-stem-cell (hESC)-derived retinal pigment epithelium. |
No evidence of adverse serious safety issues. |
Stargardt macular dystrophy. |
|
Visual acuity improvement. |
|
Intravitreal autologous bone marrow CD34+ cell therapy for ischemic and degenerative retinal disorders: preliminary phase 1 clinical trial findings (NCT01736059) [3] |
Irreversible vision loss from retinal vascular occlusion, hereditary or nonexudative age-related macular degeneration, or retinitis pigmentosa. |
Intravitreal human bone marrow (BM) CD34+ stem cell injection. |
No intraocular inflammation or hyperproliferation. |
|
|
Mild progression of geographic atrophy in AMD patients. |
|
A phase I clinical trial of human embryonic stem cell-derived retinal pigment epithelial cells for early-stage Stargardt macular degeneration: 5-years’ follow-up (NCT02749734) [10] |
Early-stage of Stargardt macular degeneration (STGD1). |
Subretinal transplantation of human embryonic stem cell-derived retinal pigment epithelial (hESC-RPE) cells. |
Safe and tolerable. Increased visual function. |
|
|
Visual function loss in two patients. |
|
Long-term safety of human retinal progenitor cell transplantation in retinitis pigmentosa patients (ChiCTR-TNRC-08000193) [9] |
Advanced retinitis pigmentosa. |
Transplantation of purified human fetal-derived retinal progenitor cells (RPCs) |
No immunological rejection or tumorigenesis. Long-term safety and feasibility. |
|
|
Significant improvement in visual acuity and increase in retinal sensitivity. |
The systematic search for clinical trials in the NIH database ClinicalTrials.gov produced 82 results using the searching terms “Retina Disorder” + “Stem cells”. The list was then manually filtered and 13 studies were excluded that did not actually use stem cells as therapy. The 69 remaining records included 31 studies that were also obtained using the search terms “Retinal dystrophies” + “Stem Cells” and 58 which were also found using “Retinal Degeneration” + “Stem Cells”. The main characteristics of the clinical trials are summarized in Figure 1.
The majority of the trials (68%) were in the initial phases of their studies (phases 1 and 2), which correspond to safety and feasibility outcomes. Only 2 of 69 trials reported reaching phase 4 and other 2 has reached phase 3 (Figure 1c). Eight studies were withdrawn or terminated prior to the scheduled end-date. Only 14 of the 69 clinical trials were currently recruiting or enrolling patients while other 9 trials were active but not recruiting patients. Only 3 trials had posted results at ClinicalTrials.gov. Although 36% of the trials were completed, only two of them had posted results. Seven articles from our PubMed search had published results linked with 8 of the clinical trials [1][2][4][5][6][7][10].
The problem with obtaining viable human compatible cells (photoreceptors and RPE) is that there is not an unlimited source, since so many groups have focused on obtaining this [17]. hiPSCs have been explored as a near-unlimited cell source for cell replacement of both types of retinal cells, photoreceptors and RPE cells [26][27][28][29][30][31]. Indeed, a safety and tolerability prospective clinical trial is currently underway to evaluate subretinal transplantation of iPSC-derived RPE cell sheets in AMD patients (NCT04339764). Additionally, five clinical trials are active or completed whose objective was to obtain hiPSCs for transplantation into diseased retinas, although none of the studies involve surgical procedures in patients (NCT03403699; NCT03372746; NCT02464956; NCT02162953; NCT01432847). Due to the intrinsic complexity of neural tissue reconnection, the use of neuronal precursors or in vitro differentiated neuronal constructs in retinal transplantation seems to still require further preclinical development. One interesting use of stem cells is the creation of organoids, which consist of a tiny three-dimensional mass of tissue developed in the laboratory by growing stem cells. It is possible to grow organoids that resemble human tissues or organs, or a specific type of tumor (NIH). Consequently, iPSCs can be reprogrammed to generate a retina from which an enormous amount of information about the transcriptional and epigenetic regulation of retinal development and maintenance can be obtained[32]. In addition, they serve to advance cell therapies to treat diseases such as AMD and glaucoma[32]. Besides, self-organizing optic cups and 3D neural retinas that could be clinically applied for transplantation therapy in retinal degeneration have been successfully created from hiPSCs by 3D differentiation culture [30][31][33].