Somatic Cell Therapy Medicinal Products Treat Retinal Dystrophies: History
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Contributor:
Giacomo Maria Bacci
,
Valentina Becherucci
,
Elisa Marziali
,
Andrea Sodi
,
Franco Bambi
,
Roberto Caputo

Inherited retinal dystrophies and retinal degenerations related to more common diseases (i.e., age-related macular dystrophy) are a major issue and one of the main causes of low vision in pediatric and elderly age groups. Advancement and understanding in molecular biology and the possibilities raised by gene-editing techniques opened a new era for clinicians and patients due to feasible possibilities of treating disabling diseases and the reduction in their complications burden.

  • inherited retinal dystrophies
  • Stargardt disease
  • retinitis pigmentosa
  • advanced therapy medicinal products
  • somatic cell therapy medicinal products

1. Introduction

1.1. Retinal Architecture

The retina is a complex neural network with the main goal of transducing light through electrical pulse encoding and packing visual input for visual pathways and superior visual elaboration. This process requires a sequence of events where every cell plays a definite role in the visual signal processing [1]. The first actors in this process are retinal photoreceptor cells; essentially, these specialized, first-order neurons located in the outer retina have the structure and the metabolic privilege to convert light into electricity in photopic and scotopic conditions through a molecularly driven complex defined as the visual cycle. The electric pulse is then transmitted to the second-order neurons, the bipolar cells, and, subsequently, to the third-order neurons, the ganglion cells, forming the optic nerve core with their unmyelinated axons [2]. Photoreceptor, bipolar and ganglion cells represent the main pre-geniculate circuit for visual signaling transmission located in the eye, but ancillary cell subtypes, such as amacrine cells and horizontal cells, contribute to modulating this primary pathway [3]. The other main actor in retinal anatomy is the RPE, which represents a pillar to maintain the structural and functional role of the entire retina; its strict relationship with the underlying complex Bruch’s membrane/choroid and the overhanging outer retina makes it a fundamental monolayer of polarized cells for the metabolic function of the retina [4].

1.2. Inherited Retinal Dystrophies (IRDs)

IRDs are defined as a group of degenerative disorders of the retina with clinical and genetic heterogeneity. IRDs can occur from birth through late middle age, with symptoms including night blindness, visual field abnormalities, dyschromatopsia and various degrees of central visual acuity impairment. Genotype–phenotype correlations are achieved by using electrophysiology and sophisticated imaging modalities [5]. Thanks to the increasing knowledge regarding the genetic basis of these diseases, authorized gene-therapy programs are available [6]. Clinical manifestations of IRDs can span from challenging cases, difficult to diagnose because they can present only subtle retinal abnormalities, to devastating disorders where the retinal architecture is severely affected early in life. As a consequence of these large presentation differences, retinal morphologic appearance alone can often be misleading for diagnosis or, at least, not enough for posing a specific diagnosis [7].

1.3. Stargardt Disease (STGD1)

STGD1 is the more common cause of macular degeneration in children and young adults related to mutations in the ABCA4 gene [8]. The pattern inheritance is autosomal recessive, and its prevalence span is from 1:8000 to 1:10,000. Generally speaking, the disease onset could be considered a surrogate prognostic marker: the earlier one is the disease onset, while the more severe one could be the presentation and evolution of the phenotype. Usually, STGD1 patients present with disease onset at a median age of 15 years, with the classic phenotypic fishtail appearance of yellow-white flecks at the posterior pole, eventually associated with a “bull’s eye” maculopathy, and the best-corrected visual acuity can vary between 20/70 and 20/200 [9]. Complete phenotyping with OCT, FAF and ffERG is mandatory for clinical diagnosis, together with a blood sample for molecular analysis; evidence of a severely reduced macular thickness with a diffuse alteration of the ellipsoid zone in the macular area is a frequent finding in typical STGD1, while diffuse hypofluorescence at the posterior pole, hyperfluorescence of retinal flecks and sparing of peripapillary autofluorescence are frequent features; electrophysiology results are extremely variable and classification of disease stage with ffERG has been proposed, according to rod and cone involvement during the course of the disease. In the presence of a coherent phenotypic clinical picture, mutations in the ABCA4 gene usually confirm the diagnosis [10]. This can be extremely challenging since the previous typical description cannot be respected in early-onset disease or widespread forms of cone–rod dystrophies, which are a potential expression of ABCA4 mutations [10]. Because of its extremely variable clinical course, STGD1 is potentially a perfect target for a therapeutic approach using advanced therapy medicinal products along different stages of the disease. Briefly, in early-onset disease, the macular function can be variably affected, but the integrity of the retinal architecture can still be preserved, while in late-onset disease, a variable degree of retinal atrophy can be the presenting sign [11]. As a consequence of these anatomical presentations, a different approach can be useful: mainly supportive in early-onset disease and regenerative in the atrophic phase.

1.4. Retinitis Pigmentosa (RP)

RP is the most frequent IRD, affecting more than 1.5 million patients worldwide [12]. RP has a widely variable age of onset, from childhood to adulthood [13]. RP can be associated with extra-ocular abnormalities in the syndromic form of RP. The term RP encompasses a group of progressive IRDs characterized by the primary degeneration of rod photoreceptors, followed by the loss of cone photoreceptors. Normally, the first symptom is reduced night vision (nyctalopia), which is classically followed by a progressive loss of peripheral vision. The macula and, consequently, the visual acuity are usually relatively well-preserved at the onset and could be involved in the late stages of the disease. Sometimes, the visual acuity can be affected earlier in cases of cataracts or cystoid macular oedema, both common and treatable sequelae of retinitis pigmentosa [13]. The classical fundus presentation includes the triad: bone spicule pigmentation predominantly in the periphery and/or mid-periphery, waxy pallor of the optic nerve head and attenuation of retinal vessels. The bone spicules do not develop in all patients; in some patients, dust-like pigmentation or nummular hyperpigmentation is reported [14]. Bone spicule pigmentation consists of RPE cells that detach from the Bruch’s membrane following photoreceptor degeneration and migrate to intraretinal perivascular sites, where they form melanin pigment deposits. The clinical findings in RP vary widely due to the large number of genes involved. Mutations in more than 80 genes have been implicated in non-syndromic RP, and each year, new genes are added to this list. There are gene-specific subtypes of RP with a specific age of onset, visual impairment, retinal appearance and/or rate of progression. Moreover, several factors can vary widely within each of these gene-specific subtypes, even in the same family, suggesting the presence of unidentified genetic and/or environmental factors that can influence the RP phenotype [12].

2. Somatic Cell Therapy Medicinal Products: Definition and Regulation

sCTMPs are defined as a group of ATMPs containing or consisting of cells or tissues that have been significantly manipulated to modify their biological characteristics, physiological functions or structural properties or that are not intended to be used for the same original functions in the body. The purpose of somatic cell therapy is to treat, prevent or diagnose diseases. The definition of sCTMPs is currently included in Directive 2009/120/EC amending Directive 2001/83/EC of the European Parliament and the Council on the European Community. An sCTMP is “a biological medicinal product whose active substance is made by a living organism. The product has the following characteristics: (a) contains or consists of cells or tissues that have been subject to substantial manipulation so that biological characteristics, physiological functions or structural properties relevant for the intended clinical use have been altered, or of cells or tissues that are not intended to be used for the same essential function(s) in the recipient and the donor; (b) is presented as having properties for, or is used in or administered to human beings to treat, prevent or diagnose a disease through the pharmacological, immunological or metabolic action of its cells or tissues”. The cells or tissues can be of autologous (derived from the patient himself), allogeneic (obtained from a donor) or xenogeneic (derived from a donor of an animal species other than man) origin [15]. The safety and efficacy of a somatic cell therapy medicinal product must be demonstrated through preclinical studies and human clinical trials. Human clinical trials must be particularly designed in compliance with EU regulation No. 536/2014, following the principles of GCPs as reported in Commission Directive 2005/28/EC [16][17]. The production of a CTMP must be carried out following the principles of GMP. The particularity of ATMPs consists in their extreme complexity, which makes them unique and distinguishable from other medicinal products, starting from their composition and all the necessary processes for their proper development (i.e., manufacturing, characterization). During the last few years, the development of ATMPs for the treatment of eye diseases has become a fast-growing field. The field of ATMPs is currently at the forefront of innovation as it offers novel therapeutic approaches for the treatment of pathologies that, at present, have limited or no effective alternatives. For several reasons, the eye is an ideal organ for the application of ATMPs. First, it has small dimensions, thus requiring low amounts of medicinal products for treatment. Second, the anatomical structure is compartmentalized, thus limiting the distribution of medicinal products to non-target tissues. Third, it has good accessibility for applying treatments and examining outcomes. Fourth, it is isolated from the rest of the body due to the blood–retinal barrier. This makes the eyeball an immunologically privileged site because it restricts the passage of immunoglobulins. These reasons are why ATMPs present a great potential to improve the prognosis of and potentially cure ocular diseases that currently have no effective treatment, such as inherited retinal dystrophies.

3. Excursus on Somatic Cell Therapy Medicinal Products for Inherited Retinal Dystrophies

3.1. Retinal Progenitor Cells (RPCs)

RPCs derived from fetal or neonatal retinas comprise a population of immature cells that are responsible for the generation of all retinal cells during development. Immature RPCs can be extensively expanded in vitro by manipulating time and environment and lead to the expression of photoreceptor markers [18]. Retinal repair by the transplantation of photoreceptor precursors, such as RPCs from the developing retina, into the dystrophic mature retina has been found to promote the survival of host tissue, along with integration into the neural retina and recovery of light-mediated behavior [19][20]. Unfortunately, these early studies of photoreceptor transplantation had limited success due to the poor durability of the integration into the recipient retina. Moreover, the degenerating retina is characterized by a hostile environment to the transplanted cells and strongly restricts the ability of the cells to migrate from the transplantation site into the host retina [21].

3.2. Embryonic Stem Cells (ESCs)

Currently, cell replacement therapy for the treatment of retinal diseases focuses on the development of protocols for the direct differentiation of hESCs or hiPSCs into RPCs and photoreceptor cell phenotypes. ESCs are derived from the inner cell mass of the embryonic blastocyst, with self-renewal capabilities and the ability to differentiate into cell types derived from all three embryonic germ layers [22][23]. In vitro differentiation of mouse and human ESCs into different functional retinal cell types, in particular, RPE cells and/or photoreceptors, has been demonstrated by numerous protocols [24][25]. Moreover, several studies have shown that the transplantation of ESCs derived from different species of retinal cells, in models of retinal degeneration, protected host photoreceptors, integrated into the recipient retina, differentiated into functional photoreceptors and restored visual function [26][27]. Thus, the transplantation of photoreceptors with or without RPE cells derived from hESCs offers huge potential for cell replacement therapy in treating retinal degenerative diseases [28]. Clinical trials in the United States using human ESC-derived RPE to treat Stargardt disease and AMD were approved by the FDA [29]. Furthermore, mouse ESCs can be induced to generate an eye-like structure made up of lens cells, retinal cells and RPE cells [30], and it has subsequently been shown that cells from these eye-like structures can be differentiated into RGCs when transplanted into the vitreous body of an injured adult mouse retina [31].

3.3. Induced Pluripotent Stem Cells (iPSCs)

The development of iPSCs provides several advantages as a source of retinal cells for transplantation, methods of drug testing and the development of models that can simulate human disease better than animal models [32]. The main study for generating iPSCs is authored by Takahashi et al. in 2007, where the creation of iPSCs from skin fibroblasts was induced with the viral transduction of four transcription factors—OCT4, SOX2, KLF4 and C-MYC [33][34]—that allowed mature cells to return to a pluripotent state similar to that seen in ESCs [35]. The preclinical efficacy of iPSCs must be proven before use in human trials. Studies of RPE-based disorders are the best candidates for iPSC modelling, given their accessibility through manual dissection and expansion on an assortment of substrates, behavior that mimics primary human prenatal in vitro, as well as the ease of monitoring the maturation state through distinct morphological features [36][37]. In 2012 Li et al. [38] published a pioneering study reporting methods to obtain and successfully transplant iPSC-derived RPE cells. Fibroblasts have been recovered from a skin biopsy and cocultured with mitomycin-C-treated PA6 feeder cells, which possess SIDA and promote RPE differentiation. The resulting iPSC-derived RPE cells were grafted subretinally into the subretinal space of a mouse possessing a mutation in a gene known to be responsible for certain types of retinitis pigmentosa [38], and they successfully restored retinal function, assessed by electroretinography. Other studies, such as the one by Maeda et al.’s group [39], have clarified the mechanism of action of iPSC-derived RPE cells as they produce the visual chromophore, 11-cis-retinal, and formed retinosomes in vitro.

3.4. Generation of Retinal Organoids from Human Embryonic Stem Cells or Human Induced Pluripotent Stem Cells

Organoids are “mini-organs” generated from hESCs or hiPSCs. Organoids have been developed for several organs, including the liver, lung and pancreas. In a pioneering work, Eiraku and colleagues developed approaches to differentiate mouse ESCs into a 3D structure resembling a developing retina [40]. Moreover, human stem cells could be differentiated into human retinal organoids, providing a platform to develop organoid-based methods for transplantation and therapies [41]. Additional studies showed that retinal organoids could be cultured into relatively advanced maturity stages in vitro [42][43]. Retinal organoids derived from hESCs or hiPSCs, especially hiPSCs, are affordable thanks to unlimited sources and few ethical issues, which makes the retinal organoid a popular tool for studying the pathogenesis of retinal diseases and graft treatments in vitro.

3.5. Mesenchymal Stromal Cells (MSCs)

The definition of MSCs is based on the phenotypic expression of a distinct set of cell surface markers as CD105, CD90, and CD73 but lacking CD79, CD45, CD34, CD19, CD14, CD11b and Human Leukocyte Antigen Class II (HLA-II) [44][45]. In addition, these cells can undergo in vitro tri-lineage differentiation into osteogenic, adipogenic and chondrogenic, as defined by the ISCT guideline for MSCs [45][46]. Another advantage of MSCs is that they can be easily isolated from many different tissues, exploiting their ability to adhere to plastic support. MSCs can be found abundantly in the adult tissues, such as bone marrow, adipose tissue and dental pulp, as well as in the fetal tissues and fluids, including the umbilical cord tissue, blood and amniotic fluid [47]. Cellular reparative mechanisms of MSCs for retinal diseases have been discussed for a long time [48][49], basically involving four mechanisms:
(a) 
Trans-differentiation;
(b) 
Paracrine action for cell repair;
(c) 
Immunoregulatory function;
(d) 
Anti-angiogenic trophic action.
Moreover, there are multiple routes of administration to deliver MSCs into the posterior lining of the eye, including intravitreal, intraocular, epiretinal or subtenon injections, to treat patients affected with posterior eye diseases, including AMD, DR, retinal ischemia and RP.

This entry is adapted from the peer-reviewed paper 10.3390/life12050708

References

  1. Demb, J.B.; Singer, J.H. Functional Circuitry of the Retina. Annu. Rev. Vis. Sci. 2015, 1, 263–289.
  2. Masland, R.H. The fundamental plan of the retina. Nat. Neurosci. 2001, 4, 877–886.
  3. Masland, R.H. The Neuronal Organization of the Retina. Neuron 2012, 76, 266–280.
  4. Caceres, P.S.; Rodriguez-Boulan, E. Retinal pigment epithelium polarity in health and blinding diseases. Curr. Opin. Cell Biol. 2019, 62, 37–45.
  5. Michaelides, M.; Hardcastle, A.J.; Hunt, D.M.; Moore, A.T. Progressive Cone and Cone-Rod Dystrophies: Phenotypes and Underlying Molecular Genetic Basis. Surv. Ophthalmol. 2006, 51, 232–258.
  6. Hu, M.L.; Edwards, T.L.; O’hare, F.; Hickey, D.G.; Wang, J.-H.; Liu, Z.; Ayton, L.N. Gene therapy for inherited retinal diseases: Progress and possibilities. Clin. Exp. Optom. 2021, 104, 444–454.
  7. Levi, S.R.; Jenny, L.A.; Tsang, S.H. Management and treatment of inherited retinal dystrophies. Taiwan J. Ophthalmol. 2021, 11, 205–206.
  8. Michaelides, M.; Hunt, D.M.; Moore, A.T. The genetics of inherited macular dystrophies. J. Med. Genet. 2003, 40, 641–650.
  9. Lewis, R.A.; Shroyer, N.; Singh, N.; Allikmets, R.; Hutchinson, A.; Li, Y.; Lupski, J.R.; Leppert, M.; Dean, M. Genotype/Phenotype Analysis of a Photoreceptor-Specific ATP-Binding Cassette Transporter Gene, ABCR, in Stargardt Disease. Am. J. Hum. Genet. 1999, 64, 422–434.
  10. Lambertus, S.; van Huet, R.A.; Bax, N.M.; Hoefsloot, L.H.; Cremers, F.P.; Boon, C.; Klevering, B.J.; Hoyng, C.B. Early-Onset Stargardt Disease. Ophthalmology 2014, 122, 335–344.
  11. Ku, C.A.; Yang, P. Stargardt Disease: Gene Therapy Strategies for ABCA4. Int. Ophthalmol. Clin. 2021, 61, 157–165.
  12. Verbakel, S.K.; van Huet, R.A.C.; Boon, C.J.F.; den Hollander, A.I.; Collin, R.W.J.; Klaver, C.C.W.; Hoyng, C.B.; Roepman, R.; Klevering, B.J. Non-syndromic retinitis pigmentosa. Prog. Retin. Eye Res. 2018, 66, 157–186.
  13. Hamel, C. Retinitis pigmentosa. Orphanet J. Rare Dis. 2006, 1, 40.
  14. Fahim, A.T.; Daiger, S.P.; Weleber, R.G. Nonsyndromic Retinitis Pigmentosa Overview; Adam, M.P., Ardinger, H.H., Pagon, R.A., Wallace, S.E., Bean, L.J.H., Gripp, K.W., Mirzaa, G.M., Amemiya, A., Eds.; University of Washington: Seattle, WA, USA, 1993.
  15. Regulation (EC) No. 1394/2007 of the European Parliament and of the Council of 13 November 2007 on Advanced Therapy Medicinal Products and Amending Directive 2001/83/EC and Regulation /EC N0 726/2004. Available online: https://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2007:324:0121:0137:en:PDF (accessed on 21 April 2022).
  16. Regulation (EU) No. 536/2014 of the European Parliament and of the Council of 16 April 2014 on Clinical Trials on Medicinal Products for Human Use, and Repealing Directive 2001/20/EC. Available online: https://ec.europa.eu/health/system/files/2016-11/reg_2014_536_en_0.pdf (accessed on 21 April 2022).
  17. Commission Directive 2005/28/EC of 8 April 2005 Laying down Principles and Detailed Guidelines for Good Clinical Practice as Regards Investigational Medicinal Products for Human Use. Available online: https://eur-lex.europa.eu/legal-content/EN/TXT/PDF/?uri=CELEX:32005L0028&from=CS (accessed on 21 April 2022).
  18. Merhi-Soussi, F.; Angénieux, B.; Canola, K.; Kostic, C.; Tekaya, M.; Hornfeld, D.; Arsenijevic, Y. High Yield of Cells Committed to the Photoreceptor Fate from Expanded Mouse Retinal Stem Cells. Stem Cells 2006, 24, 2060–2070.
  19. MacLaren, R.; Pearson, R.; MacNeil, A.; Douglas, R.H.; Salt, T.E.; Akimoto, M.; Swaroop, A.; Sowden, J.; Ali, R. Retinal repair by transplantation of photoreceptor precursors. Nature 2006, 444, 203–207.
  20. Aftab, U.; Jiang, C.; Tucker, B.; Kim, J.Y.; Klassen, H.; Miljan, E.; Sinden, J.; Young, M. Growth kinetics and transplantation of human retinal progenitor cells. Exp. Eye Res. 2009, 89, 301–310.
  21. Ma, J.; Kabiel, M.; Tucker, B.A.; Ge, J.; Young, M.J. Combining chondroitinase ABC and growth factors promotes the integration of murine retinal progenitor cells transplanted into Rho−/− mice. Mol. Vis. 2011, 17, 1759–1770.
  22. Reubinoff, B.; Pera, M.F.; Fong, C.-Y.; Trounson, A.; Bongso, A. Embryonic stem cell lines from human blastocysts: Somatic differentiation in vitro. Nat. Biotechnol. 2000, 18, 399–404.
  23. Cowan, C.A.; Klimanskaya, I.; McMahon, J.; Atienza, J.; Witmyer, J.; Zucker, J.P.; Wang, S.; Morton, C.C.; McMahon, A.P.; Powers, D.; et al. Derivation of Embryonic Stem-Cell Lines from Human Blastocysts. N. Engl. J. Med. 2004, 350, 1353–1356.
  24. Ikegami, Y.; Mitsuda, S.; Araki, M. Neural cell differentiation from retinal pigment epithelial cells of the newt: An organ culture model for the urodele retinal regeneration. J. Neurobiol. 2002, 50, 209–220.
  25. Osakada, F.; Ikeda, H.; Sasai, Y.; Takahashi, M. Stepwise differentiation of pluripotent stem cells into retinal cells. Nat. Protoc. 2009, 4, 811–824.
  26. Vaajasaari, H.; Ilmarinen, T.; Juuti-Uusitalo, K.; Rajala, K.; Onnela, N.; Narkilahti, S.; Suuronen, R.; Hyttinen, J.; Uusitalo, H.; Skottman, H. Toward the defined and xeno-free differentiation of functional human pluripotent stem cell-derived retinal pigment epithelial cells. Mol. Vis. 2011, 17, 558–575.
  27. Park, U.C.; Cho, M.S.; Park, J.H.; Kim, S.J.; Ku, S.-Y.; Choi, Y.M.; Moon, S.Y.; Yu, H.G. Subretinal transplantation of putative retinal pigment epithelial cells derived from human embryonic stem cells in rat retinal degeneration model. Clin. Exp. Reprod. Med. 2011, 38, 216–221.
  28. Jin, Z.-B.; Okamoto, S.; Mandai, M.; Takahashi, M. Induced pluripotent stem cells for retinal degenerative diseases: A new perspective on the challenges. J. Genet. 2009, 88, 417–424.
  29. Schwartz, S.D.; Hubschman, J.-P.; Heilwell, G.; Franco-Cardenas, V.; Pan, C.; Ostrick, R.M.; Mickunas, E.; Gay, R.; Klimanskaya, I.; Lanza, R. Embryonic stem cell trials for macular degeneration: A preliminary report. Lancet 2012, 379, 713–720.
  30. Hirano, M.; Yamamoto, A.; Yoshimura, N.; Tokunaga, T.; Motohashi, T.; Ishizaki, K.; Yoshida, H.; Okazaki, K.; Yamazaki, H.; Hayashi, S.-I.; et al. Generation of structures formed by lens and retinal cells differentiating from embryonic stem cells. Dev. Dyn. 2003, 228, 664–671.
  31. Aoki, H.; Hara, A.; Niwa, M.; Motohashi, T.; Suzuki, T.; Kunisada, T. Transplantation of cells from eye-like structures differentiated from embryonic stem cells in vitro and in vivo regeneration of retinal ganglion-like cells. Graefes. Arch. Clin. Exp. Ophthalmol. 2007, 246, 255–265.
  32. Chen, F.K.; McLenachan, S.; Edel, M.; Da Cruz, L.; Coffey, P.J.; Mackey, D.A. iPS Cells for Modelling and Treatment of Retinal Diseases. J. Clin. Med. 2014, 3, 1511–1541.
  33. Aoi, T.; Yae, K.; Nakagawa, M.; Ichisaka, T.; Okita, K.; Takahashi, K.; Chiba, T.; Yamanaka, S. Generation of pluripotent stem cells from adult mouse liver and stomach cells. Science 2008, 321, 699–702.
  34. Takahashi, K.; Tanabe, K.; Ohnuki, M.; Narita, M.; Ichisaka, T.; Tomoda, K.; Yamanaka, S. Induction of Pluripotent Stem Cells from Adult Human Fibroblasts by Defined Factors. Cell 2007, 131, 861–872.
  35. Takahashi, K.; Okita, K.; Nakagawa, M.; Yamanaka, S. Induction of pluripotent stem cells from fibroblast cultures. Nat. Protoc. 2007, 2, 3081–3089.
  36. Buchholz, D.E.; Hikita, S.T.; Rowland, T.J.; Friedrich, A.M.; Hinman, C.R.; Johnson, L.V.; Clegg, D.O. Derivation of Functional Retinal Pigmented Epithelium from Induced Pluripotent Stem Cells. Stem Cells 2009, 27, 2427–2434.
  37. Kokkinaki, M.; Sahibzada, N.; Golestaneh, N. Human induced pluripotent stem-derived retinal pigment epithelium (RPE) cells exhibit ion transport, membrane potential, polarized vascular endothelial growth factor secretion, and gene expression pattern similar to native RPE. Stem Cells 2011, 29, 825–835.
  38. Li, Y.; Tsai, Y.-T.; Hsu, C.-W.; Erol, D.; Yang, J.; Wu, W.-H.; Davis, R.J.; Egli, D.; Tsang, S.H. Long-term Safety and Efficacy of Human-Induced Pluripotent Stem Cell (iPS) Grafts in a Preclinical Model of Retinitis Pigmentosa. Mol. Med. 2012, 18, 1312–1319.
  39. Maeda, T.; Lee, M.J.; Palczewska, G.; Marsili, S.; Tesar, P.; Palczewski, K.; Takahashi, M.; Maeda, A. Retinal Pigmented Epithelial Cells Obtained from Human Induced Pluripotent Stem Cells Possess Functional Visual Cycle Enzymes In Vitro and In Vivo. J. Biol. Chem. 2013, 288, 34484–34493.
  40. Gagliardi, G.; Ben M’Barek, K.; Goureau, O. Photoreceptor cell replacement in macular degeneration and retinitis pigmentosa: A pluripotent stem cell-based approach. Prog. Retin. Eye Res. 2019, 71, 1–25.
  41. Canto-Soler, V.; Flores-Bellver, M.; Vergara, M.N. Stem Cell Sources and Their Potential for the Treatment of Retinal Degenerations. Investig. Ophthalmol. Vis. Sci. 2016, 57, ORSFd1–ORSFd9.
  42. Kaushik, G.; Ponnusamy, M.P.; Batra, S.K. Concise Review: Current Status of Three-Dimensional Organoids as Preclinical Models. Stem Cells 2018, 36, 1329–1340.
  43. Llonch, S.; Carido, M.; Ader, M. Organoid technology for retinal repair. Dev. Biol. 2018, 433, 132–143.
  44. Ding, S.S.L.; Subbiah, S.K.; Khan, M.S.A.; Farhana, A.; Mok, P.L. Empowering Mesenchymal Stem Cells for Ocular Degenerative Disorders. Int. J. Mol. Sci. 2019, 20, 1784.
  45. Holan, V.; Palacka, K.; Hermankova, B. Mesenchymal Stem Cell-Based Therapy for Retinal Degenerative Diseases: Experimental Models and Clinical Trials. Cells 2021, 10, 588.
  46. Mok, P.L.; Leong, C.F.; Cheong, S.K. Cellular mechanisms of emerging applications of mesenchymal stem cells. Malays. J. Pathol. 2013, 35, 17–32.
  47. Dominici, M.; Le Blanc, K.; Mueller, I.; Slaper-Cortenbach, I.; Marini, F.C.; Krause, D.S.; Deans, R.J.; Keating, A.; Prockop, D.J.; Horwitz, E.M. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 2006, 8, 315–317.
  48. Kuwahara, A.; Ozone, C.; Nakano, T.; Saito, K.; Eiraku, M.; Sasai, Y. Generation of a ciliary margin-like stem cell niche from self-organizing human retinal tissue. Nat. Commun. 2015, 6, 6286.
  49. Borkowska-Kuczkowska, A.; Sługocka, D.; Świątkowska-Flis, B.; Boruczkowski, D. The use of mesenchymal stem cells for the treatment of progressive retinal diseases: A review. Regen. Med. 2019, 14, 321–329.
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