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Regenerative Medicine, Advanced Stem Cell, and Gene Therapies for Eye Diseases

Barnstable, Colin J. D.Phil*; Jonas, Jost B. MD†,‡; Zhang, Kang MD§

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Asia-Pacific Journal of Ophthalmology: July/August 2022 - Volume 11 - Issue 4 - p 299-301
doi: 10.1097/APO.0000000000000544
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Ocular disorders are among the most prevalent diseases worldwide and rank highly in the list of disability-associated life years as assessed in the Global Burden of Disease (GBD) study.1 The revolution in cell and molecular biology over recent decades has provided a new palette with which to identify, study, and treat many ocular diseases. This special issue captures some of the advances in this area and points out directions that will undoubtedly change ophthalmology practice in the coming years.

One of the most important advances has been the ability to use genetic analysis to identify disease-causing variants or risk factors. Initially microarray analysis, but now more commonly direct sequencing has provided a wealth of information about many ocular diseases. Perhaps the clearest example of this comes from many studies of diseases of the retinitis pigmentosa (RP) group. Although less common than many other ocular diseases, RP diseases as monogenetic disorders have the advantage for genetic studies of being transmitted in a Mendelian fashion. Autosomal dominant, autosomal recessive and X-linked forms of the diseases have been identified. To date, more than 70 loci (and more than 70 identified genes) have been detected as underlying causes for various forms of RP. If we include the broader range of retinopathies, the current number of identified loci is around 361 (with roughly 280 identified genes).2 Identification of genes responsible for inherited eye diseases has often been a collaborative effort. In the article by Iwata and colleagues, the development of a consortium, initially in Japan but then becoming the Asian Eye Genetics Consortium and finally the Global Eye Genetics Consortium,3 describes how it has been possible for 200 members in 30 countries to collect, identify, and catalog samples on a global scale.4

Examination of the list of gene mutations that can cause RP is both gratifying that this knowledge can often allow patients to get a precise diagnosis of their disease, but also disturbing because it suggests that each mutation needs a different treatment. The clinical trials currently registered for monogenic eye diseases are summarized by Burgess et al in their article in this issue. The 60 trials described show not only the speed with which research findings are being translated into clinical reality but also the hope that many patients may soon have treatments available.5 The most successful gene therapy for RP so far has been the subretinal application of voretigene neparvovec-rzyl (Luxturna) for the treatment of the RPE65 mutation-associated type of retinal dystrophy.6 This therapy improves vision and follow-up data so far have shown an effect lasting for at least 4 years.7 In the article by McLenachan et al8 in this issue, a different inherited disease, Usher Syndrome Type IIA, is discussed including an overview of treatments currently in clinical trials. One of the remaining problems of gene therapy is that of dosing. Too little of a gene may be ineffective and too much may be toxic. There is currently a lot of interest in using inducible gene therapy vectors in which the amount of gene transcribed can be titrated using drug inducers.

In the cornea, Fuchs corneal endothelial dystrophy can be caused by mutations in at least 6 genes.9 These genes serve very different functions and may require different therapies. One inherited form of the disease has an autosomal dominant heritage and is the result of a trinucleotide repeat insertion in the deoxyribonucleic acid (DNA). A number of neurological diseases are also caused by these insertions and there are many studies under way to use clusters of regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated protein 9 nuclease (Cas9) gene editing methods to cut out the extra DNA and restore normal gene function. The range of gene therapy and gene editing options for corneal disease is summarized in the article by Singh et al10 in this issue. Importantly, the article also describes the challenges facing the development of these therapies.

Other ocular diseases are clearly multigenic and this has important implications for both diagnosis and treatment. For most of these genes, mutations are not causative but serve as risk factors and alter the probability of an individual eventually developing a particular disease. Sometimes a clear demonstration of a risk factor can dramatically change the way we think about a particular disease. An excellent example of this is the finding of a strong association of a particular form of complement factor H and age-related macular degeneration (AMD).11–14 Prior to this finding, most efforts had been put into examining cone photoreceptors and retinal pigment epithelium (RPE) cells. The finding of an association between AMD and the complement factor H immediately suggested an involvement of the immune system in the etiology of AMD and started the hunt for other complement genes that might also affect AMD risk, resulting in number of clinical trials of complement-modulating drugs.

The lack of clear gene associations with a number of major ocular degenerations has been an important stimulus for the development of novel cell-based therapeutics. Many ocular cells do not replicate and cannot be used to regenerate lost tissue. Advances in the use of gene transfer to generate progenitor cells from many tissues, and more importantly to channel their differentiation into specific cell types, has opened up a new era of regenerative medicine using stem cell-derived tissues.

It has long been known that corneal epithelial cells are continuously derived from limbal stem cells. Isolation and culture of these stem cells has allowed new methods of replacement of corneal epithelium. The article by Kinoshita et al15 in this issue describes these advances and also discusses the more intractable problems of culturing corneal endothelial cells. The other ocular tissue that has promise for replacement therapy is the RPE. RPE cells can be isolated from donor tissue or can be derived by differentiation of stem cells.16 The article by Zarbin and Gullapalli17 in this issue summarizes the current state of RPE transplantation therapy. The retina presents a much harder problem for regenerative medicine. The function of the retina, the reception and processing of visual information, requires not only the correct cell types but also their appropriate synaptic connections. There are active programs to generate photoreceptors from stem cells and transplant them into the subretinal space. These have achieved some success and hold much promise for the future. A more ambitious approach will be to generate retinal ganglion cells and transplant them into the retina to replace cells lost in glaucoma and other optic neuropathies.18 An alternative approach is suggested in the article by Seiler et al19 in this issue. Retinal cells have the ability to organize themselves into functional units during development. Instead of trying to graft new cells onto a preformed retina, allowing cells to generate miniretinas, as retinal organoids, could provide the circuitry necessary for visual processing. Transplantation of such retinoids could provide some measure of restoration of visual function.

Finally, it is becoming apparent that ocular tissues have strong homeostatic mechanisms that can be induced to overcome trauma and disease. The steady state of an ocular cell is maintained by a series of epigenetic controls. This limits the ability of cells to respond to trauma or disease. By modifying the epigenetic state it may be possible to move a cell back into a more plastic state and allow it to reset many pathways that can cope with the disease. One example of this is described in the article by Barnstable20 in this issue. Altering the epigenetic state of retinas affected by the pde6 mutation form of RP allows the survival of rod photoreceptors. Although only tested in an animal model so far, this approach may have widespread applicability.

Overall, ophthalmic practice has reached an exciting new threshold. A raft of new approaches is in, or near, clinical trials and may soon greatly increase the tools available to treat patients. Greater precision in diagnosis will allow the rational choice treatment most suited to that individual. Many new treatments will prevent disease progression and maintain vision. Most important, however, are the new approaches that offer hope of vision restoration to those who have already become blind.


1. GBD 2019 Diseases and Injuries Collaborators. Global burden of 369 diseases and injuries in 204 countries and territories, 1990-2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet. 2020;396:1204–1222.
2. RetNet Retinal Information Network. Available at:
3. Yusufu M, Bukhari J, Wang N, et al. Challenges in eye care in the Asia-Pacific Region. Asia Pac J Ophthalmol (Phila). 2021;10:423–429.
4. Iwata T. Japan to Global Eye Genetic Consortium: extending research collaboration for inherited eye diseases. Asia Pac J Ophthalmol (Phila). 2022;11:360–368.
5. Burgess F, Hall HN, Megaw R. Emerging gene manipulation strategies for the treatment of monogenic eye disease. Asia Pac J Ophthalmol (Phila). 2022;11:380–391.
6. Dias MF, Joo K, Kemp JA, et al. Molecular genetics and emerging therapies for retinitis pigmentosa: basic research and clinical perspectives. Prog Retin Eye Res. 2018;63:107–131.
7. Xu D, Khan MA, Ho AC. Creating an ocular biofactory: surgical approaches in gene therapy for acquired retinal diseases. Asia Pac J Ophthalmol (Phila). 2021;10:5–11.
8. McLenachan S, Zaw K, Carvalho LS, et al. Pathogenesis and treatment of usher syndrome type IIA. Asia Pac J Ophthalmol (Phila). 2022;11:369–379.
9. Liu X, Zheng T, Zhao C, et al. Genetic mutations and molecular mechanisms of Fuchs endothelial corneal dystrophy. Eye and Vis. 2021;8:24.
10. Singh V, Salman M, Verma A, et al. New frontier in the management of corneal dystrophies: basics, development, and challenges in corneal gene therapy and gene editing. Asia Pac J Ophthalmol (Phila). 2022;11:349–359.
11. Klein RJ, Zeiss C, Chew EY, et al. Complement factor H polymorphism in age-related macular degeneration. Science. 2005;308:385–389.
12. Samanta A, Aziz AA, Jhingan M, et al. Emerging therapies in nonexudative age-related macular degeneration in 2020. Asia Pac J Ophthalmol (Phila). 2021;10:408–416.
13. Chen LJ. Genetic association of age-related macular degeneration and polypoidal choroidal vasculopathy. Asia Pac J Ophthalmol (Phila). 2020;9:104–109.
14. Samanta A, Aziz AA, Jhingan M, et al. Emerging therapies in neovascular age-related macular degeneration in 2020. Asia Pac J Ophthalmol (Phila). 2020;9:250–259.
15. Kinoshita S, Kitazawa K, Sotozono C. Current advancements in corneal cell-based therapy. Asia Pac J Ophthalmol (Phila). 2022;11:335–345.
16. Ludwig AL, Gamm DM. Outer retinal cell replacement: putting the pieces together. Transl Vis Sci Technol. 2021;10:15.
17. Zarbin M, Gullapalli V. New prospects for retinal pigment epithelium transplantation. Asia Pac J Ophthalmol (Phila). 2022;11:302–313.
18. Zhang KY, Tuffy C, Mertz JL, et al. Role of the internal limiting membrane in structural engraftment and topographic spacing of transplanted human stem cell-derived retinal ganglion cells. Stem Cell Reports. 2021;16:149–167.
19. Seiler MJ, Xue Y, Lin B, et al. The prospects for retinal organoids in treatment of retinal diseases. Asia Pac J Ophthalmol (Phila). 2022;11:314–327.
20. Barnstable C. Epigenetics and degenerative retinal diseases: prospects for new therapeutic approaches. Asia Pac J Ophthalmol (Phila). 2022;11:328–334.
Copyright © 2022 Asia-Pacific Academy of Ophthalmology. Published by Wolters Kluwer Health, Inc. on behalf of the Asia-Pacific Academy of Ophthalmology.