Yang Xuejiao
Yan Junwei- 1Department of Ophthalmology, The Affiliated Hospital of Qingdao University, Qingdao, China
- 2Department of Vascular Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China
Glaucoma is a progressive, irreversible loss of retinal ganglion cells (RGCs) and axons that results in characteristic optic atrophy and corresponding progressive visual field defect. The exact mechanisms underlying glaucomatous neuron loss are not clear. The main risk factor for glaucoma onset and development is high intraocular pressure (IOP), however traditional IOP-lowering therapies are often not sufficient to prevent degeneration of RGCs and the vision loss may progress, indicating the need for complementary neuroprotective therapy. This review summarizes the progress for neuro protection in glaucoma in recent 5 years, including modulation of neuroinflammation, gene and cell therapy, dietary supplementation, and sustained-release system.
Introduction
Glaucoma is a progressive, irreversible loss of retinal ganglion cells (RGCs) and axons that results in a characteristic optic atrophy and a corresponding progressive visual field defect. The most common types of glaucoma are primary open-angle glaucoma and primary angle closure glaucoma (PACG) (Dietze et al., 2022). Acute PACG has typical anatomical characteristics, such as shallow anterior chamber, pupillary block, plateau iris, etc., it usually causes acute attack. However, patients with POAG and chronic PACG are often asymptomatic until the optic nerve damage is severe. The exact mechanisms underlying glaucomatous neuron loss are not clear.
Although some scholars believe that it is a neurodegenerative disease (Ramirez et al., 2017), it is not exactly the same as Parkinson’s disease, Alzheimer’s disease, and other neurodegenerative diseases that mainly occur in the middle-aged and the elderly. Glaucoma has a wide age, some young and middle-aged patients with open and chronic closure have very late visual field, obvious C/D cupping and optic nerve atrophy. Because irreversible blindness seriously affects patients’ quality of life and heavy social burden, it is critical to explore the possible pathogenesis of optic nerve injury and effective treatment targets.
The main risk factor for glaucoma onset and development is high intraocular pressure (IOP), and the current treatments available target the lowering of IOP (Dietze et al., 2022). However, degeneration of RGCs and the vision loss may progress despite significant IOP lowering in some patients, indicating that complementary neuroprotective therapy are needed. In recent years, a large number of studies on optic nerve protection have emerged, this review summarizes the progress for neuro protection in glaucoma in recent 5 years, including modulation of neuroinflammation, gene, and cell therapy, dietary supplementation, and sustained-release system.
Neuroimmunity
Immune system dysregulation is increasingly being attributed to the development of a multitude of neurodegenerative diseases (Stothert and Kaur 2021). In recent years, a large amount of studies focus on the glia cells and immune system in the development of glaucomatous optic neuropathy (de Hoz et al., 2018). An excessive microglial response may be a significant degenerative factor for increased cell death (Grotegut et al., 2020), microglia activation and release of pro-inflammatory cytokines are the main contributors for retinal cell death in glaucoma (de Hoz et al., 2018). OPN was found to enhance the proliferation and activation of retinal microglia, and contribute to the eventual RGCs loss and vision function impairment in glaucoma (Yu et al., 2021). Blocking microglial A2A R prevents microglial cell response to elevated pressure and it is sufficient to protect retinal cells from elevated pressure-induced death (Aires et al., 2019). Another study found activation of Adenosine A (3) receptor could hinder the microglia reactivity (Ferreira-Silva et al., 2020), attenuated the impairment in retrograde axonal transport, and afford protection against glaucomatous degeneration. In addition, P2X7 receptor antagonist protects retinal ganglion cells by inhibiting microglial activation in a rat chronic ocular hypertension model (Dong et al., 2018).
Astrocytes perform critical non-cell autonomous roles following CNS injury that involve either neurotoxic or neuroprotective effects. Astrocyte-derived lipoxins A4 and B4 promote neuroprotection from acute and chronic injury neuroprotective signal (Livne-Bar et al., 2017). Statins promotes the survival of RGCs by reduce apoptosis and suppress chronic high IOP induced glial activation (Kim et al., 2021).
Gene therapy
Gene therapy, which uses a viral vectors to deliver genetic material into cells, is a promising approach to directly target pathogenetic molecules (Keeler et al., 2017). The retina is a favorable target for gene therapy because of its easy access, established clear functional readouts, partial immune privilege and confined non-systemic localization (Ratican et al., 2018). The success of adeno-associated virus (AAV)-mediated gene replacement therapy for inherited retinal disease (Maguire et al., 2008; Busskamp et al., 2010; Smalley 2017) has made RGC-specific gene expression and AAV editing a promising gene therapy strategy for optic neuropathies. Table 1 lists the gene therapy studies on neuroprotection of glaucoma in recent 5 years, their findings indicate that gene therapy has a broad prospect in protecting both structure and function of RGC. Apart from this, reprogramming cells with defined factors is another promising strategy to produce functional cells for therapeutic purposes (Wang et al., 2021). OSK-induced reprogramming in mouse RGC was found to promote axon regeneration and reverse vision loss (Lu et al., 2020). Math5 and Brn3b transcription factors (TFs) combination can reprogram mature mouse Müller glia into RGC, resulting in proper projection of RGC in the visual pathway, and improved visual function (Xiao et al., 2021). Recently, another study, using a CRISPR-Cas9-based genome-wide screen of 1,893 TFs, found that manipulation of ATF3/CHOP and ATF4/C/EBPγ protected RGC in a glaucoma model (Tian et al., 2022).
TABLE 1. Gene therapy studies on neuroprotection of glaucoma in recent 5 years.
Cell therapy
Cell therapy provides a new therapeutic strategy for glaucoma. Stem cell therapy mainly involves the transplantation of cells to replace the dead and lost RGC. However, it is associated with a number of major challenges besides ethical issue. Regeneration of RGCs requires full synaptic integration of host inner retinal stem cells and the development of long-distance axons, which project to the brain and accurately form effective synaptic connections with corresponding targets to complete signal transmission. Up to now, the replacement of RGCs has not made a breakthrough (Zhang J. et al., 2021). Several recently studied cell types for transplantation including mouse induced pluripotent stem cell (miPSC) or mouse embryonic stem cell (mESC)-derived RGC (Oswald et al., 2021) and spermatogonial stem cell-derived RGC (Suen et al., 2019). Another study found mesenchymal stem cells (MSC) secreted exosomes can promote survival of RGC and regeneration of their axons (Mead and Tomarev 2017). In addition, further study found that TNF-α stimulated gingival MSC derived exosomes play neuroprotection and anti-inflammation roles by delivering miR-21-5p-enriched exosomes through MEG3/miR-21-5p/PDCD4 axis (Yu et al., 2022).
Dietotherapy
In animal models of glaucoma, various diet-related treatments were found as non-IOP-related neuroprotective mechanisms. High VitK1 intake (Deng et al., 2020) , Coenzyme Q10 + Vitamin E (Zhang et al., 2017; Ekicier Acar et al., 2020), Nicotinamide riboside of the vitamin B3 family (Zhang X. et al., 2021), probiotic bacteria (Fafure et al., 2021) and other dietary supplementation (Cammalleri et al., 2020) were proved to attenuate the loss of RGCs by regulating glia-mediated neuroinflammatory or BDNF activity, etc.
New drug loading system
Several preclinical studies demonstrate that neurotrophins (NTs) prevent RGCs loss (Gupta et al., 2022). NTs can be conjugated to nanoparticles, which act as smart drug carriers. This enables the self-localization of drugs in the retina and the prevention of rapid degradation of drugs (Giannaccini et al., 2018).
Sunitinib is a protein kinase inhibitor with activity against the neuroprotective targets dual leucine zipper kinase (DLK) and leucine zipper kinase (LZK). It was found to enhance survival of RGCs for neuroprotection. Recently, a hypotonic, thermosensitive gel-forming eye drop (Kim et al., 2022) and a sunitinib-pamoate complex (SPC) microcrystals for subconjunctival injection (Hsueh et al., 2021) were devised to continuously release for 1 and 20 weeks.
Others
Cannabinoids (CBs) was found to target several factors that related with the progression of glaucoma, it promotes neuroprotection, abrogates changes in ECM protein, and normalizes the IOP levels in the eye (Maguire et al., 2022; Somvanshi et al., 2022).
In summary, various neuroprotective therapy (Figure 1) can help us to better understand the pathological basis of visual function impairment and progression in glaucoma. At present, many scholars have committed to clinical translation to save RGCs and visual function of glaucoma patients from the molecular and cellular levels. These new strategies will bring hope for the prevention and treatment of glaucoma.
FIGURE 1. New neuroprotective strategy of glaucoma in recent 5 years.
Author contributions
YX contributed to writing of the manuscript. YJ contributed to manuscript revision.
Funding
This work was supported by the National Natural Science Foundation of China (81600726), Natural Science Foundation of Shandong Province (ZR2016HB53), 2021 Qingdao Medical and Health Scientific Research Project and Youth Science Foundation of the affiliated hospital of Qingdao University.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher’s note
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References
Aires, I. D., Boia, R., Rodrigues-Neves, A. C., Madeira, M. H., Marques, C., Ambrosio, A. F., et al. (2019). Blockade of microglial adenosine A2A receptor suppresses elevated pressure-induced inflammation, oxidative stress, and cell death in retinal cells. Glia 67, 896–914. doi:10.1002/glia.23579
Bosco, A., Anderson, S. R., Breen, K. T., Romero, C. O., Steele, M. R., Chiodo, V. A., et al. (2018). Complement C3-targeted gene therapy restricts onset and progression of neurodegeneration in chronic mouse glaucoma. Mol. Ther. 26, 2379–2396. doi:10.1016/j.ymthe.2018.08.017
Busskamp, V., Duebel, J., Balya, D., Fradot, M., Viney, T. J., Siegert, S., et al. (2010). Genetic reactivation of cone photoreceptors restores visual responses in retinitis pigmentosa. Science 329, 413–417. doi:10.1126/science.1190897
Cammalleri, M., Dal Monte, M., Amato, R., Bagnoli, P., and Rusciano, D. (2020). A dietary combination of forskolin with homotaurine, spearmint and B vitamins protects injured retinal ganglion cells in a rodent model of hypertensive glaucoma. Nutrients 12, E1189. doi:10.3390/nu12041189
de Hoz, R., Ramirez, A. I., Gonzalez-Martin, R., Ajoy, D., Rojas, B., Salobrar-Garcia, E., et al. (2018). Bilateral early activation of retinal microglial cells in a mouse model of unilateral laser-induced experimental ocular hypertension. Exp. Eye Res. 171, 12–29. doi:10.1016/j.exer.2018.03.006
Deng, C., Yao, K., Peng, F., Zhao, B., Chen, Z., Chen, W., et al. (2020). The effect of dietary vitamin K1 supplementation on trabecular meshwork and retina in a chronic ocular hypertensive rat model. Invest. Ophthalmol. Vis. Sci. 61, 40. doi:10.1167/iovs.61.8.40
Dietze, J., Blair, K., and Havens, S. J. (2022). Glaucoma. Treasure Island (FL): StatPearls. Treasure Island (FL).
Donahue, R. J., Fehrman, R. L., Gustafson, J. R., and Nickells, R. W. (2021). BCLXL gene therapy moderates neuropathology in the DBA/2J mouse model of inherited glaucoma. Cell. Death Dis. 12, 781. doi:10.1038/s41419-021-04068-x
Dong, L., Hu, Y., Zhou, L., and Cheng, X. (2018). P2X7 receptor antagonist protects retinal ganglion cells by inhibiting microglial activation in a rat chronic ocular hypertension model. Mol. Med. Rep. 17, 2289–2296. doi:10.3892/mmr.2017.8137
Ekicier Acar, S., Saricaoglu, M. S., Colak, A., Aktas, Z., and Sepici Dincel, A. (2020). Neuroprotective effects of topical coenzyme Q10 + vitamin E in mechanic optic nerve injury model. Eur. J. Ophthalmol. 30, 714–722. doi:10.1177/1120672119833271
Fafure, A. A., Edem, E. E., Obisesan, A. O., Enye, L. A., Adekeye, A. O., Adetunji, A. E., et al. (2021). Fermented maize slurry (Ogi) and its supernatant (Omidun) mitigate elevated intraocular pressure by modulating BDNF expression and glial plasticity in the retina-gut axis of glaucomatous rats. J. Complement. Integr. Med. 0. doi:10.1515/jcim-2021-0114
Fang, F., Zhuang, P., Feng, X., Liu, P., Liu, D., Huang, H., et al. (2022). NMNAT2 is downregulated in glaucomatous RGCs, and RGC-specific gene therapy rescues neurodegeneration and visual function. Mol. Ther. 30, 1421–1431. doi:10.1016/j.ymthe.2022.01.035
Ferreira-Silva, J., Aires, I. D., Boia, R., Ambrósio, A. F., and Santiago, A. R. (2020). Activation of adenosine A(3) receptor inhibits microglia reactivity elicited by elevated pressure. Int. J. Mol. Sci. 21, E7218. doi:10.3390/ijms21197218
Giannaccini, M., Usai, A., Chiellini, F., Guadagni, V., Andreazzoli, M., Ori, M., et al. (2018). Neurotrophin-conjugated nanoparticles prevent retina damage induced by oxidative stress. Cell. Mol. Life Sci. 75, 1255–1267. doi:10.1007/s00018-017-2691-x
Grotegut, P., Perumal, N., Kuehn, S., Smit, A., Dick, H. B., Grus, F. H., et al. (2020). Minocycline reduces inflammatory response and cell death in a S100B retina degeneration model. J. Neuroinflammation 17, 375. doi:10.1186/s12974-020-02012-y
Guo, X., Zhou, J., Starr, C., Mohns, E. J., Li, Y., Chen, E. P., et al. (2021). Preservation of vision after CaMKII-mediated protection of retinal ganglion cells. Cell. 184, 4299–4314.e12. doi:10.1016/j.cell.2021.06.031
Gupta, V., Chitranshi, N., Gupta, V., You, Y., Rajput, R., Paulo, J. A., et al. (2022). TrkB receptor agonist 7, 8 dihydroxyflavone is protective against the inner retinal deficits induced by experimental glaucoma. Neuroscience 490, 36–48. doi:10.1016/j.neuroscience.2022.01.020
Hsueh, H. T., Kim, Y. C., Pitha, I., Shin, M. D., Berlinicke, C. A., Chou, R. T., et al. (2021). Ion-complex microcrystal formulation provides sustained delivery of a multimodal kinase inhibitor from the subconjunctival space for protection of retinal ganglion cells. Pharmaceutics 13, 647. doi:10.3390/pharmaceutics13050647
Keeler, A. M., ElMallah, M. K., and Flotte, T. R. (2017). Gene therapy 2017: Progress and future directions. Clin. Transl. Sci. 10, 242–248. doi:10.1111/cts.12466
Khatib, T. Z., Osborne, A., Yang, S., Ali, Z., Jia, W., Manyakin, I., et al. (2021). Receptor-ligand supplementation via a self-cleaving 2A peptide-based gene therapy promotes CNS axonal transport with functional recovery. Sci. Adv. 7, eabd2590. doi:10.1126/sciadv.abd2590
Kim, M. L., Sung, K. R., Kwon, J., Choi, G. W., and Shin, J. A. (2021). Neuroprotective effect of statins in a rat model of chronic ocular hypertension. Int. J. Mol. Sci. 22, 12500. doi:10.3390/ijms222212500
Kim, Y. C., Hsueh, H. T., Shin, M. D., Berlinicke, C. A., Han, H., Anders, N. M., et al. (2022). A hypotonic gel-forming eye drop provides enhanced intraocular delivery of a kinase inhibitor with melanin-binding properties for sustained protection of retinal ganglion cells. Drug Deliv. Transl. Res. 12, 826–837. doi:10.1007/s13346-021-00987-6
Lani-Louzada, R., Marra, C., Dias, M. S., de Araújo, V. G., Abreu, C. A., Ribas, V. T., et al. (2022). Neuroprotective gene therapy by overexpression of the transcription factor MAX in rat models of glaucomatous neurodegeneration. Invest. Ophthalmol. Vis. Sci. 63, 5. doi:10.1167/iovs.63.2.5
Livne-Bar, I., Wei, J., Liu, H. H., Alqawlaq, S., Won, G. J., Tuccitto, A., et al. (2017). Astrocyte-derived lipoxins A4 and B4 promote neuroprotection from acute and chronic injury. J. Clin. Invest. 127, 4403–4414. doi:10.1172/JCI77398
Lu, Y., Brommer, B., Tian, X., Krishnan, A., Meer, M., Wang, C., et al. (2020). Reprogramming to recover youthful epigenetic information and restore vision. Nature 588, 124–129. doi:10.1038/s41586-020-2975-4
Maguire, A. M., Simonelli, F., Pierce, E. A., Pugh, E. N., Mingozzi, F., Bennicelli, J., et al. (2008). Safety and efficacy of gene transfer for Leber's congenital amaurosis. N. Engl. J. Med. 358, 2240–2248. doi:10.1056/NEJMoa0802315
Maguire, G., Eubanks, C., and Ayoub, G. (2022). Neuroprotection of retinal ganglion cells in vivo using the activation of the endogenous cannabinoid signaling system in mammalian eyes. Neuronal Signal. 6, Ns20210038. doi:10.1042/ns20210038
Mead, B., and Tomarev, S. (2017). Bone marrow-derived mesenchymal stem cells-derived exosomes promote survival of retinal ganglion cells through miRNA-dependent mechanisms. Stem Cells Transl. Med. 6, 1273–1285. doi:10.1002/sctm.16-0428
Osborne, A., Khatib, T. Z., Songra, L., Barber, A. C., Hall, K., Kong, G. Y. X., et al. (2018). Neuroprotection of retinal ganglion cells by a novel gene therapy construct that achieves sustained enhancement of brain-derived neurotrophic factor/tropomyosin-related kinase receptor-B signaling. Cell. Death Dis. 9, 1007. doi:10.1038/s41419-018-1041-8
Oswald, J., Kegeles, E., Minelli, T., Volchkov, P., and Baranov, P. (2021). Transplantation of miPSC/mESC-derived retinal ganglion cells into healthy and glaucomatous retinas. Mol. Ther. Methods Clin. Dev. 21, 180–198. doi:10.1016/j.omtm.2021.03.004
Ramirez, A. I., de Hoz, R., Salobrar-Garcia, E., Salazar, J. J., Rojas, B., Ajoy, D., et al. (2017). The role of microglia in retinal neurodegeneration: Alzheimer's disease, Parkinson, and glaucoma. Front. Aging Neurosci. 9, 214. doi:10.3389/fnagi.2017.00214
Ratican, S. E., Osborne, A., and Martin, K. R. (2018). Progress in gene therapy to prevent retinal ganglion cell loss in glaucoma and leber's hereditary optic neuropathy. Neural Plast. 2018, 7108948. doi:10.1155/2018/7108948
Shen, J., Xiao, R., Bair, J., Wang, F., Vandenberghe, L. H., Dartt, D., et al. (2018). Novel engineered, membrane-localized variants of vascular endothelial growth factor (VEGF) protect retinal ganglion cells: A proof-of-concept study. Cell. Death Dis. 9, 1018. doi:10.1038/s41419-018-1049-0
Smalley, E. (2017). First AAV gene therapy poised for landmark approval. Nat. Biotechnol. 35, 998–999. doi:10.1038/nbt1117-998
Somvanshi, R. K., Zou, S., Kadhim, S., Padania, S., Hsu, E., and Kumar, U. (2022). Cannabinol modulates neuroprotection and intraocular pressure: A potential multi-target therapeutic intervention for glaucoma. Biochim. Biophys. Acta. Mol. Basis Dis. 1868, 166325. doi:10.1016/j.bbadis.2021.166325
Stothert, A. R., and Kaur, T. (2021). Innate immunity to spiral ganglion neuron loss: A neuroprotective role of fractalkine signaling in injured cochlea. Front. Cell. Neurosci. 15, 694292. doi:10.3389/fncel.2021.694292
Suen, H. C., Qian, Y., Liao, J., Luk, C. S., Lee, W. T., Ng, J. K. W., et al. (2019). Transplantation of retinal ganglion cells derived from male germline stem cell as a potential treatment to glaucoma. Stem Cells Dev. 28, 1365–1375. doi:10.1089/scd.2019.0060
Tian, F., Cheng, Y., Zhou, S., Wang, Q., Monavarfeshani, A., Gao, K., et al. (2022). Core transcription programs controlling injury-induced neurodegeneration of retinal ganglion cells. Neuron 110, 2607–2624.e8. doi:10.1016/j.neuron.2022.06.003
Visuvanathan, S., Baker, A. N., Lagali, P. S., Coupland, S. G., Miller, G., Hauswirth, W. W., et al. (2022). XIAP gene therapy effects on retinal ganglion cell structure and function in a mouse model of glaucoma. Gene Ther. 29, 147–156. doi:10.1038/s41434-021-00281-7
Wang, H., Yang, Y., Liu, J., and Qian, L. (2021). Direct cell reprogramming: Approaches, mechanisms and progress. Nat. Rev. Mol. Cell. Biol. 22, 410–424. doi:10.1038/s41580-021-00335-z
Wang, Q., Zhuang, P., Huang, H., Li, L., Liu, L., Webber, H. C., et al. (2020). Mouse γ-synuclein promoter-mediated gene expression and editing in mammalian retinal ganglion cells. J. Neurosci. 40, 3896–3914. doi:10.1523/jneurosci.0102-20.2020
Wojcik-Gryciuk, A., Gajewska-Wozniak, O., Kordecka, K., Boguszewski, P. M., Waleszczyk, W., and Skup, M. (2020). Neuroprotection of retinal ganglion cells with AAV2-BDNF pretreatment restoring normal TrkB receptor protein levels in glaucoma. Int. J. Mol. Sci. 21, E6262. doi:10.3390/ijms21176262
Xiao, D., Jin, K., Qiu, S., Lei, Q., Huang, W., Chen, H., et al. (2021). In vivo regeneration of ganglion cells for vision restoration in mammalian retinas. Front. Cell. Dev. Biol. 9, 755544. doi:10.3389/fcell.2021.755544
Yu, H., Zhong, H., Li, N., Chen, K., Chen, J., Sun, J., et al. (2021). Osteopontin activates retinal microglia causing retinal ganglion cells loss via p38 MAPK signaling pathway in glaucoma. FASEB J. 35, e21405. doi:10.1096/fj.202002218R
Yu, Z., Wen, Y., Jiang, N., Li, Z., Guan, J., Zhang, Y., et al. (2022). TNF-α stimulation enhances the neuroprotective effects of gingival MSCs derived exosomes in retinal ischemia-reperfusion injury via the MEG3/miR-21a-5p axis. Biomaterials 284, 121484. doi:10.1016/j.biomaterials.2022.121484
Zhang, J., Wu, S., Jin, Z. B., and Wang, N. (2021). Stem cell-based regeneration and restoration for retinal ganglion cell: Recent advancements and current challenges. Biomolecules 11, 987. doi:10.3390/biom11070987
Zhang, X., Tohari, A. M., Marcheggiani, F., Zhou, X., Reilly, J., Tiano, L., et al. (2017). Therapeutic potential of Co-enzyme Q10 in retinal diseases. Curr. Med. Chem. 24, 4329–4339. doi:10.2174/0929867324666170801100516
Keywords: retinal ganglion cells, glaucoma, neuroprotection, gliocyte, gene therapy
Citation: Xuejiao Y and Junwei Y (2022) New strategies for neuro protection in glaucoma. Front. Cell Dev. Biol. 10:983195. doi: 10.3389/fcell.2022.983195
Received: 30 June 2022; Accepted: 30 August 2022;
Published: 15 September 2022.
Edited by:
Wei Qiu, Third Affiliated Hospital of Sun Yat-sen University, ChinaReviewed by:
Ling Zhao, Zhongshan Ophthalmic Center, Sun Yat-sen University, ChinaCopyright © 2022 Xuejiao and Junwei. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Yang Xuejiao, eXhqNTIxMUAxNjMuY29t