Advances in the application of optogenetic in the treatment of retinal degenerative diseases_Chinese Journal of Ocular Fundus Diseases

Authors：

Chen Fei ,  Shen Yin

Eye Center, Renmin Hospital of Wuhan University, Wuhan 430060, China;

Corresponding author：

Shen Yin, Email: yinshen@whu.edu.cn

Keywords：

Retinal diseases; Optogenetic; Review

DOI：

10.3760/cma.j.cn511434-20200408-00150

Video：

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Abstract Full text Figures/Tables Video References Cited by

Retinal degeneration is a blind eye disease caused by changes in the function of retinal pigment epithelial cells and photoreceptor cells. Stem cell transplantation, gene therapy, retinal prosthesis implantation and other new biological technologies have made great progress in the restoration of visual function, but they still face many difficulties. Optogenetic is a new interdisciplinary technology that combines optics, physiology and genetics. It can express photosensitive proteins on retinal neurons in retinal degeneration. The light stimulation causing depolarization or hyperpolarization reaction of cells that expressed photosensitive proteins to gain light sensitivity. Compared with the immune rejection of stem cell therapy, the greater individualization of gene therapy and the greater traumatic nature of retinal prosthesis implantation, optogenetic technology has significant advantages, and it is also urgent to solve the problems of low spatial and temporal resolution and light sensitivity. With the gradual development of optogenetics technology, it is bound to form a deeper level of cross and fusion with other fields, so as to contribute to the recovery of visual function of patients with retinal degeneration.

Citation： Chen Fei, Shen Yin. Advances in the application of optogenetic in the treatment of retinal degenerative diseases. Chinese Journal of Ocular Fundus Diseases, 2021, 37(6): 483-487. doi: 10.3760/cma.j.cn511434-20200408-00150 Copy

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2.	Campochiaro PA, Mir TA. The mechanism of cone cell death in retinitis pigmentosa[J]. Prog Retin Eye Res, 2018, 62: 24-37. DOI: 10.1016/j.preteyeres.2017.08.004.
3.	DeAngelis MM, Owen LA, Morrison MA, et al. Genetics of age-related macular degeneration (AMD)[J]. Hum Mol Genet, 2017, 26(R1): R45-R50. DOI: 10.1093/hmg/ddx228.
4.	Gauvain G, Akolkar H, Chaffiol A, et al. Optogenetic therapy: high spatiotemporal resolution and pattern discrimination compatible with vision restoration in non-human primates[J/OL]. Commun Biol, 2021, 4(1): 125[2021-01-27]. https://pubmed.ncbi.nlm.nih.gov/33504896/. DOI: 10.1038/s42003-020-01594-w.
5.	Nagel G, Szellas T, Huhn W, et al. Channelrhodopsin-2, a directly light-gated cation-selective membrane channel[J]. Proc Natl Acad Sci USA, 2003, 100(24): 13940-13945. DOI: 10.1073/pnas.1936192100.
6.	Lagali PS, Balya D, Awatramani GB, et al. Light-activated channels targeted to on bipolar cells restore visual function in retinal degeneration[J]. Nat Neurosci, 2008, 11(6): 667-675. DOI: 10.1038/nn.2117.
7.	Kleinlogel S, Terpitz U, Legrum B, et al. A gene-fusion strategy for stoichiometric and colocalized expression of light-gated membrane proteins[J]. Nat Methods, 2011, 8(12): 1083-1088. DOI: 10.1038/nmeth.1766.
8.	Simunovic MP, Shen W, Lin JY, et al. Optogenetic approaches to vision restoration[J]. Exp Eye Res, 2019, 178: 15-26. DOI: 10.1016/j.exer.2018.09.003.
9.	Joly S, Francke M, Ulbricht E, et al. Cooperative phagocytes: resident microglia and bone marrow immigrants remove dead photoreceptors in retinal lesions[J]. Am J Pathol, 2009, 174(6): 2310-2323. DOI: 10.2353/ajpath.2009.090023.
10.	Hunter JJ, Morgan JI, Merigan WH, et al. The susceptibility of the retina to photochemical damage from visible light[J]. Prog Retin Eye Res, 2012, 31(1): 28-42. DOI: 10.1016/j.preteyeres.2011.11.001.
11.	Sengupta A, Chaffiol A, Mace E, et al. Red-shifted channelrhodopsin stimulation restores light responses in blind mice, macaque retina, and human retina[J]. EMBO Mol Med, 2016, 8(11): 1248-1264. DOI: 10.15252/emmm.201505699.
12.	Pan ZH, Ganjawala TH, Lu Q, et al. ChR2 mutants at L132 and T159 with improved operational light sensitivity for vision restoration[J/OL]. PLoS One, 2014, 9(6): e98924[2014-06-05]. https://pubmed.ncbi.nlm.nih.gov/24901492/. DOI: 10.1371/journal.pone.0098924.
13.	Ganjawala TH, Lu Q, Fenner MD, et al. Improved CoChR variants restore visual acuity and contrast sensitivity in a mouse model of blindness under ambient light conditions[J]. Mol Ther, 2019, 27(6): 1195-1205. DOI: 10.1016/j.ymthe.2019.04.002.
14.	Kleinlogel S, Feldbauer K, Dempski RE, et al. Ultra light-sensitive and fast neuronal activation with the Ca²⁺-permeable channelrhodopsin CatCh[J]. Nat Neurosci, 2011, 14(4): 513-518. DOI: 10.1038/nn.2776.
15.	Chaffiol A, Caplette R, Jaillard C, et al. A new promoter allows optogenetic vision restoration with enhanced sensitivity in macaque retina[J]. Mol Ther, 2017, 25(11): 2546-2560. DOI: 10.1016/j.ymthe.2017.07.011.
16.	Chow BY, Han X, Dobry AS, et al. High-performance genetically targetable optical neural silencing by light-driven proton pumps[J]. Nature, 2010, 463(7277): 98-102. DOI: 10.1038/nature08652.
17.	Idnurm A, Howlett BJ. Characterization of an opsin gene from the ascomycete leptosphaeria maculans[J]. Genome, 2001, 44(2): 167-171. DOI: 10.1139/g00-113.
18.	Gradinaru V, Thompson KR, Deisseroth K. eNpHR: a natronomonas halorhodopsin enhanced for optogenetic applications[J]. Brain Cell Biol, 2008, 36(1-4): 129-139. DOI: 10.1007/s11068-008-9027-6.
19.	Chuong AS, Miri ML, Busskamp V, et al. Noninvasive optical inhibition with a red-shifted microbial rhodopsin[J]. Nat Neurosci, 2014, 17(8): 1123-1129. DOI: 10.1038/nn.3752.
20.	Claes E, Seeliger M, Michalakis S, et al. Morphological characterization of the retina of the CNGA₃(-/-)Rho(-/-) mutant mouse lacking functional cones and rods[J]. Invest Ophthalmol Vis Sci, 2004, 45(6): 2039-2048. DOI: 10.1167/iovs.03-0741.
21.	Busskamp V, Duebel J, Balya D, et al. Genetic reactivation of cone photoreceptors restores visual responses in retinitis pigmentosa[J]. Science, 2010, 329(5990): 413-417. DOI: 10.1126/science.1190897.
22.	Khabou H, Garita-Hernandez M, Chaffiol A, et al. Noninvasive gene delivery to foveal cones for vision restoration[J/OL]. JCI Insight, 2018, 3(2): e96029[2018-01-25]. https://pubmed.ncbi.nlm.nih.gov/29367457/. DOI: 10.1172/jci.insight.96029.
23.	Garita-Hernandez M, Lampic M, Chaffiol A, et al. Restoration of visual function by transplantation of optogenetically engineered photoreceptors[J/OL]. Nat Commun, 2019, 10(1): 4524[2019-10-04]. https://pubmed.ncbi.nlm.nih.gov/31586094/. DOI: 10.1038/s41467-019-12330-2.
24.	Garita-Hernandez M, Guibbal L, Toualbi L, et al. Optogenetic light sensors in human retinal organoids[J/OL]. Front Neurosci, 2018, 12: 789[2018-11-02]. https://pubmed.ncbi.nlm.nih.gov/30450028/. DOI: 10.3389/fnins.2018.00789.
25.	Cehajic-Kapetanovic J, Eleftheriou C, Allen AE, et al. Restoration of vision with ectopic expression of human rod opsin[J]. Curr Biol, 2015, 25(16): 2111-2122. DOI: 10.1016/j.cub.2015.07.029.
26.	Gaub BM, Berry MH, Holt AE, et al. Optogenetic vision restoration using rhodopsin for enhanced sensitivity[J]. Mol Ther, 2015, 23(10): 1562-1571. DOI: 10.1038/mt.2015.121.
27.	De Silva SR, Barnard AR, Hughes S, et al. Long-term restoration of visual function in end-stage retinal degeneration using subretinal human melanopsin gene therapy[J]. Proc Natl Acad Sci USA, 2017, 114(42): 11211-11216. DOI: 10.1073/pnas.1701589114.
28.	Berry MH, Holt A, Salari A, et al. Restoration of high-sensitivity and adapting vision with a cone opsin[J/OL]. Nat Commun, 2019, 10(1): 1221[2019-03-15]. https://pubmed.ncbi.nlm.nih.gov/30874546/. DOI: 10.1038/s41467-019-09124-x.
29.	van Wyk M, Pielecka-Fortuna J, Lowel S, et al. Restoring the on switch in blind retinas: opto-mGluR6, a next-generation, cell-tailored optogenetic tool[J/OL]. PLoS Biol, 2015, 13(5): e1002143[2015-05-07]. https://pubmed.ncbi.nlm.nih.gov/25950461/. DOI: 10.1371/journal.pbio.1002143.
30.	Singh MS, Charbel Issa P, Butler R, et al. Reversal of end-stage retinal degeneration and restoration of visual function by photoreceptor transplantation[J]. Proc Natl Acad Sci USA, 2013, 110(3): 1101-1106. DOI: 10.1073/pnas.1119416110.
31.	Barber AC, Hippert C, Duran Y, et al. Repair of the degenerate retina by photoreceptor transplantation[J]. Proc Natl Acad Sci USA, 2013, 110(1): 354-359. DOI: 10.1073/pnas.1212677110.
32.	Mandai M, Fujii M, Hashiguchi T, et al. iPSC-derived retina transplants improve vision in rd1 end-stage retinal-degeneration mice[J]. Stem Cell Reports, 2017, 8(1): 69-83. DOI: 10.1016/j.stemcr.2016.12.008.
33.	Iraha S, Tu HY, Yamasaki S, et al. Establishment of immunodeficient retinal degeneration model mice and functional maturation of human ESC-derived retinal sheets after transplantation[J]. Stem Cell Reports, 2018, 10(3): 1059-1074. DOI: 10.1016/j.stemcr.2018.01.032.
34.	Eberle D, Schubert S, Postel K, et al. Increased integration of transplanted CD73-positive photoreceptor precursors into adult mouse retina[J]. Invest Ophthalmol Vis Sci, 2011, 52(9): 6462-6471. DOI: 10.1167/iovs.11-7399.
35.	da Cruz L, Dorn JD, Humayun MS, et al. Five-year safety and performance results from the argus Ⅱ retinal prosthesis system clinical trial[J]. Ophthalmology, 2016, 123(10): 2248-2254. DOI: 10.1016/j.ophtha.2016.06.049.
36.	Edwards TL, Cottriall CL, Xue K, et al. Assessment of the electronic retinal implant alpha AMS in restoring vision to blind patients with end-stage retinitis pigmentosa[J]. Ophthalmology, 2018, 125(3): 432-443. DOI: 10.1016/j.ophtha.2017.09.019.
37.	Shivdasani MN, Sinclair NC, Gillespie LN, et al. Identification of characters and localization of images using direct multiple-electrode stimulation with a suprachoroidal retinal prosthesis[J]. Invest Ophthalmol Vis Sci, 2017, 58(10): 3962-3974. DOI: 10.1167/iovs.16-21311.
38.	Soltan A, Barrett JM, Maaskant P, et al. A head mounted device stimulator for optogenetic retinal prosthesis[J/OL]. J Neural Eng, 2018, 15(6): 065002[2018-08-29]. https://pubmed.ncbi.nlm.nih.gov/30156188/. DOI: 10.1088/1741-2552/aadd55.
39.	Soltan A, McGovern B, Drakakis E, et al. High density, high radiance $\mu$ LED matrix for optogenetic retinal prostheses and planar neural stimulation[J]. IEEE Trans Biomed Circuits Syst, 2017, 11(2): 347-359. DOI: 10.1109/TBCAS.2016.2623949.
40.	Montazeri L, El Zarif N, Trenholm S, et al. Optogenetic stimulation for restoring vision to patients suffering from retinal degenerative diseases: current strategies and future directions[J]. IEEE Trans Biomed Circuits Syst, 2019, 13(6): 1792-1807. DOI: 10.1109/tbcas.2019.2951298.

1. Verbakel SK, van Huet RAC, Boon CJF, et al. Non-syndromic retinitis pigmentosa[J]. Prog Retin Eye Res, 2018, 66: 157-186. DOI: 10.1016/j.preteyeres.2018.03.005.
2. Campochiaro PA, Mir TA. The mechanism of cone cell death in retinitis pigmentosa[J]. Prog Retin Eye Res, 2018, 62: 24-37. DOI: 10.1016/j.preteyeres.2017.08.004.
3. DeAngelis MM, Owen LA, Morrison MA, et al. Genetics of age-related macular degeneration (AMD)[J]. Hum Mol Genet, 2017, 26(R1): R45-R50. DOI: 10.1093/hmg/ddx228.
4. Gauvain G, Akolkar H, Chaffiol A, et al. Optogenetic therapy: high spatiotemporal resolution and pattern discrimination compatible with vision restoration in non-human primates[J/OL]. Commun Biol, 2021, 4(1): 125[2021-01-27]. https://pubmed.ncbi.nlm.nih.gov/33504896/. DOI: 10.1038/s42003-020-01594-w.
5. Nagel G, Szellas T, Huhn W, et al. Channelrhodopsin-2, a directly light-gated cation-selective membrane channel[J]. Proc Natl Acad Sci USA, 2003, 100(24): 13940-13945. DOI: 10.1073/pnas.1936192100.
6. Lagali PS, Balya D, Awatramani GB, et al. Light-activated channels targeted to on bipolar cells restore visual function in retinal degeneration[J]. Nat Neurosci, 2008, 11(6): 667-675. DOI: 10.1038/nn.2117.
7. Kleinlogel S, Terpitz U, Legrum B, et al. A gene-fusion strategy for stoichiometric and colocalized expression of light-gated membrane proteins[J]. Nat Methods, 2011, 8(12): 1083-1088. DOI: 10.1038/nmeth.1766.
8. Simunovic MP, Shen W, Lin JY, et al. Optogenetic approaches to vision restoration[J]. Exp Eye Res, 2019, 178: 15-26. DOI: 10.1016/j.exer.2018.09.003.
9. Joly S, Francke M, Ulbricht E, et al. Cooperative phagocytes: resident microglia and bone marrow immigrants remove dead photoreceptors in retinal lesions[J]. Am J Pathol, 2009, 174(6): 2310-2323. DOI: 10.2353/ajpath.2009.090023.
10. Hunter JJ, Morgan JI, Merigan WH, et al. The susceptibility of the retina to photochemical damage from visible light[J]. Prog Retin Eye Res, 2012, 31(1): 28-42. DOI: 10.1016/j.preteyeres.2011.11.001.
11. Sengupta A, Chaffiol A, Mace E, et al. Red-shifted channelrhodopsin stimulation restores light responses in blind mice, macaque retina, and human retina[J]. EMBO Mol Med, 2016, 8(11): 1248-1264. DOI: 10.15252/emmm.201505699.
12. Pan ZH, Ganjawala TH, Lu Q, et al. ChR2 mutants at L132 and T159 with improved operational light sensitivity for vision restoration[J/OL]. PLoS One, 2014, 9(6): e98924[2014-06-05]. https://pubmed.ncbi.nlm.nih.gov/24901492/. DOI: 10.1371/journal.pone.0098924.
13. Ganjawala TH, Lu Q, Fenner MD, et al. Improved CoChR variants restore visual acuity and contrast sensitivity in a mouse model of blindness under ambient light conditions[J]. Mol Ther, 2019, 27(6): 1195-1205. DOI: 10.1016/j.ymthe.2019.04.002.
14. Kleinlogel S, Feldbauer K, Dempski RE, et al. Ultra light-sensitive and fast neuronal activation with the Ca²⁺-permeable channelrhodopsin CatCh[J]. Nat Neurosci, 2011, 14(4): 513-518. DOI: 10.1038/nn.2776.
15. Chaffiol A, Caplette R, Jaillard C, et al. A new promoter allows optogenetic vision restoration with enhanced sensitivity in macaque retina[J]. Mol Ther, 2017, 25(11): 2546-2560. DOI: 10.1016/j.ymthe.2017.07.011.
16. Chow BY, Han X, Dobry AS, et al. High-performance genetically targetable optical neural silencing by light-driven proton pumps[J]. Nature, 2010, 463(7277): 98-102. DOI: 10.1038/nature08652.
17. Idnurm A, Howlett BJ. Characterization of an opsin gene from the ascomycete leptosphaeria maculans[J]. Genome, 2001, 44(2): 167-171. DOI: 10.1139/g00-113.
18. Gradinaru V, Thompson KR, Deisseroth K. eNpHR: a natronomonas halorhodopsin enhanced for optogenetic applications[J]. Brain Cell Biol, 2008, 36(1-4): 129-139. DOI: 10.1007/s11068-008-9027-6.
19. Chuong AS, Miri ML, Busskamp V, et al. Noninvasive optical inhibition with a red-shifted microbial rhodopsin[J]. Nat Neurosci, 2014, 17(8): 1123-1129. DOI: 10.1038/nn.3752.
20. Claes E, Seeliger M, Michalakis S, et al. Morphological characterization of the retina of the CNGA₃(-/-)Rho(-/-) mutant mouse lacking functional cones and rods[J]. Invest Ophthalmol Vis Sci, 2004, 45(6): 2039-2048. DOI: 10.1167/iovs.03-0741.
21. Busskamp V, Duebel J, Balya D, et al. Genetic reactivation of cone photoreceptors restores visual responses in retinitis pigmentosa[J]. Science, 2010, 329(5990): 413-417. DOI: 10.1126/science.1190897.
22. Khabou H, Garita-Hernandez M, Chaffiol A, et al. Noninvasive gene delivery to foveal cones for vision restoration[J/OL]. JCI Insight, 2018, 3(2): e96029[2018-01-25]. https://pubmed.ncbi.nlm.nih.gov/29367457/. DOI: 10.1172/jci.insight.96029.
23. Garita-Hernandez M, Lampic M, Chaffiol A, et al. Restoration of visual function by transplantation of optogenetically engineered photoreceptors[J/OL]. Nat Commun, 2019, 10(1): 4524[2019-10-04]. https://pubmed.ncbi.nlm.nih.gov/31586094/. DOI: 10.1038/s41467-019-12330-2.
24. Garita-Hernandez M, Guibbal L, Toualbi L, et al. Optogenetic light sensors in human retinal organoids[J/OL]. Front Neurosci, 2018, 12: 789[2018-11-02]. https://pubmed.ncbi.nlm.nih.gov/30450028/. DOI: 10.3389/fnins.2018.00789.
25. Cehajic-Kapetanovic J, Eleftheriou C, Allen AE, et al. Restoration of vision with ectopic expression of human rod opsin[J]. Curr Biol, 2015, 25(16): 2111-2122. DOI: 10.1016/j.cub.2015.07.029.
26. Gaub BM, Berry MH, Holt AE, et al. Optogenetic vision restoration using rhodopsin for enhanced sensitivity[J]. Mol Ther, 2015, 23(10): 1562-1571. DOI: 10.1038/mt.2015.121.
27. De Silva SR, Barnard AR, Hughes S, et al. Long-term restoration of visual function in end-stage retinal degeneration using subretinal human melanopsin gene therapy[J]. Proc Natl Acad Sci USA, 2017, 114(42): 11211-11216. DOI: 10.1073/pnas.1701589114.
28. Berry MH, Holt A, Salari A, et al. Restoration of high-sensitivity and adapting vision with a cone opsin[J/OL]. Nat Commun, 2019, 10(1): 1221[2019-03-15]. https://pubmed.ncbi.nlm.nih.gov/30874546/. DOI: 10.1038/s41467-019-09124-x.
29. van Wyk M, Pielecka-Fortuna J, Lowel S, et al. Restoring the on switch in blind retinas: opto-mGluR6, a next-generation, cell-tailored optogenetic tool[J/OL]. PLoS Biol, 2015, 13(5): e1002143[2015-05-07]. https://pubmed.ncbi.nlm.nih.gov/25950461/. DOI: 10.1371/journal.pbio.1002143.
30. Singh MS, Charbel Issa P, Butler R, et al. Reversal of end-stage retinal degeneration and restoration of visual function by photoreceptor transplantation[J]. Proc Natl Acad Sci USA, 2013, 110(3): 1101-1106. DOI: 10.1073/pnas.1119416110.
31. Barber AC, Hippert C, Duran Y, et al. Repair of the degenerate retina by photoreceptor transplantation[J]. Proc Natl Acad Sci USA, 2013, 110(1): 354-359. DOI: 10.1073/pnas.1212677110.
32. Mandai M, Fujii M, Hashiguchi T, et al. iPSC-derived retina transplants improve vision in rd1 end-stage retinal-degeneration mice[J]. Stem Cell Reports, 2017, 8(1): 69-83. DOI: 10.1016/j.stemcr.2016.12.008.
33. Iraha S, Tu HY, Yamasaki S, et al. Establishment of immunodeficient retinal degeneration model mice and functional maturation of human ESC-derived retinal sheets after transplantation[J]. Stem Cell Reports, 2018, 10(3): 1059-1074. DOI: 10.1016/j.stemcr.2018.01.032.
34. Eberle D, Schubert S, Postel K, et al. Increased integration of transplanted CD73-positive photoreceptor precursors into adult mouse retina[J]. Invest Ophthalmol Vis Sci, 2011, 52(9): 6462-6471. DOI: 10.1167/iovs.11-7399.
35. da Cruz L, Dorn JD, Humayun MS, et al. Five-year safety and performance results from the argus Ⅱ retinal prosthesis system clinical trial[J]. Ophthalmology, 2016, 123(10): 2248-2254. DOI: 10.1016/j.ophtha.2016.06.049.
36. Edwards TL, Cottriall CL, Xue K, et al. Assessment of the electronic retinal implant alpha AMS in restoring vision to blind patients with end-stage retinitis pigmentosa[J]. Ophthalmology, 2018, 125(3): 432-443. DOI: 10.1016/j.ophtha.2017.09.019.
37. Shivdasani MN, Sinclair NC, Gillespie LN, et al. Identification of characters and localization of images using direct multiple-electrode stimulation with a suprachoroidal retinal prosthesis[J]. Invest Ophthalmol Vis Sci, 2017, 58(10): 3962-3974. DOI: 10.1167/iovs.16-21311.
38. Soltan A, Barrett JM, Maaskant P, et al. A head mounted device stimulator for optogenetic retinal prosthesis[J/OL]. J Neural Eng, 2018, 15(6): 065002[2018-08-29]. https://pubmed.ncbi.nlm.nih.gov/30156188/. DOI: 10.1088/1741-2552/aadd55.
39. Soltan A, McGovern B, Drakakis E, et al. High density, high radiance $\mu$ LED matrix for optogenetic retinal prostheses and planar neural stimulation[J]. IEEE Trans Biomed Circuits Syst, 2017, 11(2): 347-359. DOI: 10.1109/TBCAS.2016.2623949.
40. Montazeri L, El Zarif N, Trenholm S, et al. Optogenetic stimulation for restoring vision to patients suffering from retinal degenerative diseases: current strategies and future directions[J]. IEEE Trans Biomed Circuits Syst, 2019, 13(6): 1792-1807. DOI: 10.1109/tbcas.2019.2951298.

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