Advances of optogenetics in the treatment of retinitis pigmentosa_Chinese Journal of Ocular Fundus Diseases

Authors：

Zhang Yi , Huang Xi ,  Zhang Junjun

Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu 610041, China;

Corresponding author：

Zhang Junjun, Email: 18980601735@189.cn

Keywords：

Retinitis pigmentosa/therapy; Optogenetics; Review

DOI：

10.3760/cma.j.issn.1005-1015.2018.06.018

Video：

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Abstract Full text Figures/Tables Video References Cited by

Retinitis pigmentosa (RP) is a disease that seriously affects vision. It mainly affects rod cells and causes night blindness. At the end of the disease, due to the simultaneous involvement of cone cells, the patient’s central vision and peripheral vision loss are not effective. There is no effective treatment method. However, some studies have found that although the function of photoreceptors is lost in the pathological process of RP, the function of bipolar cells and ganglion cells and the neural connection with the visual center are preserved, which provides a condition of therapeutic application in optogenetics for optogenetics. Optogenetics controls the excitability of neurons by expressing the light-sensitive protein represented by rhodopsin ion channel protein-2 on neurons, and has shown great application prospects in reshaping the photoreceptor function of the retina. The treatment of a type of retinal degenerative disease provides an effective treatment option.

Citation： Zhang Yi, Huang Xi, Zhang Junjun. Advances of optogenetics in the treatment of retinitis pigmentosa. Chinese Journal of Ocular Fundus Diseases, 2018, 34(6): 601-604. doi: 10.3760/cma.j.issn.1005-1015.2018.06.018 Copy

1.	Masland RH. The neuronal organization of the retina[J]. Neuron, 2012, 76(2): 266-280. DOI: 10.1016/j.neuron.2012.10.002.
2.	Wassle H. Parallel processing in the mammalian retina[J]. Nat Rev Neurosci, 2004, 5(10): 747-757. DOI: 10.1038/nrn1497.
3.	Haverkamp S, Grunert U, Wassle H. The synaptic architecture of AMPA receptors at the cone pedicle of the primate retina[J]. J Neurosci, 2001, 21(7): 2488-2500.
4.	Haverkamp S, Grunert U, Wassle H. Localization of kainate receptors at the cone pedicles of the primate retina[J]. J Comp Neurol, 2001, 436(4): 471-486.
5.	Vardi N, Duvoisin R, Wu G, et al. Localization of mGluR6 to dendrites of ON bipolar cells in primate retina[J]. J Comp Neurol, 2000, 423(3): 402-412.
6.	Morgans CW, Zhang J, Jeffrey BG, et al. TRPM1 is required for the depolarizing light response in retinal ON-bipolar cells[J]. Proc Natl Acad Sci USA, 2009, 106(45): 19174-19178. DOI: 10.1073/pnas.0908711106.
7.	Shen Y, Heimel JA, Kamermans M, et al. A transient receptor potential-like channel mediates synaptic transmission in rod bipolar cells[J]. J Neurosci, 2009, 29(19): 6088-6093. DOI: 10.1523/jneurosci.0132-09.2009.
8.	Berntson A, Taylor WR. Response characteristics and receptive field widths of on-bipolar cells in the mouse retina[J]. J Physiol, 2000, 524 Pt 3: 879-889.
9.	Euler T, Masland RH. Light-evoked responses of bipolar cells in a mammalian retina[J]. J Neurophysiol, 2000, 83(4): 1817-1829.
10.	Famiglietti EV Jr, Kolb H. A bistratified amacrine cell and synaptic cirucitry in the inner plexiform layer of the retina[J]. Brain Res, 1975, 84(2): 293-300.
11.	Raviola E, Dacheux RF. Excitatory dyad synapse in rabbit retina[J]. Proc Natl Acad Sci USA, 1987, 84(20): 7324-7328.
12.	Hartong DT, Berson EL, Dryja TP. Retinitis pigmentosa[J]. Lancet, 2006, 368(9549): 1795-1809. DOI: 10.1016/s0140-6736(06)69740-7.
13.	O’Neal TB, Luther EE. Retinitis pigmentosa[M]. Treasure Island (FL): StatPearls Publishing LLC, 2018.
14.	Le Meur G, Lebranchu P, Billaud F, et al. Safety and long-term efficacy of AAV4 gene therapy in patients with RPE65 Leber congenital amaurosis[J]. Mol Ther, 2018, 26(1): 256-268. DOI: 10.1016/j.ymthe.2017.09.014.
15.	Daiger SP, Sullivan LS, Bowne SJ. Genes and mutations causing retinitis pigmentosa[J]. Clin Genet, 2013, 84(2): 132-141. DOI: 10.1111/cge.12203.
16.	Simunovic MP, Shen W, Lin JY, et al. Optogenetic approaches to vision restoration[J]. Exp Eye Res, 2018, 178: 15-26. DOI: 10.1016/j.exer.2018.09.003.
17.	Sakmar TP, Menon ST, Marin EP, et al. Rhodopsin: insights from recent structural studies[J]. Annu Rev Biophys Biomol Struct, 2002, 31: 443-484. DOI: 10.1146/annurev.biophys.31.082901.134348.
18.	Hardie RC, Raghu P. Visual transduction in drosophila[J]. Nature, 2001, 413(6852): 186-193. DOI: 10.1038/35093002.
19.	Nagel G, Ollig D, Fuhrmann M, et al. Channelrhodopsin-1: a light-gated proton channel in green algae[J]. Science, 2002, 296(5577): 2395-2398. DOI: 10.1126/science.1072068.
20.	Sineshchekov OA, Jung KH, Spudich JL. Two rhodopsins mediate phototaxis to low- and high-intensity light in chlamydomonas reinhardtii[J]. Proc Natl Acad Sci USA, 2002, 99(13): 8689-8694. DOI: 10.1073/pnas.122243399.
21.	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.
22.	Bamann C, Kirsch T, Nagel G, et al. Spectral characteristics of the photocycle of channelrhodopsin-2 and its implication for channel function[J]. J Mol Biol, 2008, 375(3): 686-694. DOI: 10.1016/j.jmb.2007.10.072.
23.	Nagel G, Brauner M, Liewald JF, et al. Light activation of channelrhodopsin-2 in excitable cells of Caenorhabditis elegans triggers rapid behavioral responses[J]. Curr Biol, 2005, 15(24): 2279-2284. DOI: 10.1016/j.cub.2005.11.032.
24.	Ishizuka T, Kakuda M, Araki R, et al. Kinetic evaluation of photosensitivity in genetically engineered neurons expressing green algae light-gated channels[J]. Neurosci Res, 2006, 54(2): 85-94. DOI: 10.1016/j.neures.2005.10.009.
25.	Boyden ES, Zhang F, Bamberg E, et al. Millisecond-timescale, genetically targeted optical control of neural activity[J]. Nat Neurosci, 2005, 8(9): 1263-1268. DOI: 10.1038/nn1525.
26.	Zhang F, Wang LP, Brauner M, et al. Multimodal fast optical interrogation of neural circuitry[J]. Nature, 2007, 446(7136): 633-639. DOI: 10.1038/nature05744.
27.	Lee S, Chen L, Chen M, et al. An unconventional glutamatergic circuit in the retina formed by vGluT3 amacrine cells[J]. Neuron, 2014, 84(4): 708-715. DOI: 10.1016/j.neuron.2014.10.021.
28.	Yizhar O, Fenno LE, Davidson TJ, et al. Optogenetics in neural systems[J]. Neuron, 2011, 71(1): 9-34. DOI: 10.1016/j.neuron.2011.06.004.
29.	Fenno L, Yizhar O, Deisseroth K. The development and application of optogenetics[J]. Annu Rev Neurosci, 2011, 34: 389-412. DOI: 10.1146/annurev-neuro-061010-113817.
30.	Bi A, Cui J, Ma YP, et al. Ectopic expression of a microbial-type rhodopsin restores visual responses in mice with photoreceptor degeneration[J]. Neuron, 2006, 50(1): 23-33. DOI: 10.1016/j.neuron.2006.02.026.
31.	Flannery JG, Farber DB, Bird AC, et al. Degenerative changes in a retina affected with autosomal dominant retinitis pigmentosa[J]. Invest Ophthalmol Vis Sci, 1989, 30(2): 191-211.
32.	Lee S, Zhang Y, Chen M, et al. Segregated glycine-glutamate co-transmission from vGluT3 amacrine cells to contrast-suppressed and contrast-enhanced retinal circuits[J]. Neuron, 2016, 90(1): 27-34. DOI: 10.1016/j.neuron.2016.02.023.
33.	Gollisch T, Meister M. Eye smarter than scientists believed: neural computations in circuits of the retina[J]. Neuron, 2010, 65(2): 150-164. DOI: 10.1016/j.neuron.2009.12.009.
34.	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.
35.	Doroudchi MM, Greenberg KP, Liu J, et al. Virally delivered channelrhodopsin-2 safely and effectively restores visual function in multiple mouse models of blindness[J]. Mol Ther, 2011, 19(7): 1220-1229. DOI: 10.1038/mt.2011.69.
36.	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.
37.	Zhang Y, Ivanova E, Bi A, et al. Ectopic expression of multiple microbial rhodopsins restores ON and OFF light responses in retinas with photoreceptor degeneration[J]. J Neurosci, 2009, 29(29): 9186-9196. DOI: 10.1523/jneurosci.0184-09.2009.
38.	Stone JL, Barlow WE, Humayun MS, et al. Morphometric analysis of macular photoreceptors and ganglion cells in retinas with retinitis pigmentosa[J]. Arch Ophthalmol, 1992, 110(11): 1634-1639.
39.	Yue L, Weiland JD, Roska B, et al. Retinal stimulation strategies to restore vision: fundamentals and systems[J]. Prog Retin Eye Res, 2016, 53: 21-47. DOI: 10.1016/j.preteyeres.2016.05.002.
40.	De Silva SR, Barnard AR. 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.
41.	Liu MM, Dai JM, Liu WY, et al. Human melanopsin-AAV2/8 transfection to retina transiently restores visual function in rd1 mice[J]. Int J Ophthalmol, 2016, 9(5): 655-661. DOI: 10.18240/ijo.2016.05.03.
42.	Greenberg KP, Pham A, Werblin FS. Differential targeting of optical neuromodulators to ganglion cell soma and dendrites allows dynamic control of center-surround antagonism[J]. Neuron, 2011, 69(4): 713-720. DOI: 10.1016/j.neuron.2011.01.024.
43.	Beltran WA, Boye SL, Boye SE, et al. rAAV2/5 gene-targeting to rods: dose-dependent efficiency and complications associated with different promoters[J]. Gene Ther, 2010, 17(9): 1162-1174. DOI: 10.1038/gt.2010.56.
44.	Boye SE, Boye SL, Lewin AS, et al. A comprehensive review of retinal gene therapy[J]. Mol Ther, 2013, 21(3): 509-519. DOI: 10.1038/mt.2012.280.
45.	Ivanova E, Pan ZH. Evaluation of the adeno-associated virus mediated long-term expression of channelrhodopsin-2 in the mouse retina[J]. Mol Vis, 2009, 15: 1680-1689.
46.	Sugano E, Isago H, Wang Z, et al. Immune responses to adeno-associated virus type 2 encoding channelrhodopsin-2 in a genetically blind rat model for gene therapy[J]. Gene Ther, 2011, 18(3): 266-274. DOI: 10.1038/gt.2010.140.
47.	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.
48.	Kleinlogel S, Terpitz U, Legrum B, et al. A gene-fusion strategy for stoichiometric and co-localized expression of light-gated membrane proteins[J]. Nat Methods, 2011, 8(12): 1083-1088. DOI: 10.1038/nmeth.1766.
49.	Fradot M, Busskamp V, Forster V, et al. Gene therapy in ophthalmology: validation on cultured retinal cells and explants from postmortem human eyes[J]. Hum Gene Ther, 2011, 22(5): 587-593. DOI: 10.1089/hum.2010.157.

1. Masland RH. The neuronal organization of the retina[J]. Neuron, 2012, 76(2): 266-280. DOI: 10.1016/j.neuron.2012.10.002.
2. Wassle H. Parallel processing in the mammalian retina[J]. Nat Rev Neurosci, 2004, 5(10): 747-757. DOI: 10.1038/nrn1497.
3. Haverkamp S, Grunert U, Wassle H. The synaptic architecture of AMPA receptors at the cone pedicle of the primate retina[J]. J Neurosci, 2001, 21(7): 2488-2500.
4. Haverkamp S, Grunert U, Wassle H. Localization of kainate receptors at the cone pedicles of the primate retina[J]. J Comp Neurol, 2001, 436(4): 471-486.
5. Vardi N, Duvoisin R, Wu G, et al. Localization of mGluR6 to dendrites of ON bipolar cells in primate retina[J]. J Comp Neurol, 2000, 423(3): 402-412.
6. Morgans CW, Zhang J, Jeffrey BG, et al. TRPM1 is required for the depolarizing light response in retinal ON-bipolar cells[J]. Proc Natl Acad Sci USA, 2009, 106(45): 19174-19178. DOI: 10.1073/pnas.0908711106.
7. Shen Y, Heimel JA, Kamermans M, et al. A transient receptor potential-like channel mediates synaptic transmission in rod bipolar cells[J]. J Neurosci, 2009, 29(19): 6088-6093. DOI: 10.1523/jneurosci.0132-09.2009.
8. Berntson A, Taylor WR. Response characteristics and receptive field widths of on-bipolar cells in the mouse retina[J]. J Physiol, 2000, 524 Pt 3: 879-889.
9. Euler T, Masland RH. Light-evoked responses of bipolar cells in a mammalian retina[J]. J Neurophysiol, 2000, 83(4): 1817-1829.
10. Famiglietti EV Jr, Kolb H. A bistratified amacrine cell and synaptic cirucitry in the inner plexiform layer of the retina[J]. Brain Res, 1975, 84(2): 293-300.
11. Raviola E, Dacheux RF. Excitatory dyad synapse in rabbit retina[J]. Proc Natl Acad Sci USA, 1987, 84(20): 7324-7328.
12. Hartong DT, Berson EL, Dryja TP. Retinitis pigmentosa[J]. Lancet, 2006, 368(9549): 1795-1809. DOI: 10.1016/s0140-6736(06)69740-7.
13. O’Neal TB, Luther EE. Retinitis pigmentosa[M]. Treasure Island (FL): StatPearls Publishing LLC, 2018.
14. Le Meur G, Lebranchu P, Billaud F, et al. Safety and long-term efficacy of AAV4 gene therapy in patients with RPE65 Leber congenital amaurosis[J]. Mol Ther, 2018, 26(1): 256-268. DOI: 10.1016/j.ymthe.2017.09.014.
15. Daiger SP, Sullivan LS, Bowne SJ. Genes and mutations causing retinitis pigmentosa[J]. Clin Genet, 2013, 84(2): 132-141. DOI: 10.1111/cge.12203.
16. Simunovic MP, Shen W, Lin JY, et al. Optogenetic approaches to vision restoration[J]. Exp Eye Res, 2018, 178: 15-26. DOI: 10.1016/j.exer.2018.09.003.
17. Sakmar TP, Menon ST, Marin EP, et al. Rhodopsin: insights from recent structural studies[J]. Annu Rev Biophys Biomol Struct, 2002, 31: 443-484. DOI: 10.1146/annurev.biophys.31.082901.134348.
18. Hardie RC, Raghu P. Visual transduction in drosophila[J]. Nature, 2001, 413(6852): 186-193. DOI: 10.1038/35093002.
19. Nagel G, Ollig D, Fuhrmann M, et al. Channelrhodopsin-1: a light-gated proton channel in green algae[J]. Science, 2002, 296(5577): 2395-2398. DOI: 10.1126/science.1072068.
20. Sineshchekov OA, Jung KH, Spudich JL. Two rhodopsins mediate phototaxis to low- and high-intensity light in chlamydomonas reinhardtii[J]. Proc Natl Acad Sci USA, 2002, 99(13): 8689-8694. DOI: 10.1073/pnas.122243399.
21. 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.
22. Bamann C, Kirsch T, Nagel G, et al. Spectral characteristics of the photocycle of channelrhodopsin-2 and its implication for channel function[J]. J Mol Biol, 2008, 375(3): 686-694. DOI: 10.1016/j.jmb.2007.10.072.
23. Nagel G, Brauner M, Liewald JF, et al. Light activation of channelrhodopsin-2 in excitable cells of Caenorhabditis elegans triggers rapid behavioral responses[J]. Curr Biol, 2005, 15(24): 2279-2284. DOI: 10.1016/j.cub.2005.11.032.
24. Ishizuka T, Kakuda M, Araki R, et al. Kinetic evaluation of photosensitivity in genetically engineered neurons expressing green algae light-gated channels[J]. Neurosci Res, 2006, 54(2): 85-94. DOI: 10.1016/j.neures.2005.10.009.
25. Boyden ES, Zhang F, Bamberg E, et al. Millisecond-timescale, genetically targeted optical control of neural activity[J]. Nat Neurosci, 2005, 8(9): 1263-1268. DOI: 10.1038/nn1525.
26. Zhang F, Wang LP, Brauner M, et al. Multimodal fast optical interrogation of neural circuitry[J]. Nature, 2007, 446(7136): 633-639. DOI: 10.1038/nature05744.
27. Lee S, Chen L, Chen M, et al. An unconventional glutamatergic circuit in the retina formed by vGluT3 amacrine cells[J]. Neuron, 2014, 84(4): 708-715. DOI: 10.1016/j.neuron.2014.10.021.
28. Yizhar O, Fenno LE, Davidson TJ, et al. Optogenetics in neural systems[J]. Neuron, 2011, 71(1): 9-34. DOI: 10.1016/j.neuron.2011.06.004.
29. Fenno L, Yizhar O, Deisseroth K. The development and application of optogenetics[J]. Annu Rev Neurosci, 2011, 34: 389-412. DOI: 10.1146/annurev-neuro-061010-113817.
30. Bi A, Cui J, Ma YP, et al. Ectopic expression of a microbial-type rhodopsin restores visual responses in mice with photoreceptor degeneration[J]. Neuron, 2006, 50(1): 23-33. DOI: 10.1016/j.neuron.2006.02.026.
31. Flannery JG, Farber DB, Bird AC, et al. Degenerative changes in a retina affected with autosomal dominant retinitis pigmentosa[J]. Invest Ophthalmol Vis Sci, 1989, 30(2): 191-211.
32. Lee S, Zhang Y, Chen M, et al. Segregated glycine-glutamate co-transmission from vGluT3 amacrine cells to contrast-suppressed and contrast-enhanced retinal circuits[J]. Neuron, 2016, 90(1): 27-34. DOI: 10.1016/j.neuron.2016.02.023.
33. Gollisch T, Meister M. Eye smarter than scientists believed: neural computations in circuits of the retina[J]. Neuron, 2010, 65(2): 150-164. DOI: 10.1016/j.neuron.2009.12.009.
34. 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.
35. Doroudchi MM, Greenberg KP, Liu J, et al. Virally delivered channelrhodopsin-2 safely and effectively restores visual function in multiple mouse models of blindness[J]. Mol Ther, 2011, 19(7): 1220-1229. DOI: 10.1038/mt.2011.69.
36. 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.
37. Zhang Y, Ivanova E, Bi A, et al. Ectopic expression of multiple microbial rhodopsins restores ON and OFF light responses in retinas with photoreceptor degeneration[J]. J Neurosci, 2009, 29(29): 9186-9196. DOI: 10.1523/jneurosci.0184-09.2009.
38. Stone JL, Barlow WE, Humayun MS, et al. Morphometric analysis of macular photoreceptors and ganglion cells in retinas with retinitis pigmentosa[J]. Arch Ophthalmol, 1992, 110(11): 1634-1639.
39. Yue L, Weiland JD, Roska B, et al. Retinal stimulation strategies to restore vision: fundamentals and systems[J]. Prog Retin Eye Res, 2016, 53: 21-47. DOI: 10.1016/j.preteyeres.2016.05.002.
40. De Silva SR, Barnard AR. 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.
41. Liu MM, Dai JM, Liu WY, et al. Human melanopsin-AAV2/8 transfection to retina transiently restores visual function in rd1 mice[J]. Int J Ophthalmol, 2016, 9(5): 655-661. DOI: 10.18240/ijo.2016.05.03.
42. Greenberg KP, Pham A, Werblin FS. Differential targeting of optical neuromodulators to ganglion cell soma and dendrites allows dynamic control of center-surround antagonism[J]. Neuron, 2011, 69(4): 713-720. DOI: 10.1016/j.neuron.2011.01.024.
43. Beltran WA, Boye SL, Boye SE, et al. rAAV2/5 gene-targeting to rods: dose-dependent efficiency and complications associated with different promoters[J]. Gene Ther, 2010, 17(9): 1162-1174. DOI: 10.1038/gt.2010.56.
44. Boye SE, Boye SL, Lewin AS, et al. A comprehensive review of retinal gene therapy[J]. Mol Ther, 2013, 21(3): 509-519. DOI: 10.1038/mt.2012.280.
45. Ivanova E, Pan ZH. Evaluation of the adeno-associated virus mediated long-term expression of channelrhodopsin-2 in the mouse retina[J]. Mol Vis, 2009, 15: 1680-1689.
46. Sugano E, Isago H, Wang Z, et al. Immune responses to adeno-associated virus type 2 encoding channelrhodopsin-2 in a genetically blind rat model for gene therapy[J]. Gene Ther, 2011, 18(3): 266-274. DOI: 10.1038/gt.2010.140.
47. 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.
48. Kleinlogel S, Terpitz U, Legrum B, et al. A gene-fusion strategy for stoichiometric and co-localized expression of light-gated membrane proteins[J]. Nat Methods, 2011, 8(12): 1083-1088. DOI: 10.1038/nmeth.1766.
49. Fradot M, Busskamp V, Forster V, et al. Gene therapy in ophthalmology: validation on cultured retinal cells and explants from postmortem human eyes[J]. Hum Gene Ther, 2011, 22(5): 587-593. DOI: 10.1089/hum.2010.157.

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