The application of optogenetics in the treatment of retinal degeneration disease_Chinese Journal of Ocular Fundus Diseases

Authors：

ShenYumeng , XingYiqiao ,  ShenYin

Department of Ophthalmology, Renmin Hospital of Wuhan University, Wuhan 430060, China;

Corresponding author：

ShenYin, Email: yinshen@whu.edu.com

Keywords：

degeneration/therapy; Opsins; Genetic techniques; Review

DOI：

10.3760/cma.j.issn.1005-1015.2016.03.030

Video：

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Optogenetics is a novel technique which combines optics with genetics. Using genetic means, a selected opsin protein is ectopically expressed in target neurons, which are then stimulated by light to moderate the neuronal circuit, as a consequence to regulate the animal's behaviors. Retinal degeneration like retinitis pigmentosa and aged macular degeneration causes visual impairment and eventual blindness. Optogenetics techniques have opened the door to creating artificial photoreceptors in the remaining retinal circuits of retinal degeneration retinas via gene therapy. However, there are still limitations in optogenetics technique, for example, potential risk in virus infection, the choice of target cells and the low visual resolution of the experiment animal. It has been reported that vision was successfully restored to a certain extent in animal model using optogenetics technique. With higher photosensitivity of opsin protein, longer activation kinetics and higher transfection efficiency of virus vector, optogenetics techniques' application in ophthalmology will be improved.

Citation： ShenYumeng, XingYiqiao, ShenYin. The application of optogenetics in the treatment of retinal degeneration disease. Chinese Journal of Ocular Fundus Diseases, 2016, 32(3): 338-342. doi: 10.3760/cma.j.issn.1005-1015.2016.03.030 Copy

1.	Peralvarez-Marin A, Garriga P. Optogenetics comes of age:novel inhibitory light-gated anionic channels allow efficient silencing of neural function[J]. Chembiochem, 2016, 17(3):204-206.DOI:10.1002/cbic.201500608.
2.	Deisseroth K. Optogenetics[J]. Nature methods, 2011, 8(1):26-29.DOI:10.1038/nmeth.f.324.
3.	Lin SC, Deisseroth K, Henderson JM. Optogenetics:background and concepts for neurosurgery[J]. Neurosurgery, 2011, 69(1):1-3.DOI:10.1227/NEU.0b013e318224688e.
4.	Adamantidis AR, Zhang F, De Lecea L, et al. Optogenetics:opsins and optical interfaces in neuroscience[J]. Cold Spring Harb Protoc, 2014, 2014(8):815-822.DOI:10.1101/pdb.top083329.
5.	Adamantidis AR. Modern neurosciences:with or without optogenetics?[J]. Med Sci (Paris), 2015, 31(3):231-232.DOI:10.1051/medsci/20153103001.
6.	Sakmar TP. Structure of rhodopsin and the superfamily of seven-helical receptors:the same and not the same[J]. Curr Opin Cell Biol, 2002, 14(2):189-195.
7.	Ranaghan MJ, Greco JA, Wagner NL, et al. Photochromic bacteriorhodopsin mutant with high holographic efficiency and enhanced stability via a putative self-repair mechanism[J]. ACS Appl Mater Interfaces, 2014, 6(4):2799-2808.DOI:10.1021/am405363z.
8.	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.
9.	Wu C, Ivanova E, Zhang Y, et al. rAAV-mediated subcellular targeting of optogenetic tools in retinal ganglion cells in vivo[J/OL]. PLoS One, 2013, 8(6):66332[2013-01-14].http://dx.plos.org/10.1371/journal.pone.0066332. DOI:10.1371/journal.pone.0066332.
10.	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.
11.	Holmes D. Is neurology ready to see the light?[J]. Lancet Neurol, 2012, 11(8):663-664.DOI:10.1016/S1474-4422(12)70170-9.
12.	Adamantidis A, Arber S2, Bains JS, et al. Optogenetics:10 years after ChR2 in neurons——views from the community[J]. Nat Neurosci, 2015, 18(9):1202-1212. DOI:10.1038/nn.4106.
13.	Ji ZG, Wang H. ChR2 transgenic animals in peripheral sensory system:sensing light as various sensations[J]. Life Sci, 2016, 150:95-102. DOI:10.1016/j.lfs.2016.02.057.
14.	Lin JY. Optogenetic excitation of neurons with channelrhodopsins:light instrumentation, expression systems, and channelrhodopsin variants[J]. Prog Brain Res, 2012, 196:29-47.DOI:10.1016/B978-0-444-59426-6.00002-1.
15.	Sekharan S, Wei JN, Batista VS. The active site of melanopsin:the biological clock photoreceptor[J]. J Am Chem Soc, 2012, 134(48):19536-19539.DOI:10.1021/ja308763b.
16.	Hughes S, Jagannath A, Rodgers J, et al. Signalling by melanopsin (OPN4) expressing photosensitive retinal ganglion cells[J]. Eye, 2016, 30(2):247-254.DOI:10.1038/eye.2015.264.
17.	Spitschan M, Datta R, Stern AM, et al. Human visual cortex responses to rapid cone and melanopsin-directed flicker[J]. J Neurosci, 2016, 36(5):1471-1482. DOI:10.1523/JNEUROSCI.1932-15.2016.
18.	Sexton T, Buhr E, Van Gelder RN. Melanopsin and mechanisms of non-visual ocular photoreception[J]. J Biol Chem, 2012, 287(3):1649-1656. DOI:10.1074/jbc.R111.301226.
19.	Tsunematsu T, Tanaka KF, Yamanaka A, et al. Ectopic expression of melanopsin in orexin/hypocretin neurons enables control of wakefulness of mice in vivo by blue light[J]. Neurosci Res, 2013, 75(1):23-28.DOI:10.1016/j.neures.2012.07.005.
20.	Liske H, Qian X, Anikeeva P, et al. Optical control of neuronal excitation and inhibition using a single opsin protein, ChR2[J]. Sci Rep, 2013, 3:3110. DOI:10.1038/srep03110.
21.	Koizumi A, Tanaka KF, Yamanaka A. The manipulation of neural and cellular activities by ectopic expression of melanopsin[J]. Neurosci Res, 2013, 75(1):3-5.DOI:10.1016/j.neures.2012.07.010.
22.	Lin B, Koizumi A, Tanaka N, et al. Restoration of visual function in retinal degeneration mice by ectopic expression of melanopsin[J]. Proc Natl Acad Sci USA, 2008, 105(41):16009-16014.DOI:10.1073/pnas.0806114105.
23.	Byrne LC, Khalid F, Lee T, et al. AAV-mediated, optogenetic ablation of Muller Glia leads to structural and functional changes in the mouse retina[J/OL]. PLoS One, 2013, 8(9):76075[2013-09-27]. http://dx.plos.org/10.1371/journal.pone.0076075.DOI:10.1371/journal.pone.0076075.
24.	Stutika C, Gogol-D ring A, Botschen L, et al. A comprehensive RNA sequencing analysis of the adeno-associated virus (AAV) type 2 transcriptome reveals novel AAV transcripts, splice variants, and derived proteins[J]. J Virol, 2015, 90(3):1278-1289.DOI:10.1128/JVI.02750-15.
25.	Arenkiel BR, Peca J, Davison IG, et al. In vivo light-induced activation of neural circuitry in transgenic mice expressing channelrhodopsin-2[J]. Neuron, 2007, 54(2):205-218.
26.	Schoonheim PJ, Arrenberg AB, Del Bene F, et al. Optogenetic localization and genetic perturbation of saccade-generating neurons in zebrafish[J].J Neurosci, 2010, 30(20):7111-7120.DOI:10.1523/JNEUROSCI.5193-09.2010.
27.	Hsiao PY, Wu MC, Lin YY, et al. Optogenetic manipulation of selective neural activity in free-moving drosophila adults[J]. Methods Mol Biol, 2016, 1408:377-387.DOI:10.1007/978-1-4939-3512-3_26.
28.	Inoue K, Takada M, Matsumoto M. Neuronal and behavioural modulations by pathway-selective optogenetic stimulation of the primate oculomotor system[J]. Nat Commun, 2015, 6:8378.DOI:10.1038/ncomms9378.
29.	Weick JP, Johnson MA, Skroch SP, et al. Functional control of transplantable human ESC-derived neurons via optogenetic targeting[J]. Stem cells, 2010, 28(11):2008-2016.DOI:10.1002/stem.514.
30.	Flusberg BA, Jung JC, Cocker ED, et al. In vivo brain imaging using a portable 3.9 gram two-photon fluorescence microendoscope[J]. Opt Lett, 2005, 30(17):2272-2274.
31.	Busskamp V, Picaud S, Sahel JA, et al. Optogenetic therapy for retinitis pigmentosa[J]. Gene Ther, 2012, 19(2):169-175.DOI:10.1038/gt.2011.155.
32.	Roska B, Busskamp V, Sahel JA, et al. Retinitis pigmentosa:eye sight restoration by optogenetic therapy[J]. Biol Aujourdhui, 2013, 207(2):109-121.DOI:10.1051/jbio/2013011.
33.	Castilho Á, Ambrósio AF, Hartveit E, et al. Disruption of a neural microcircuit in the rod pathway of the mammalian retina by diabetes mellitus[J]. J Neurosci, 2015, 35(13):5422-5433.DOI:10.1523/JNEUROSCI.5285-14.2015.
34.	Song H, Rossi EA, Latchney L, et al. Cone and rod loss in Stargardt disease revealed by adaptive optics scanning light ophthalmoscopy[J]. JAMA Ophthalmol, 2015, 133(10):1198-1203.DOI:10.1001/jamaophthalmol.2015.2443.
35.	Hidalgo-de-Quintana J, Schwarz N, Meschede IP, et al. The Leber congenital amaurosis protein AIPL1 and EB proteins co-localize at the photoreceptor cilium[J]. PLoS One, 2015, 10(3):0121440[2015-03-25]. http://dx.plos.org/10.1371/journal.pone.0121440. DOI:10.1371/journal.pone.0121440.
36.	Lin B, Masland RH, Strettoi E. Remodeling of cone photoreceptor cells after rod degeneration in rd mice[J]. Exp Eye Res, 2009, 88(3):589-599.DOI:10.1016/j.exer.2008.11.022.
37.	Cho AK, Sampath AP, Weiland JD. Physiological response of normal and RD mouse retinal ganglion cells to electrical stimulation[J]. Conf Proc IEEE Eng Med Biol Soc, 2012, 2012:2985-2988.DOI:10.1109/EMBC.2012.6346591.
38.	May CA. Fibrae medullares in the retina of the RD mouse:a case report[J]. Curr Eye Res, 2009, 34(5):411-413.DOI:10.1080/02713680902825507.
39.	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.
40.	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.
41.	Ikeda Y, Ishibashi T. Neuroprotective gene therapy to treat patients with retinitis pigmentosa[J]. Fukuoka Igaku Zasshi, 2010, 101(9):183-189.
42.	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.
43.	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.
44.	Thyagarajan S, van Wyk M, Lehmann K, et al. Visual function in mice with photoreceptor degeneration and transgenic expression of channelrhodopsin 2 in ganglion cells[J]. J Neurosci, 2010, 30(26):8745-8758.DOI:10.1523/JNEUROSCI.4417-09.2010.
45.	Kleinlogel S. Optogenetic user's guide to Opto-GPCRs[J]. Front Biosci (Landmark Ed)., 2016, 21:794-805.

1. Peralvarez-Marin A, Garriga P. Optogenetics comes of age:novel inhibitory light-gated anionic channels allow efficient silencing of neural function[J]. Chembiochem, 2016, 17(3):204-206.DOI:10.1002/cbic.201500608.
2. Deisseroth K. Optogenetics[J]. Nature methods, 2011, 8(1):26-29.DOI:10.1038/nmeth.f.324.
3. Lin SC, Deisseroth K, Henderson JM. Optogenetics:background and concepts for neurosurgery[J]. Neurosurgery, 2011, 69(1):1-3.DOI:10.1227/NEU.0b013e318224688e.
4. Adamantidis AR, Zhang F, De Lecea L, et al. Optogenetics:opsins and optical interfaces in neuroscience[J]. Cold Spring Harb Protoc, 2014, 2014(8):815-822.DOI:10.1101/pdb.top083329.
5. Adamantidis AR. Modern neurosciences:with or without optogenetics?[J]. Med Sci (Paris), 2015, 31(3):231-232.DOI:10.1051/medsci/20153103001.
6. Sakmar TP. Structure of rhodopsin and the superfamily of seven-helical receptors:the same and not the same[J]. Curr Opin Cell Biol, 2002, 14(2):189-195.
7. Ranaghan MJ, Greco JA, Wagner NL, et al. Photochromic bacteriorhodopsin mutant with high holographic efficiency and enhanced stability via a putative self-repair mechanism[J]. ACS Appl Mater Interfaces, 2014, 6(4):2799-2808.DOI:10.1021/am405363z.
8. 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.
9. Wu C, Ivanova E, Zhang Y, et al. rAAV-mediated subcellular targeting of optogenetic tools in retinal ganglion cells in vivo[J/OL]. PLoS One, 2013, 8(6):66332[2013-01-14].http://dx.plos.org/10.1371/journal.pone.0066332. DOI:10.1371/journal.pone.0066332.
10. 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.
11. Holmes D. Is neurology ready to see the light?[J]. Lancet Neurol, 2012, 11(8):663-664.DOI:10.1016/S1474-4422(12)70170-9.
12. Adamantidis A, Arber S2, Bains JS, et al. Optogenetics:10 years after ChR2 in neurons——views from the community[J]. Nat Neurosci, 2015, 18(9):1202-1212. DOI:10.1038/nn.4106.
13. Ji ZG, Wang H. ChR2 transgenic animals in peripheral sensory system:sensing light as various sensations[J]. Life Sci, 2016, 150:95-102. DOI:10.1016/j.lfs.2016.02.057.
14. Lin JY. Optogenetic excitation of neurons with channelrhodopsins:light instrumentation, expression systems, and channelrhodopsin variants[J]. Prog Brain Res, 2012, 196:29-47.DOI:10.1016/B978-0-444-59426-6.00002-1.
15. Sekharan S, Wei JN, Batista VS. The active site of melanopsin:the biological clock photoreceptor[J]. J Am Chem Soc, 2012, 134(48):19536-19539.DOI:10.1021/ja308763b.
16. Hughes S, Jagannath A, Rodgers J, et al. Signalling by melanopsin (OPN4) expressing photosensitive retinal ganglion cells[J]. Eye, 2016, 30(2):247-254.DOI:10.1038/eye.2015.264.
17. Spitschan M, Datta R, Stern AM, et al. Human visual cortex responses to rapid cone and melanopsin-directed flicker[J]. J Neurosci, 2016, 36(5):1471-1482. DOI:10.1523/JNEUROSCI.1932-15.2016.
18. Sexton T, Buhr E, Van Gelder RN. Melanopsin and mechanisms of non-visual ocular photoreception[J]. J Biol Chem, 2012, 287(3):1649-1656. DOI:10.1074/jbc.R111.301226.
19. Tsunematsu T, Tanaka KF, Yamanaka A, et al. Ectopic expression of melanopsin in orexin/hypocretin neurons enables control of wakefulness of mice in vivo by blue light[J]. Neurosci Res, 2013, 75(1):23-28.DOI:10.1016/j.neures.2012.07.005.
20. Liske H, Qian X, Anikeeva P, et al. Optical control of neuronal excitation and inhibition using a single opsin protein, ChR2[J]. Sci Rep, 2013, 3:3110. DOI:10.1038/srep03110.
21. Koizumi A, Tanaka KF, Yamanaka A. The manipulation of neural and cellular activities by ectopic expression of melanopsin[J]. Neurosci Res, 2013, 75(1):3-5.DOI:10.1016/j.neures.2012.07.010.
22. Lin B, Koizumi A, Tanaka N, et al. Restoration of visual function in retinal degeneration mice by ectopic expression of melanopsin[J]. Proc Natl Acad Sci USA, 2008, 105(41):16009-16014.DOI:10.1073/pnas.0806114105.
23. Byrne LC, Khalid F, Lee T, et al. AAV-mediated, optogenetic ablation of Muller Glia leads to structural and functional changes in the mouse retina[J/OL]. PLoS One, 2013, 8(9):76075[2013-09-27]. http://dx.plos.org/10.1371/journal.pone.0076075.DOI:10.1371/journal.pone.0076075.
24. Stutika C, Gogol-D ring A, Botschen L, et al. A comprehensive RNA sequencing analysis of the adeno-associated virus (AAV) type 2 transcriptome reveals novel AAV transcripts, splice variants, and derived proteins[J]. J Virol, 2015, 90(3):1278-1289.DOI:10.1128/JVI.02750-15.
25. Arenkiel BR, Peca J, Davison IG, et al. In vivo light-induced activation of neural circuitry in transgenic mice expressing channelrhodopsin-2[J]. Neuron, 2007, 54(2):205-218.
26. Schoonheim PJ, Arrenberg AB, Del Bene F, et al. Optogenetic localization and genetic perturbation of saccade-generating neurons in zebrafish[J].J Neurosci, 2010, 30(20):7111-7120.DOI:10.1523/JNEUROSCI.5193-09.2010.
27. Hsiao PY, Wu MC, Lin YY, et al. Optogenetic manipulation of selective neural activity in free-moving drosophila adults[J]. Methods Mol Biol, 2016, 1408:377-387.DOI:10.1007/978-1-4939-3512-3_26.
28. Inoue K, Takada M, Matsumoto M. Neuronal and behavioural modulations by pathway-selective optogenetic stimulation of the primate oculomotor system[J]. Nat Commun, 2015, 6:8378.DOI:10.1038/ncomms9378.
29. Weick JP, Johnson MA, Skroch SP, et al. Functional control of transplantable human ESC-derived neurons via optogenetic targeting[J]. Stem cells, 2010, 28(11):2008-2016.DOI:10.1002/stem.514.
30. Flusberg BA, Jung JC, Cocker ED, et al. In vivo brain imaging using a portable 3.9 gram two-photon fluorescence microendoscope[J]. Opt Lett, 2005, 30(17):2272-2274.
31. Busskamp V, Picaud S, Sahel JA, et al. Optogenetic therapy for retinitis pigmentosa[J]. Gene Ther, 2012, 19(2):169-175.DOI:10.1038/gt.2011.155.
32. Roska B, Busskamp V, Sahel JA, et al. Retinitis pigmentosa:eye sight restoration by optogenetic therapy[J]. Biol Aujourdhui, 2013, 207(2):109-121.DOI:10.1051/jbio/2013011.
33. Castilho Á, Ambrósio AF, Hartveit E, et al. Disruption of a neural microcircuit in the rod pathway of the mammalian retina by diabetes mellitus[J]. J Neurosci, 2015, 35(13):5422-5433.DOI:10.1523/JNEUROSCI.5285-14.2015.
34. Song H, Rossi EA, Latchney L, et al. Cone and rod loss in Stargardt disease revealed by adaptive optics scanning light ophthalmoscopy[J]. JAMA Ophthalmol, 2015, 133(10):1198-1203.DOI:10.1001/jamaophthalmol.2015.2443.
35. Hidalgo-de-Quintana J, Schwarz N, Meschede IP, et al. The Leber congenital amaurosis protein AIPL1 and EB proteins co-localize at the photoreceptor cilium[J]. PLoS One, 2015, 10(3):0121440[2015-03-25]. http://dx.plos.org/10.1371/journal.pone.0121440. DOI:10.1371/journal.pone.0121440.
36. Lin B, Masland RH, Strettoi E. Remodeling of cone photoreceptor cells after rod degeneration in rd mice[J]. Exp Eye Res, 2009, 88(3):589-599.DOI:10.1016/j.exer.2008.11.022.
37. Cho AK, Sampath AP, Weiland JD. Physiological response of normal and RD mouse retinal ganglion cells to electrical stimulation[J]. Conf Proc IEEE Eng Med Biol Soc, 2012, 2012:2985-2988.DOI:10.1109/EMBC.2012.6346591.
38. May CA. Fibrae medullares in the retina of the RD mouse:a case report[J]. Curr Eye Res, 2009, 34(5):411-413.DOI:10.1080/02713680902825507.
39. 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.
40. 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.
41. Ikeda Y, Ishibashi T. Neuroprotective gene therapy to treat patients with retinitis pigmentosa[J]. Fukuoka Igaku Zasshi, 2010, 101(9):183-189.
42. 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.
43. 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.
44. Thyagarajan S, van Wyk M, Lehmann K, et al. Visual function in mice with photoreceptor degeneration and transgenic expression of channelrhodopsin 2 in ganglion cells[J]. J Neurosci, 2010, 30(26):8745-8758.DOI:10.1523/JNEUROSCI.4417-09.2010.
45. Kleinlogel S. Optogenetic user's guide to Opto-GPCRs[J]. Front Biosci (Landmark Ed)., 2016, 21:794-805.

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