A light in the dark: state of the art and perspectives in optogenetics and optopharmacology for restoring vision.

In the last decade, innovative therapeutic strategies against inherited retinal degenerations (IRDs) have emerged. In particular, chemical- and opto-genetics approaches or a combination of them have been identified for modulating neuronal/optical activity in order to restore vision in blinding diseases. The 'chemical-genetics approach' (optopharmacology) uses small molecules (exogenous photoswitches) for restoring light sensitivity by activating ion channels. The 'opto-genetics approach' employs light-activated photosensitive proteins (exogenous opsins), introduced by viral vectors in injured tissues, to restore light response. These approaches offer control of neuronal activities with spatial precision and limited invasiveness, although with some drawbacks. Currently, a combined therapeutic strategy (optogenetic pharmacology) is emerging. This review describes the state of the art and provides an overview of the future perspectives in vision restoration.

[1]  François Stricher,et al.  Analysis of disease-linked rhodopsin mutations based on structure, function, and protein stability calculations. , 2011, Journal of molecular biology.

[2]  Qi Zhao,et al.  IBS: an illustrator for the presentation and visualization of biological sequences , 2015, Bioinform..

[3]  H. Adesnik,et al.  Optogenetic pharmacology for control of native neuronal signaling proteins , 2013, Nature Neuroscience.

[4]  Retinitis pigmentosa and allied diseases: numerous diseases, genes, and inheritance patterns , 2002 .

[5]  S. Daiger,et al.  Genes and mutations causing retinitis pigmentosa , 2013, Clinical genetics.

[6]  S. Halford,et al.  Unravelling the genetics of inherited retinal dystrophies: Past, present and future , 2017, Progress in Retinal and Eye Research.

[7]  Dirk Trauner,et al.  Restoring Visual Function to Blind Mice with a Photoswitch that Exploits Electrophysiological Remodeling of Retinal Ganglion Cells , 2014, Neuron.

[8]  Z. Marinova,et al.  The mood stabilizers lithium and valproate selectively activate the promoter IV of brain-derived neurotrophic factor in neurons , 2009, Molecular Psychiatry.

[9]  Martin Biel,et al.  Photopharmacological control of bipolar cells restores visual function in blind mice , 2017, The Journal of clinical investigation.

[10]  Z. Pan,et al.  Evaluation of the adeno-associated virus mediated long-term expression of channelrhodopsin-2 in the mouse retina , 2009, Molecular vision.

[11]  H. Hamm,et al.  Interaction of rhodopsin with the G‐protein, transducin , 1993, BioEssays : news and reviews in molecular, cellular and developmental biology.

[12]  C. H. Ide,et al.  Coats'-type retinitis pigmentosa. , 1988, Survey of ophthalmology.

[13]  Olivier Marre,et al.  Targeting channelrhodopsin-2 to ON-bipolar cells with vitreally administered AAV Restores ON and OFF visual responses in blind mice. , 2015, Molecular therapy : the journal of the American Society of Gene Therapy.

[14]  J. Sahel,et al.  Insight into the mechanisms of enhanced retinal transduction by the engineered AAV2 capsid variant ‐7m8 , 2016, Biotechnology and bioengineering.

[15]  Eriko Sugano,et al.  Channelrhodopsin-2 gene transduced into retinal ganglion cells restores functional vision in genetically blind rats. , 2010, Experimental eye research.

[16]  Dirk Trauner,et al.  Restoration of patterned vision with an engineered photoactivatable G protein-coupled receptor , 2017, Nature Communications.

[17]  W. Hauswirth,et al.  Increased sensitivity to light-induced damage in a mouse model of autosomal dominant retinal disease. , 2007, Investigative ophthalmology & visual science.

[18]  Jacob G. Bernstein,et al.  Optogenetic tools for analyzing the neural circuits of behavior , 2011, Trends in Cognitive Sciences.

[19]  Chris A. Johnson,et al.  Clinical trial of lutein in patients with retinitis pigmentosa receiving vitamin A. , 2010, Archives of ophthalmology.

[20]  Michael H Berry,et al.  Optogenetic Vision Restoration Using Rhodopsin for Enhanced Sensitivity , 2015, Molecular therapy : the journal of the American Society of Gene Therapy.

[21]  Jean Bennett,et al.  Efficient transduction and optogenetic stimulation of retinal bipolar cells by a synthetic adeno-associated virus capsid and promoter , 2014, EMBO molecular medicine.

[22]  Timothy W. Dunn,et al.  Photochemical control of endogenous ion channels and cellular excitability , 2008, Nature Methods.

[23]  Gebhard F. X. Schertler,et al.  Ligand channel in pharmacologically stabilized rhodopsin , 2018, Proceedings of the National Academy of Sciences.

[24]  Botond Roska,et al.  Gene therapy for blindness. , 2013, Annual review of neuroscience.

[25]  Rahul S. Rajan,et al.  A Rhodopsin Mutant Linked to Autosomal Dominant Retinitis Pigmentosa Is Prone to Aggregate and Interacts with the Ubiquitin Proteasome System* , 2002, The Journal of Biological Chemistry.

[26]  Dirk Trauner,et al.  Tuning photochromic ion channel blockers. , 2011, ACS chemical neuroscience.

[27]  E. Bamberg,et al.  Channelrhodopsin-2, a directly light-gated cation-selective membrane channel , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[28]  A. Felipe,et al.  Spectral transmission of the human crystalline lens in adult and elderly persons: color and total transmission of visible light. , 2012, Investigative ophthalmology & visual science.

[29]  Siegrid Löwel,et al.  Restoring the ON Switch in Blind Retinas: Opto-mGluR6, a Next-Generation, Cell-Tailored Optogenetic Tool , 2015, PLoS biology.

[30]  M. Cheetham,et al.  Mechanisms of cell death in rhodopsin retinitis pigmentosa: implications for therapy. , 2005, Trends in molecular medicine.

[31]  E. Strettoi,et al.  Retinal Ganglion Cells Survive and Maintain Normal Dendritic Morphology in a Mouse Model of Inherited Photoreceptor Degeneration , 2008, The Journal of Neuroscience.

[32]  H. M. Petry,et al.  Vision improvement in retinal degeneration patients by implantation of retina together with retinal pigment epithelium. , 2008, American journal of ophthalmology.

[33]  K. Palczewski.  Chemistry and biology of the initial steps in vision: the Friedenwald lecture. , 2014, Investigative ophthalmology & visual science.

[34]  B. Falsini,et al.  NGF eye-drops topical administration in patients with retinitis pigmentosa, a pilot study , 2016, Journal of Translational Medicine.

[35]  P. Stewart,et al.  A novel small molecule chaperone of rod opsin and its potential therapy for retinal degeneration , 2018, Nature Communications.

[36]  Dirk Trauner,et al.  Orthogonal Optical Control of a G Protein-Coupled Receptor with a SNAP-Tethered Photochromic Ligand , 2015, ACS central science.

[37]  Kathleen A. Marshall,et al.  Efficacy and safety of voretigene neparvovec (AAV2-hRPE65v2) in patients with RPE65-mediated inherited retinal dystrophy: a randomised, controlled, open-label, phase 3 trial , 2017, The Lancet.

[38]  P. Hargrave,et al.  Rhodopsin and phototransduction. , 1992, International review of cytology.

[39]  Steven Hughes,et al.  Long-term restoration of visual function in end-stage retinal degeneration using subretinal human melanopsin gene therapy , 2017, Proceedings of the National Academy of Sciences.

[40]  Christopher Hamel.  Retinitis pigmentosa , 2006, Orphanet journal of rare diseases.

[41]  C. Zelinka,et al.  Valproic Acid for a Treatment of Retinitis Pigmentosa: Reasons for Optimism and Caution , 2017, The Journal of Neuroscience.

[42]  Edward S Boyden,et al.  Virally delivered channelrhodopsin-2 safely and effectively restores visual function in multiple mouse models of blindness. , 2011, Molecular therapy : the journal of the American Society of Gene Therapy.

[43]  D C Teller,et al.  Crystal structure of rhodopsin: a template for cone visual pigments and other G protein-coupled receptors. , 2002, Biochimica et biophysica acta.

[44]  K. Palczewski,et al.  Diseases caused by defects in the visual cycle: retinoids as potential therapeutic agents. , 2007, Annual review of pharmacology and toxicology.

[45]  E. Isacoff,et al.  Allosteric control of an ionotropic glutamate receptor with an optical switch , 2006, Nature chemical biology.

[46]  Michael A. Goren,et al.  Dimerization deficiency of enigmatic retinitis pigmentosa-linked rhodopsin mutants , 2016, Nature Communications.

[47]  Z. Yin,et al.  Human melanopsin-AAV2/8 transfection to retina transiently restores visual function in rd1 mice. , 2016, International journal of ophthalmology.

[48]  Chris A. Johnson,et al.  Further evaluation of docosahexaenoic acid in patients with retinitis pigmentosa receiving vitamin A treatment: subgroup analyses. , 2004, Archives of ophthalmology.

[49]  X. Xia,et al.  Chemical chaperone 4-phenylbutyrate prevents endoplasmic reticulum stress induced by T17M rhodopsin , 2014, Cell & Bioscience.

[50]  Serge Picaud,et al.  Noninvasive gene delivery to foveal cones for vision restoration. , 2018, JCI insight.

[51]  Volker Busskamp,et al.  Optogenetic approaches to restoring visual function in retinitis pigmentosa , 2011, Current Opinion in Neurobiology.

[52]  C. M. Davenport,et al.  Rhodopsin mutations in autosomal dominant retinitis pigmentosa. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[53]  H. Manji,et al.  The Mood Stabilizer Valproic Acid Activates Mitogen-activated Protein Kinases and Promotes Neurite Growth* , 2001, The Journal of Biological Chemistry.

[54]  Annette E. Allen,et al.  Restoration of Vision with Ectopic Expression of Human Rod Opsin , 2015, Current Biology.

[55]  Krzysztof Palczewski,et al.  Chemistry and Biology of Vision* , 2011, The Journal of Biological Chemistry.

[56]  Richard H. Kramer,et al.  Restoring visual function to the blind retina with a potent, safe and long-lasting photoswitch , 2017, Scientific Reports.

[57]  Dirk Trauner,et al.  Photochromic blockers of voltage-gated potassium channels. , 2009, Angewandte Chemie.

[58]  H. Ohguro,et al.  Study of drug effects of calcium channel blockers on retinal degeneration of rd mouse. , 2004, Biochemical and biophysical research communications.

[59]  K. Deisseroth,et al.  Circuit-breakers: optical technologies for probing neural signals and systems , 2007, Nature Reviews Neuroscience.

[60]  Laura Focareta,et al.  Recombinant Human Nerve Growth Factor Treatment Promotes Photoreceptor Survival in the Retinas of Rats with Retinitis Pigmentosa , 2017, Current eye research.

[61]  Olivier Marre,et al.  Red‐shifted channelrhodopsin stimulation restores light responses in blind mice, macaque retina, and human retina , 2016, EMBO molecular medicine.

[62]  F. Liang,et al.  AAV-mediated delivery of ciliary neurotrophic factor prolongs photoreceptor survival in the rhodopsin knockout mouse. , 2001, Molecular therapy : the journal of the American Society of Gene Therapy.

[63]  R. Kramer,et al.  Optopharmacological tools for restoring visual function in degenerative retinal diseases , 2015, Current Opinion in Neurobiology.

[64]  Livia S. Carvalho,et al.  Evolution and spectral tuning of visual pigments in birds and mammals , 2009, Philosophical Transactions of the Royal Society B: Biological Sciences.

[65]  S. Kaushal,et al.  Therapeutic potential of valproic acid for retinitis pigmentosa , 2010, British Journal of Ophthalmology.

[66]  R. Masland,et al.  Restoration of visual function in retinal degeneration mice by ectopic expression of melanopsin , 2008, Proceedings of the National Academy of Sciences.

[67]  Jessica A. Cardin,et al.  Noninvasive optical inhibition with a red-shifted microbial rhodopsin , 2014, Nature Neuroscience.

[68]  T. van Veen,et al.  Photoreceptor rescue and toxicity induced by different calpain inhibitors , 2010, Journal of neurochemistry.

[69]  M Tamai,et al.  Immune responses to adeno-associated virus type 2 encoding channelrhodopsin-2 in a genetically blind rat model for gene therapy , 2011, Gene Therapy.

[70]  Gen-Lin Li,et al.  Construction of a plasmid for human brain-derived neurotrophic factor and its effect on retinal pigment epithelial cell viability , 2016, Neural regeneration research.

[71]  Deniz Dalkara,et al.  In Vivo–Directed Evolution of a New Adeno-Associated Virus for Therapeutic Outer Retinal Gene Delivery from the Vitreous , 2013, Science Translational Medicine.

[72]  M. Karplus,et al.  The signaling pathway of rhodopsin. , 2007, Structure.

[73]  V. Kefalov.  Rod and Cone Visual Pigments and Phototransduction through Pharmacological, Genetic, and Physiological Approaches* , 2011, The Journal of Biological Chemistry.

[74]  Volker Busskamp,et al.  Biophysical Properties of Optogenetic Tools and Their Application for Vision Restoration Approaches , 2016, Front. Syst. Neurosci..

[75]  R. MacLaren,et al.  CNTF Gene Therapy Confers Lifelong Neuroprotection in a Mouse Model of Human Retinitis Pigmentosa. , 2015, Molecular therapy : the journal of the American Society of Gene Therapy.

[76]  Toru Ishizuka,et al.  Restoration of visual response in aged dystrophic RCS rats using AAV-mediated channelopsin-2 gene transfer. , 2007, Investigative ophthalmology & visual science.

[77]  W. Strohl,et al.  Adeno-Associated Virus (AAV) as a Vector for Gene Therapy , 2017, BioDrugs.

[78]  Raag D. Airan,et al.  Temporally precise in vivo control of intracellular signalling , 2009, Nature.

[79]  T. Sakmar,et al.  Structure of rhodopsin and the superfamily of seven-helical receptors: the same and not the same. , 2002, Current opinion in cell biology.

[80]  L. Ayton,et al.  Charles Bonnet Syndrome in Advanced Retinitis Pigmentosa. , 2015, Ophthalmology.

[81]  George J. Augustine,et al.  Light-Emitting Channelrhodopsins for Combined Optogenetic and Chemical-Genetic Control of Neurons , 2013, PloS one.

[82]  F. Werblin,et al.  Differential Targeting of Optical Neuromodulators to Ganglion Cell Soma and Dendrites Allows Dynamic Control of Center-Surround Antagonism , 2011, Neuron.

[83]  Philippe Hantraye,et al.  A New Promoter Allows Optogenetic Vision Restoration with Enhanced Sensitivity in Macaque Retina. , 2017, Molecular therapy : the journal of the American Society of Gene Therapy.

[84]  P. Greenberg,et al.  Retinal implants: a systematic review , 2014, British Journal of Ophthalmology.

[85]  M. Nakazawa.  Therapy options for retinitis pigmentosa , 2014 .

[86]  Peiquan Zhao,et al.  Mutation screening in genes known to be responsible for Retinitis Pigmentosa in 98 Small Han Chinese Families , 2017, Scientific Reports.

[87]  W. Willett,et al.  ω-3 intake and visual acuity in patients with retinitis pigmentosa receiving vitamin A. , 2012, Archives of ophthalmology.

[88]  R. Massof,et al.  How strong is the evidence that nutritional supplements slow the progression of retinitis pigmentosa? , 2010, Archives of ophthalmology.

[89]  Stefan R. Pulver,et al.  Independent Optical Excitation of Distinct Neural Populations , 2014, Nature Methods.

[90]  Yoshinori Shichida,et al.  Cone visual pigments. , 2014, Biochimica et biophysica acta.

[91]  K. Deisseroth,et al.  Bi-stable neural state switches , 2009, Nature Neuroscience.

[92]  T. L. McGee,et al.  Mutations within the rhodopsin gene in patients with autosomal dominant retinitis pigmentosa. , 1990, The New England journal of medicine.

[93]  J. Findlay,et al.  A novel mutation within the rhodopsin gene (Thr‐94‐Ile) causing autosomal dominant congenital stationary night blindness , 1999, Human mutation.

[94]  Dirk Trauner,et al.  Dual optical control and mechanistic insights into photoswitchable group II and III metabotropic glutamate receptors , 2017, Proceedings of the National Academy of Sciences.

[95]  Birgit Lorenz,et al.  Mutations in RPE65 cause autosomal recessive childhood–onset severe retinal dystrophy , 1997, Nature Genetics.

[96]  D. Oprian,et al.  Heterozygous missense mutation in the rhodopsin gene as a cause of congenital stationary night blindness , 1993, Nature Genetics.

[97]  D. Oprian,et al.  Rhodopsin mutation G90D and a molecular mechanism for congenital night blindness , 1994, Nature.

[98]  R. N. Gelder.  Photochemical approaches to vision restoration , 2015, Vision Research.

[99]  J. Spudich.  The multitalented microbial sensory rhodopsins. , 2006, Trends in microbiology.

[100]  John G. Flannery,et al.  Restoration of visual function by expression of a light-gated mammalian ion channel in retinal ganglion cells or ON-bipolar cells , 2014, Proceedings of the National Academy of Sciences.

[101]  A. Dizhoor,et al.  Ectopic Expression of a Microbial-Type Rhodopsin Restores Visual Responses in Mice with Photoreceptor Degeneration , 2006, Neuron.

[102]  J. Duncan,et al.  Long-term Follow-up of Patients With Retinitis Pigmentosa Receiving Intraocular Ciliary Neurotrophic Factor Implants. , 2016, American journal of ophthalmology.

[103]  J. Heckenlively,et al.  Clinical findings and common symptoms in retinitis pigmentosa. , 1988, American journal of ophthalmology.

[104]  K. Palczewski,et al.  Activation of rhodopsin: new insights from structural and biochemical studies. , 2001, Trends in biochemical sciences.

[105]  B. Roska,et al.  Optogenetic therapy for retinitis pigmentosa , 2011, Gene Therapy.

[106]  K. Deisseroth,et al.  Millisecond-timescale, genetically targeted optical control of neural activity , 2005, Nature Neuroscience.

[107]  Young Jik Kwon,et al.  Molecular genetics and emerging therapies for retinitis pigmentosa: Basic research and clinical perspectives , 2017, Progress in Retinal and Eye Research.

[108]  Jean Bennett,et al.  Safety and durability of effect of contralateral-eye administration of AAV2 gene therapy in patients with childhood-onset blindness caused by RPE65 mutations: a follow-on phase 1 trial , 2016, The Lancet.

[109]  P. Hargrave.  Rhodopsin structure, function, and topography the Friedenwald lecture. , 2001, Investigative ophthalmology & visual science.

[110]  Genshiro A. Sunagawa,et al.  Efficacy of valproic acid for retinitis pigmentosa patients: a pilot study , 2016, Clinical ophthalmology.

[111]  S. Kaushal,et al.  Pharmacological Chaperone-mediated in Vivo Folding and Stabilization of the P23H-opsin Mutant Associated with Autosomal Dominant Retinitis Pigmentosa* , 2003, The Journal of Biological Chemistry.

[112]  Benjamin R. Arenkiel,et al.  In Vivo Light-Induced Activation of Neural Circuitry in Transgenic Mice Expressing Channelrhodopsin-2 , 2007, Neuron.

[113]  M. Sandberg,et al.  Absence of photoreceptor rescue with D-cis-diltiazem in the rd mouse. , 2002, Investigative ophthalmology & visual science.

[114]  Dirk Trauner,et al.  LiGluR restores visual responses in rodent models of inherited blindness. , 2011, Molecular therapy : the journal of the American Society of Gene Therapy.

[115]  G. Wald.  The Molecular Basis of Visual Excitation , 1968, Nature.

[116]  B. J. Klevering,et al.  Non-syndromic retinitis pigmentosa , 2018, Progress in Retinal and Eye Research.

[117]  Douglas S Kim,et al.  Light-activated channels targeted to ON bipolar cells restore visual function in retinal degeneration , 2008, Nature Neuroscience.

[118]  P. Sieving,et al.  CNTF and retina , 2012, Progress in Retinal and Eye Research.

[119]  E. Bamberg,et al.  Channelrhodopsin-1: A Light-Gated Proton Channel in Green Algae , 2002, Science.

[120]  D. Kleinfeld,et al.  ReaChR: A red-shifted variant of channelrhodopsin enables deep transcranial optogenetic excitation , 2013, Nature Neuroscience.

[121]  Simone Brogi,et al.  Discovery of GPCR ligands for probing signal transduction pathways , 2014, Front. Pharmacol..

[122]  E. Bamberg,et al.  Ultra light-sensitive and fast neuronal activation with the Ca2+-permeable channelrhodopsin CatCh , 2011, Nature Neuroscience.

[123]  Michael Z. Lin,et al.  Characterization of engineered channelrhodopsin variants with improved properties and kinetics. , 2009, Biophysical journal.

[124]  Glenn J Jaffe,et al.  Randomized trial of ciliary neurotrophic factor delivered by encapsulated cell intraocular implants for retinitis pigmentosa. , 2013, American journal of ophthalmology.

[125]  S. Kaushal,et al.  A high-throughput screening method for small-molecule pharmacologic chaperones of misfolded rhodopsin. , 2008, Investigative ophthalmology & visual science.

[126]  Satoshi Hirano,et al.  Protection of Cone Photoreceptor M-Opsin Degradation with 9-Cis-β-Carotene-Rich Alga Dunaliella bardawil in Rpe65−/− Mouse Retinal Explant Culture , 2014, Current eye research.

[127]  D. Trauner,et al.  Optochemical genetics. , 2011, Angewandte Chemie.

[128]  Lief E. Fenno,et al.  The Microbial Opsin Family of Optogenetic Tools , 2011, Cell.

[129]  J. Flannery,et al.  AAV mediated GDNF secretion from retinal glia slows down retinal degeneration in a rat model of retinitis pigmentosa. , 2011, Molecular therapy : the journal of the American Society of Gene Therapy.

[130]  Satoru Kawamura,et al.  Rod and cone photoreceptors: molecular basis of the difference in their physiology. , 2008, Comparative biochemistry and physiology. Part A, Molecular & integrative physiology.

[131]  Dirk Trauner,et al.  Photochemical Restoration of Visual Responses in Blind Mice , 2012, Neuron.

[132]  Dirk Trauner,et al.  A red-shifted, fast-relaxing azobenzene photoswitch for visible light control of an ionotropic glutamate receptor. , 2013, Journal of the American Chemical Society.

[133]  P. Hegemann,et al.  Microbial and Animal Rhodopsins: Structures, Functions, and Molecular Mechanisms , 2013, Chemical reviews.

[134]  K. Palczewski,et al.  A Small Chaperone Improves Folding and Routing of Rhodopsin Mutants Linked to Inherited Blindness , 2018, iScience.

[135]  J. Klein-Seetharaman,et al.  Retinitis pigmentosa associated with rhodopsin mutations: Correlation between phenotypic variability and molecular effects , 2006, Vision Research.

[136]  M. Michaelides,et al.  Leber congenital amaurosis/early-onset severe retinal dystrophy: clinical features, molecular genetics and therapeutic interventions , 2017, British Journal of Ophthalmology.

[137]  Karl Deisseroth,et al.  Genetic Reactivation of Cone Photoreceptors Restores Visual Responses in Retinitis Pigmentosa , 2010, Science.

[138]  Keita Sato,et al.  Comparative studies on the late bleaching processes of four kinds of cone visual pigments and rod visual pigment. , 2012, Biochemistry.

[139]  E. Strettoi,et al.  Pharmacological approaches to retinitis pigmentosa: A laboratory perspective , 2015, Progress in Retinal and Eye Research.

[140]  Zhuo-Hua Pan,et al.  Ectopic Expression of Multiple Microbial Rhodopsins Restores ON and OFF Light Responses in Retinas with Photoreceptor Degeneration , 2009, The Journal of Neuroscience.

[141]  D. Athanasiou,et al.  The molecular and cellular basis of rhodopsin retinitis pigmentosa reveals potential strategies for therapy , 2017, Progress in Retinal and Eye Research.