Salvaging ruins: reverting blind retinas into functional visual sensors.

Blindness is one of the most devastating conditions affecting the quality of life. Hereditary degenerative diseases, such as retinitis pigmentosa, are characterized by the progressive loss of photoreceptors, leading to complete blindness. No treatment is known, the current state-of-the-art of restoring vision are implanted electrode arrays. As a recently discovered alternative, optical neuromodulators, such as channelrhodopsin, allow new strategies for treating these diseases by imparting light-sensitivity onto the remaining retinal neurons after photoreceptor cell death. Retinal degeneration is a heterogeneous set of diseases with diverse secondary effects on the retinal circuitry. Successful treatment strategies have to take into account this diversity, as only the existing retinal hardware can serve as substrate for optogenetic intervention. The goal is to salvage the retinal ruins and to revert the leftover tissue into a functional visual sensor that operates as optimally as possible. Here, we discuss three different successful approaches that have been applied to degenerated mouse retina.

[1]  E. Bamberg,et al.  General concept for ion translocation by halobacterial retinal proteins: the isomerization/switch/transfer (IST) model. , 1997, Biochemistry.

[2]  Lief E. Fenno,et al.  The development and application of optogenetics. , 2011, Annual review of neuroscience.

[3]  C. Cepko,et al.  Controlled expression of transgenes introduced by in vivo electroporation , 2007, Proceedings of the National Academy of Sciences.

[4]  A. Watts,et al.  Photoreceptor rhodopsin: structural and conformational study of its chromophore 11‐cis retinal in oriented membranes by deuterium solid state NMR , 1998, FEBS letters.

[5]  E. Zrenner Will Retinal Implants Restore Vision ? , 2002 .

[6]  T. Léveillard,et al.  Inherited retinal degenerations: therapeutic prospects. , 2004, Biology of the cell.

[7]  Oliver P. Ernst,et al.  Channelrhodopsin-1 Initiates Phototaxis and Photophobic Responses in Chlamydomonas by Immediate Light-Induced Depolarization[W] , 2008, The Plant Cell Online.

[8]  Peter Hegemann,et al.  Glu 87 of Channelrhodopsin‐1 Causes pH‐dependent Color Tuning and Fast Photocurrent Inactivation † , 2009, Photochemistry and photobiology.

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

[10]  Enrica Strettoi,et al.  Retinal organization in the retinal degeneration 10 (rd10) mutant mouse: A morphological and ERG study , 2007, The Journal of comparative neurology.

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

[12]  W. Hauswirth,et al.  A comprehensive review of retinal gene therapy. , 2013, Molecular therapy : the journal of the American Society of Gene Therapy.

[13]  Angelika Braun,et al.  Artificial vision with wirelessly powered subretinal electronic implant alpha-IMS , 2013, Proceedings of the Royal Society B: Biological Sciences.

[14]  C. Cepko,et al.  Seeing the Light of Day , 2010, Science.

[15]  Tim Gollisch,et al.  Eye Smarter than Scientists Believed: Neural Computations in Circuits of the Retina , 2010, Neuron.

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

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

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

[19]  J. Flannery,et al.  Degenerative changes in a retina affected with autosomal dominant retinitis pigmentosa. , 1989, Investigative ophthalmology & visual science.

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

[21]  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.

[22]  Andreas Wenzel,et al.  Spectral domain optical coherence tomography in mouse models of retinal degeneration. , 2009, Investigative ophthalmology & visual science.

[23]  J. Flannery,et al.  Looking within for Vision , 2006, Neuron.

[24]  J. Heckenlively,et al.  Two mouse retinal degenerations caused by missense mutations in the β-subunit of rod cGMP phosphodiesterase gene , 2007, Vision Research.

[25]  T. Münch,et al.  Strategies for Expanding the Operational Range of Channelrhodopsin in Optogenetic Vision , 2013, PloS one.

[26]  Tiansen Li,et al.  Retinal degeneration in the rd mouse is caused by a defect in the β subunit of rod cGMP-phosphodiesterase , 1990, Nature.

[27]  Edward S Boyden,et al.  A gene-fusion strategy for stoichiometric and co-localized expression of light-gated membrane proteins , 2011, Nature Methods.

[28]  Jean Bennett,et al.  Gene therapy restores vision in a canine model of childhood blindness , 2001, Nature Genetics.

[29]  Karl Deisseroth,et al.  Optogenetics in Neural Systems , 2011, Neuron.

[30]  S. Petersen-Jones Viral vectors for targeting the canine retina: a review. , 2012, Veterinary ophthalmology.

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

[32]  C. Cepko,et al.  Electroporation and RNA interference in the rodent retina in vivo and in vitro , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[33]  Marion Mutter,et al.  Characterizing visual performance in mice: an objective and automated system based on the optokinetic reflex. , 2013, Behavioral neuroscience.

[34]  D. Baylor,et al.  Activation, deactivation, and adaptation in vertebrate photoreceptor cells. , 2001, Annual review of neuroscience.

[35]  J. Lanyi Halorhodopsin, a light-driven electrogenic chloride-transport system. , 1990, Physiological reviews.