LiGluR Restores Visual Responses in Rodent Models of Inherited Blindness

被引:126
作者
Caporale, Natalia [1 ]
Kolstad, Kathleen D. [1 ]
Lee, Trevor [1 ]
Tochitsky, Ivan [2 ]
Dalkara, Deniz [1 ]
Trauner, Dirk [3 ]
Kramer, Richard [1 ,2 ,4 ]
Dan, Yang [1 ,2 ,5 ]
Isacoff, Ehud Y. [1 ,2 ,4 ]
Flannery, John G. [1 ,2 ,6 ]
机构
[1] Univ Calif Berkeley, Helen Wills Neurosci Inst, Berkeley, CA 94720 USA
[2] Univ Calif Berkeley, Dept Mol & Cell Biol, Berkeley, CA 94720 USA
[3] Univ Munich, Dept Chem, Munich, Germany
[4] Univ Calif Berkeley, Lawrence Berkeley Lab, Phys Biosci Div, Berkeley, CA 94720 USA
[5] Univ Calif Berkeley, Howard Hughes Med Inst, Berkeley, CA 94720 USA
[6] Univ Calif Berkeley, Sch Optometry, Berkeley, CA 94720 USA
基金
美国国家卫生研究院;
关键词
ECTOPIC EXPRESSION; GENE-THERAPY; CONGENITAL AMAUROSIS; GANGLION-CELLS; MOUSE MODEL; LIGHT; DEGENERATION; MICE; PHOTORECEPTORS; RESTORATION;
D O I
10.1038/mt.2011.103
中图分类号
Q81 [生物工程学(生物技术)]; Q93 [微生物学];
学科分类号
071005 ; 0836 ; 090102 ; 100705 ;
摘要
Inherited retinal degeneration results from many different mutations in either photoreceptor-specific or nonphoto-receptor-specific genes. However, nearly all mutations lead to a common blinding phenotype that initiates with rod cell death, followed by loss of cones. In most retinal degenerations, other retinal neuron cell types survive for long periods after blindness from photoreceptor loss. One strategy to restore light responsiveness to a retina rendered blind by photoreceptor degeneration is to express light-regulated ion channels or transporters in surviving retinal neurons. Recent experiments in rodents have restored light-sensitivity by expressing melanopsin or microbial opsins either broadly throughout the retina or selectively in the inner segments of surviving cones or in bipolar cells. Here, we present an approach whereby a genetically and chemically engineered light-gated ionotropic glutamate receptor (LiGluR) is expressed selectively in retinal ganglion cells (RGCs), the longest-surviving cells in retinal blinding diseases. When expressed in the RGCs of a well-established model of retinal degeneration, the rd1 mouse, LiGluR restores light sensitivity to the RGCs, reinstates light responsiveness to the primary visual cortex, and restores both the pupillary reflex and a natural light-avoidance behavior. Received 31 March 2011; accepted 29 April 2011; published online 24 May 2011. doi: 10.1038/mt.2011.103
引用
收藏
页码:1212 / 1219
页数:8
相关论文
共 47 条
[1]   Effect of gene therapy on visual function in Leber's congenital amaurosis [J].
Bainbridge, James W. B. ;
Smith, Alexander J. ;
Barker, Susie S. ;
Robbie, Scott ;
Henderson, Robert ;
Balaggan, Kamaljit ;
Viswanathan, Ananth ;
Holder, Graham E. ;
Stockman, Andrew ;
Tyler, Nick ;
Petersen-Jones, Simon ;
Bhattacharya, Shomi S. ;
Thrasher, Adrian J. ;
Fitzke, Fred W. ;
Carter, Barrie J. ;
Rubin, Gary S. ;
Moore, Anthony T. ;
Ali, Robin R. .
NEW ENGLAND JOURNAL OF MEDICINE, 2008, 358 (21) :2231-2239
[2]   Brief light as a practical aversive stimulus for the albino rat [J].
Barker, David J. ;
Sanabria, Federico ;
Lasswell, Anne ;
Thrailkill, Eric A. ;
Pawlak, Anthony P. ;
Killeen, Peter R. .
BEHAVIOURAL BRAIN RESEARCH, 2010, 214 (02) :402-408
[3]   Ectopic expression of a microbial-type rhodopsin restores visual responses in mice with photoreceptor degeneration [J].
Bi, AD ;
Cui, JJ ;
Ma, YP ;
Olshevskaya, E ;
Pu, ML ;
Dizhoor, AM ;
Pan, ZH .
NEURON, 2006, 50 (01) :23-33
[4]   Genetic Reactivation of Cone Photoreceptors Restores Visual Responses in Retinitis Pigmentosa [J].
Busskamp, Volker ;
Duebel, Jens ;
Balya, David ;
Fradot, Mathias ;
Viney, Tim James ;
Siegert, Sandra ;
Groner, Anna C. ;
Cabuy, Erik ;
Forster, Valerie ;
Seeliger, Mathias ;
Biel, Martin ;
Humphries, Peter ;
Paques, Michel ;
Mohand-Said, Saddek ;
Trono, Didier ;
Deisseroth, Karl ;
Sahel, Jose A. ;
Picaud, Serge ;
Roska, Botond .
SCIENCE, 2010, 329 (5990) :413-417
[5]  
CARTERDAWSON LD, 1978, INVEST OPHTH VIS SCI, V17, P489
[6]   Artificial vision: needs, functioning, and testing of a retinal electronic prosthesis [J].
Chader, Gerald J. ;
Weiland, James ;
Humayun, Mark S. .
NEUROTHERAPY: PROGRESS IN RESTORATIVE NEUROSCIENCE AND NEUROLOGY, 2009, 175 :317-332
[7]   A blue-green absorbing cross-linker for rapid photoswitching of peptide helix content [J].
Chi, Lei ;
Sadovski, Oleg ;
Woolley, G. Andrew .
BIOCONJUGATE CHEMISTRY, 2006, 17 (03) :670-676
[8]   Centrosomal,Ciliary gene CEP290/NPHP6 mutations result in blindness with unexpected sparing of Photoreceptors and visual brain: Implications for therapy of Leber congenital amaurosis [J].
Cideciyan, Artur V. ;
Aleman, Tomas S. ;
Jacobson, Samuel G. ;
Khanna, Hemant ;
Sumaroka, Alexander ;
Aguirre, Geoffrey K. ;
Schwartz, Sharon B. ;
Windsor, Elizabeth A. M. ;
He, Shirley ;
Chang, Bo ;
Stone, Edwin M. ;
Swaroop, Anand .
HUMAN MUTATION, 2007, 28 (11) :1074-1083
[9]   Human RPE65 Gene Therapy for Leber Congenital Amaurosis: Persistence of Early Visual Improvements and Safety at 1 Year [J].
Cideciyan, Artur V. ;
Hauswirth, William W. ;
Aleman, Tomas S. ;
Kaushal, Shalesh ;
Schwartz, Sharon B. ;
Boye, Sanford L. ;
Windsor, Elizabeth A. M. ;
Conlon, Thomas J. ;
Sumaroka, Alexander ;
Pang, Ji-jing ;
Roman, Alejandro J. ;
Byrne, Barry J. ;
Jacobson, Samuel G. .
HUMAN GENE THERAPY, 2009, 20 (09) :999-1004
[10]   Morphological characterization of the retina of the CNGA3-/-Rho-/- mutant mouse lacking functional cones and rods [J].
Claes, E ;
Seeliger, M ;
Michalakis, S ;
Biel, M ;
Humphries, P ;
Haverkamp, S .
INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE, 2004, 45 (06) :2039-2048