Genomes and Genes
VISUAL CYCLE IN HUMAN PHOTORECEPTOR AND RPE DISEASE
Principal Investigator: ARTUR CIDECIYAN
Affiliation: University of Pennsylvania
Abstract: DESCRIPTION (Adapted from applicant's abstract): Biochemical and physiological studies in vitro and in retina-specific ABC transporter (ABCR) -/- knockout mice suggest that ABCR accelerates recovery of rod photoreceptor resensitization after intense light exposure by transporting isomerized chromphore, all-trans-retinal, across the rod outer segment disk membrane. The current proposal is to test hypotheses about the role of ABCR in human disease as follows: (1) Study the visual cycle abnormalities in patients with retinopathy due to ABCR mutations with the goals of dissecting the contributions of primary rod effects vs. secondary disease consequences and learning the relationship between primary rod abnormalities and the genotype; (2) Investigate the basis of rod visual loss in these patients by testing the hypothesis that desensitization by equivalent light contributes to the visual loss, and determine if short term trial of unilateral light reduction can alter rod sensitivity and select mutations; (3) Test whether heterozygotes of ABCR mutations show visual cycle abnormalities and to approach from the visual function perspective the issue of ABCR sequence variance as risk factors in age related macular degeneration.
Funding Period: 2000-08-05 - 2005-01-31
more information: NIH RePORT
- Canine retina has a primate fovea-like bouquet of cone photoreceptors which is affected by inherited macular degenerationsWilliam A Beltran
Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
PLoS ONE 9:e90390. 2014..Furthermore, a predilection for naturally-occurring retinal degenerations to alter this cone-enriched area fills the void for a clinically-relevant animal model of human macular degenerations. ..
- Inner and outer retinal changes in retinal degenerations associated with ABCA4 mutationsWei Chieh Huang
Scheie Eye Institute, Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
Invest Ophthalmol Vis Sci 55:1810-22. 2014..To investigate in vivo inner and outer retinal microstructure and effects of structural abnormalities on visual function in patients with retinal degeneration caused by ABCA4 mutations (ABCA4-RD)...
- Human cone visual pigment deletions spare sufficient photoreceptors to warrant gene therapyArtur V Cideciyan
1 Department of Ophthalmology, Scheie Eye Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104
Hum Gene Ther 24:993-1006. 2013..The evidence indicates that human cones in patients with deletions in the red/green opsin gene array can survive in reduced numbers with limited outer segment material, suggesting potential value of gene therapy for BCM...
- Macular function in macular degenerations: repeatability of microperimetry as a potential outcome measure for ABCA4-associated retinopathy trialsArtur V Cideciyan
Scheie Eye Institute, Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
Invest Ophthalmol Vis Sci 53:841-52. 2012..To measure macular visual function in patients with unstable fixation, to define the photoreceptor source of this function, and to estimate its test-retest repeatability as a prerequisite to clinical trials...
- The Usher 1B protein, MYO7A, is required for normal localization and function of the visual retinoid cycle enzyme, RPE65Vanda S Lopes
Jules Stein Eye Institute and Department of Neurobiology, UCLA School of Medicine, University of California Los Angeles, 200 Stein Plaza, Los Angeles, CA 90095, USA
Hum Mol Genet 20:2560-70. 2011..Together, the results support a role for MYO7A in the translocation of RPE65, illustrating the involvement of a molecular motor in the spatiotemporal organization of the retinoid cycle in vision...
- Leber congenital amaurosis due to RPE65 mutations and its treatment with gene therapyArtur V Cideciyan
Scheie Eye Institute, University of Pennsylvania, 51 North 39th St, Philadelphia, PA 19104, USA
Prog Retin Eye Res 29:398-427. 2010..This article reviews the current knowledge on retinal degeneration and visual dysfunction in animal models and human patients with RPE65 disease, and examines the consequences of gene therapy in terms of improvement of vision reported...
- Loss of cone photoreceptors caused by chromophore depletion is partially prevented by the artificial chromophore pro-drug, 9-cis-retinyl acetateTadao Maeda
Department of Pharmacology, School of Medicine, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106 4965, USA
Hum Mol Genet 18:2277-87. 2009..These results suggest that chronic lack of chromophore leads to progressive loss of cones in mice and humans. Therapy for LCA patients should be geared toward early adequate delivery of chromophore to cone photoreceptors...
- Retinal pigment epithelium defects in humans and mice with mutations in MYO7A: imaging melanosome-specific autofluorescenceDaniel Gibbs
Departments of Pharmacology, UCSD School of Medicine, La Jolla, California, USA
Invest Ophthalmol Vis Sci 50:4386-93. 2009..This study was undertaken to identify an imaging method for noninvasively monitoring the RPE component of the USH1B disease...
- ABCA4 disease progression and a proposed strategy for gene therapyArtur V Cideciyan
Scheie Eye Institute, Department of Ophthalmology, University of Pennsylvania, Philadelphia, PA 19104, USA
Hum Mol Genet 18:931-41. 2009..Genotype-based inclusion/exclusion criteria and prediction of the age of retina-wide disease initiation will be invaluable for selecting appropriate candidates for clinical trials in ABCA4 disease...
- Mutation analysis identifies GUCY2D as the major gene responsible for autosomal dominant progressive cone degenerationVeronique B D Kitiratschky
Molecular Genetics Laboratory, Institute for Ophthalmic Research, Centre for Ophthalmology, University Tübingen, Tubingen, Germany
Invest Ophthalmol Vis Sci 49:5015-23. 2008..The present study was a comprehensive screening of the GUCY2D gene in 27 adCD and adCRD unrelated families of these rare disorders...
- ABCA4 gene analysis in patients with autosomal recessive cone and cone rod dystrophiesVeronique B D Kitiratschky
Institute for Ophthalmic Research, Centre for Ophthalmology, University Tübingen, Tubingen, Germany
Eur J Hum Genet 16:812-9. 2008....
- Reduced-illuminance autofluorescence imaging in ABCA4-associated retinal degenerationsArtur V Cideciyan
Scheie Eye Institute, Department of Ophthalmology, University of Pennsylvania, Philadelphia 19104, and Howard Hughes Medical Institute, University of Iowa Hospitals and Clinics, Iowa City 52242, USA
J Opt Soc Am A Opt Image Sci Vis 24:1457-67. 2007....
- Macular pigment and lutein supplementation in ABCA4-associated retinal degenerationsTomas S Aleman
Scheie Eye Institute, Department of Ophthalmology, University of Pennsylvania, Philadelphia, Pennsylvania, USA
Invest Ophthalmol Vis Sci 48:1319-29. 2007..To determine macular pigment (MP) optical density (OD) in patients with ABCA4-associated retinal degenerations (ABCA4-RD) and the response of MP and vision to supplementation with lutein...
- ABCA4-associated retinal degenerations spare structure and function of the human parapapillary retinaArtur V Cideciyan
Scheie Eye Institute, Department of Ophthalmology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
Invest Ophthalmol Vis Sci 46:4739-46. 2005..To study the parapapillary retinal region in patients with ABCA4-associated retinal degenerations...
- Identifying photoreceptors in blind eyes caused by RPE65 mutations: Prerequisite for human gene therapy successSamuel G Jacobson
Department of Ophthalmology, University of Pennsylvania, Philadelphia, PA 19104, USA
Proc Natl Acad Sci U S A 102:6177-82. 2005....
- Nonhuman primate models for diabetic ocular neovascularization using AAV2-mediated overexpression of vascular endothelial growth factorCorinna Lebherz
Department of Medical Genetics, University of Pennsylvania, Philadelphia, Pennsylvania 190104 6069, USA
Diabetes 54:1141-9. 2005..Nonhuman primate models will be useful in testing long-term safety and efficacy of novel therapeutic agents for blinding neovascular diseases...