VISUAL CYCLE IN HUMAN PHOTORECEPTOR AND RPE DISEASE

Summary

Principal Investigator: ARTUR CIDECIYAN
Affiliation: University of Pennsylvania
Country: USA
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

Top Publications

  1. ncbi Nonhuman primate models for diabetic ocular neovascularization using AAV2-mediated overexpression of vascular endothelial growth factor
    Corinna Lebherz
    Department of Medical Genetics, University of Pennsylvania, Philadelphia, Pennsylvania 190104 6069, USA
    Diabetes 54:1141-9. 2005
  2. pmc Retinal pigment epithelium defects in humans and mice with mutations in MYO7A: imaging melanosome-specific autofluorescence
    Daniel Gibbs
    Departments of Pharmacology, UCSD School of Medicine, La Jolla, California, USA
    Invest Ophthalmol Vis Sci 50:4386-93. 2009
  3. pmc ABCA4 disease progression and a proposed strategy for gene therapy
    Artur V Cideciyan
    Scheie Eye Institute, Department of Ophthalmology, University of Pennsylvania, Philadelphia, PA 19104, USA
    Hum Mol Genet 18:931-41. 2009
  4. doi Mutation analysis identifies GUCY2D as the major gene responsible for autosomal dominant progressive cone degeneration
    Veronique 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
  5. pmc ABCA4 gene analysis in patients with autosomal recessive cone and cone rod dystrophies
    Veronique B D Kitiratschky
    Institute for Ophthalmic Research, Centre for Ophthalmology, University Tübingen, Tubingen, Germany
    Eur J Hum Genet 16:812-9. 2008
  6. pmc Reduced-illuminance autofluorescence imaging in ABCA4-associated retinal degenerations
    Artur 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
  7. pmc Macular pigment and lutein supplementation in ABCA4-associated retinal degenerations
    Tomas S Aleman
    Scheie Eye Institute, Department of Ophthalmology, University of Pennsylvania, Philadelphia, Pennsylvania, USA
    Invest Ophthalmol Vis Sci 48:1319-29. 2007
  8. pmc ABCA4-associated retinal degenerations spare structure and function of the human parapapillary retina
    Artur V Cideciyan
    Scheie Eye Institute, Department of Ophthalmology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
    Invest Ophthalmol Vis Sci 46:4739-46. 2005
  9. pmc Identifying photoreceptors in blind eyes caused by RPE65 mutations: Prerequisite for human gene therapy success
    Samuel G Jacobson
    Department of Ophthalmology, University of Pennsylvania, Philadelphia, PA 19104, USA
    Proc Natl Acad Sci U S A 102:6177-82. 2005
  10. pmc Loss of cone photoreceptors caused by chromophore depletion is partially prevented by the artificial chromophore pro-drug, 9-cis-retinyl acetate
    Tadao 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

Scientific Experts

  • ARTUR CIDECIYAN
  • Samuel Jacobson
  • T S Aleman
  • Veronique B D Kitiratschky
  • Daniel Gibbs
  • Tadao Maeda
  • Susanne Kohl
  • Agnes B Renner
  • Bernd Wissinger
  • Ulrich Kellner
  • Eberhart Zrenner
  • Corinna Lebherz
  • David S Williams
  • Marcin Golczak
  • Akiko Maeda
  • Krzysztof Palczewski
  • David G Birch
  • Gunther Rudolph
  • Antje Bernd
  • Maria Vadalà
  • Robert Wilke
  • Herbert Jagle
  • Simone Schaich
  • Tanja Grau
  • Rebecca Grant
  • Jean Bennett
  • Waixing Tang
  • Zhangyong Wei
  • James M Wilson
  • Albert M Maguire
  • Alberto Auricchio

Detail Information

Publications10

  1. ncbi Nonhuman primate models for diabetic ocular neovascularization using AAV2-mediated overexpression of vascular endothelial growth factor
    Corinna 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...
  2. pmc Retinal pigment epithelium defects in humans and mice with mutations in MYO7A: imaging melanosome-specific autofluorescence
    Daniel 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...
  3. pmc ABCA4 disease progression and a proposed strategy for gene therapy
    Artur 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...
  4. doi Mutation analysis identifies GUCY2D as the major gene responsible for autosomal dominant progressive cone degeneration
    Veronique 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...
  5. pmc ABCA4 gene analysis in patients with autosomal recessive cone and cone rod dystrophies
    Veronique B D Kitiratschky
    Institute for Ophthalmic Research, Centre for Ophthalmology, University Tübingen, Tubingen, Germany
    Eur J Hum Genet 16:812-9. 2008
    ....
  6. pmc Reduced-illuminance autofluorescence imaging in ABCA4-associated retinal degenerations
    Artur 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
    ....
  7. pmc Macular pigment and lutein supplementation in ABCA4-associated retinal degenerations
    Tomas 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...
  8. pmc ABCA4-associated retinal degenerations spare structure and function of the human parapapillary retina
    Artur 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...
  9. pmc Identifying photoreceptors in blind eyes caused by RPE65 mutations: Prerequisite for human gene therapy success
    Samuel G Jacobson
    Department of Ophthalmology, University of Pennsylvania, Philadelphia, PA 19104, USA
    Proc Natl Acad Sci U S A 102:6177-82. 2005
    ....
  10. pmc Loss of cone photoreceptors caused by chromophore depletion is partially prevented by the artificial chromophore pro-drug, 9-cis-retinyl acetate
    Tadao 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...