April 2011
Volume 52, Issue 14
Free
ARVO Annual Meeting Abstract  |   April 2011
AAV-mediated Gene Therapy Restores Cone Function In A Rat With An M-cone Opsin Deficiency, A Model For Blue Cone Monochromacy
Zuoming Zhang; Jijing Pang; Feng Xia; Qun Guo; Li Li; Jing An; Lei Zhang; William W. Hauswirth; Shaowei Yang; Zhenfeng Li
Author Affiliations & Notes
  • Zuoming Zhang
    Clinical Aerospace Medicine, Fourth Military Medical University, Xi'an, China
  • Jijing Pang
    Department of Ophthalmology, University of Florida, Gainesville, Florida
  • Feng Xia
    Clinical Aerospace Medicine, Fourth Military Medical University, Xi'an, China
  • Qun Guo
    Clinical Aerospace Medicine, Fourth Military Medical University, Xi'an, China
  • Li Li
    Clinical Aerospace Medicine, Fourth Military Medical University, Xi'an, China
  • Jing An
    Clinical Aerospace Medicine, Fourth Military Medical University, Xi'an, China
  • Lei Zhang
    Clinical Aerospace Medicine, Fourth Military Medical University, Xi'an, China
  • William W. Hauswirth
    Department of Ophthalmology, University of Florida, Gainesville, Florida
  • Shaowei Yang
    Clinical Aerospace Medicine, Fourth Military Medical University, Xi'an, China
  • Zhenfeng Li
    Clinical Aerospace Medicine, Fourth Military Medical University, Xi'an, China
  • Footnotes
    Commercial Relationships  Zuoming Zhang, None; Jijing Pang, None; Feng Xia, None; Qun Guo, None; Li Li, None; Jing An, None; Lei Zhang, None; William W. Hauswirth, AGTC (P); Shaowei Yang, None; Zhenfeng Li, None
  • Footnotes
    Support  NSFC grant 30872838,30571999 and 30371517, EY018331, EY13729, EY11123, NS36302, EY08571EY007758, FFB, MVRF, RPB, Inc.
Investigative Ophthalmology & Visual Science April 2011, Vol.52, 1403. doi:
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      Zuoming Zhang, Jijing Pang, Feng Xia, Qun Guo, Li Li, Jing An, Lei Zhang, William W. Hauswirth, Shaowei Yang, Zhenfeng Li; AAV-mediated Gene Therapy Restores Cone Function In A Rat With An M-cone Opsin Deficiency, A Model For Blue Cone Monochromacy. Invest. Ophthalmol. Vis. Sci. 2011;52(14):1403.

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Abstract

Purpose: : Using an AAV vector targeting human L-cone opsin or rat M-cone opsin expression to cones, we aimed to test gene therapy in a naturally occurring m-cone opsin mutant rat model.

Methods: : Abnormal cone response phenotype male Sprague-Dawley (SD) rats (outbreed strain) were analyzed to identify the inherited trait and the causative mutation. To develop a gene therapy, two AAV vectors were constructed. The first was a serotype 5 AAV with the human red opsin promoter (PR2.1) driving expression of a human L-opsin cDNA (hROps). The second was a serotype 8 AAV containing a Y-F mutation at capsid position 733 (AAV8-733) with the same promoter driving a rat M-opsin cDNA. One microliter of each vector containing 1010 vector genomes was subretinally injected into one eye of a cohort of 30 mutant rats, respectively at postnatal day 14 (P14). At 2 months post-treatment the therapeutic effect of vector expression of the two opsin cDNAs was tested by full field photopic and flicker ERG analyses.

Results: : The rat with abnormal cone function has an X-linked recessive trait and the causative mutation is in the Opn1mw gene. There was no cone response or flicker ERG under standard intensity flashes in untreated rats, a phenotype that was stably maintained for 16 generations over 7 years. Histologically, there was no obvious change in retinal thickness, structure or the number of M-cones. After subretinal injection of the AAV5 vector expressing the human L-opsin in rat cones, there was no obviously change in cone single flash or flicker ERG at 2 months post-treatment. In contrast, the AAV8 (733) vector encoding the rat M-opsin yielded robust cone function rescue.

Conclusions: : Since there is no L-cone opsin in the rat, this rat strain lacking M-cone function can be considered a model for combined L and M cone function loss in humans, a condition termed Blue Cone Monochromacy. Replacement gene therapy using a subretinally delivered AAV vector restores cone function in this model when using the homologous rat M-opsin cDNA but not when using the human L-opsin cDNA perhaps due to incompatibility of the human opsin with one or more components of the rat phototransduction complex.

Keywords: color vision • gene transfer/gene therapy • retinal degenerations: hereditary 
© 2011, The Association for Research in Vision and Ophthalmology, Inc., all rights reserved. Permission to republish any abstract or part of an abstract in any form must be obtained in writing from the ARVO Office prior to publication.
Copyright © 2025 Association for Research in Vision and Ophthalmology.
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