July 2019
Volume 60, Issue 9
Free
ARVO Annual Meeting Abstract  |   July 2019
Evaluation of gene therapy via intravitreal injection for disorders associated with loss of expression or function of L/M cone opsin
Author Affiliations & Notes
  • adam crain
    University of Washington, Seattle, Washington, United States
  • James A Kuchenbecker
    University of Washington, Seattle, Washington, United States
  • Jessica S Rowlan
    University of Washington, Seattle, Washington, United States
  • Jennifer R Chao
    University of Washington, Seattle, Washington, United States
  • Jay Neitz
    University of Washington, Seattle, Washington, United States
  • Maureen Neitz
    University of Washington, Seattle, Washington, United States
  • Footnotes
    Commercial Relationships   adam crain, None; James Kuchenbecker, None; Jessica Rowlan, None; Jennifer Chao, None; Jay Neitz, University of Washington (P); Maureen Neitz, University of Washington (P)
  • Footnotes
    Support  Research to Prevent Blindness, NIH R01EY0016861, P30EY001730
Investigative Ophthalmology & Visual Science July 2019, Vol.60, 1309. doi:
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      adam crain, James A Kuchenbecker, Jessica S Rowlan, Jennifer R Chao, Jay Neitz, Maureen Neitz; Evaluation of gene therapy via intravitreal injection for disorders associated with loss of expression or function of L/M cone opsin. Invest. Ophthalmol. Vis. Sci. 2019;60(9):1309.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : A variety of clinical entities that have significant vision loss as a symptom, including blue cone monochromacy, X-linked cone dysfunction syndrome and forms of X-linked cone dystrophy are all due to mutations that affect the expression or function of the L and M cone photopigment genes. At present, there are no therapies for these disorders; however, results from adaptive optics imaging suggest that some of them are associated with viable but non-functional cones which may be amenable to therapy involving viral mediated transfer of functional opsin genes. Our goal is to test the effectiveness of a new construct developed for gene therapy for eye disorders administered via intravitreal injection.

Methods : We injected 7m8-AAV carrying a L-opsin-GFP fusion gene under the control of a newly engineered, cone specific expression cassette into the vitreous of mice and red-green colorblind monkeys and monitored expression by retinal imaging. 3 microliters (uL) of a solution containing ~5 X 10^11 viral genomes were injected into the vitreous of the mouse eye. 30 uL containing ~ 3 x 10^12 viral genomes was injected into the vitreous of a colorblind monkey. GFP fluorescence in the living animal eye was detected at 2 weeks after the injection in mice, and robust GFP fluorescence was observed 3 months after the injection in the monkey.

Results : The treatment produced expression of the human L-opsin transgene in cone photoreceptors of mice and red-green colorblind squirrel monkeys. The monkeys lack the L-opsin normally expressed in the L-cones required for normal trichromatic color vision. Because expression was from an L-opsin-GFP fusion, it was possible to demonstrate that a single intravitreal injection results in robust expression of L-opsin in L/M cones in the macular region. The treatment did not transduce any other cell types in the retina.

Conclusions : We verified that the vector targets macular cones in a nonhuman primate. The results represent successful gene therapy treatment of a naturally occurring primate retinal disease model that displays some of the important characteristics of human blue cone monochromacy. Features in common include that both are stationary disorders, present from birth, caused by mutations in OPN1MW/LW genes and that the cones remain viable in both disorders making them a good target for the gene replacement therapy described here.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.

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