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Longitudinal evaluation of expression of virally delivered transgenes in gerbil cone photoreceptors

Published online by Cambridge University Press:  03 July 2008

MATTHEW C. MAUCK ,
KATHERINE MANCUSO ,
JAMES A. KUCHENBECKER ,
THOMAS B. CONNOR ,
WILLIAM W. HAUSWIRTH ,
JAY NEITZ  and
MAUREEN NEITZ
MATTHEW C. MAUCK*
Affiliation:
Departments of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin
KATHERINE MANCUSO
Affiliation:
Department of Ophthalmology, Medical College of Wisconsin, Milwaukee, Wisconsin
JAMES A. KUCHENBECKER
Affiliation:
Department of Ophthalmology, Medical College of Wisconsin, Milwaukee, Wisconsin
THOMAS B. CONNOR
Affiliation:
Department of Ophthalmology, Medical College of Wisconsin, Milwaukee, Wisconsin
WILLIAM W. HAUSWIRTH
Affiliation:
Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, Florida
JAY NEITZ
Affiliation:
Department of Ophthalmology, Medical College of Wisconsin, Milwaukee, Wisconsin
MAUREEN NEITZ
Affiliation:
Department of Ophthalmology, Medical College of Wisconsin, Milwaukee, Wisconsin
*
Address correspondence and reprint requests to: Matthew C. Mauck, Departments of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226. E-mail: mmauck@mcw.edu
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Abstract

Delivery of foreign opsin genes to cone photoreceptors using recombinant adeno-associated virus (rAAV) is a potential tool for studying the basic mechanisms underlying cone based vision and for treating vision disorders. We used an in vivo retinal imaging system to monitor, over time, expression of virally-delivered genes targeted to cone photoreceptors in the Mongolian gerbil (Meriones unguiculatus). Gerbils have a well-developed photopic visual system, with 11–14% of their photoreceptors being cones. We used replication deficient serotype 5 rAAV to deliver a gene for green fluorescent protein (GFP). In an effort to direct expression of the gene specifically to either S or M cones, the transgene was under the control of either the human X-chromosome opsin gene regulatory elements, i.e., an enhancer termed the locus control region (LCR) and L promoter, or the human S-opsin promoter. Longitudinal fluorescence images reveal that gene expression is first detectable about 14 days post-injection, reaches a peak after about 3 months, and is observed more than a year post-injection if the initial viral concentration is sufficiently high. The regulatory elements are able to direct expression to a subpopulation of cones while excluding expression in rods and non-photoreceptor retinal cells. When the same viral constructs are used to deliver a human long-wavelength opsin gene to gerbil cones, stimulation of the introduced human photopigment with long-wavelength light produces robust cone responses.

Keywords

Cone photoreceptorColor visionGene therapyrAAVL-opsin
Type
Research Article
Information
Visual Neuroscience , Volume 25 , Issue 3 , May 2008 , pp. 273 - 282
Copyright
Copyright © Cambridge University Press 2008

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