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W. Deng, J. J. Alexander, S. H. Min, Q. Li, J. Pang, J. Li, B. Chang, J. Lem, W. W. Hauswirth; Rod Specific -Transducin Rescues Cone Function in a Mouse Model of Achromatopsia. Invest. Ophthalmol. Vis. Sci. 2007;48(13):4645.
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The cone photoreceptor function loss 3 (Gnat2cpfl3) mouse carries a missense mutation in the Gnat2 gene, which encodes the cone specific α-transducin. The Gnat2cpfl3 mouse has an undetectable cone electroretinogram (ERG) and a normal rod ERG, and is therefore a model for complete achromatopsia in humans. Gene therapy in Gnat2cpfl3 mice by rAAV mediated expression of GNAT2 in cones previously demonstrated rescue of the cone ERG and cone-mediated contrast sensitivity. Here we investigate whether cone function in Gnat2cpfl3 mice can also be restored by cone-targeted delivery of the rod-specific α-transducin GNAT1 using an AAV5 viral vector.
A murine GNAT1 cDNA was cloned into an AAV vector backbone under the control of a human red cone opsin promoter (pTR-PR2.1-GNAT1) and packaged into serotype 5 capsids. 1ul of pTR-PR2.1-GNAT1 virus (5X1013 particles/ml) was injected subretinally into the right eyes of seven Gnat2cpfl3 mice at postnatal day 23. ERG analysis was performed two months after injection.
Five of seven GNAT1 treated eyes responded to the therapy. Two eyes were corrected to within the normal range cone ERG amplitudes, while three eyes were restored to half normal. This therapeutic variation is presumably caused by injection differences.
These results demonstrate that rAAV-mediated cone targeted expression of the rod-specific GNAT1 can restore cone ERG function in Gnat2cpfl mouse. We are now investigating whether rAAV-mediated delivery of the cone specific GNAT2 into rods is able to restore rod ERGs in the Gnat1-/- knockout mouse.
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