Gene therapy restores vision in rd1 mice after removal of a confounding mutation in Gpr179

Koji M. Nishiguchi, Livia S. Carvalho, Matteo Rizzi, Kate Powell, Sophia-Martha kleine Holthaus, Selina A. Azam, Yanai Duran, Joana Ribeiro, Ulrich F. O. Luhmann, James W. B. Bainbridge, Alexander J. Smith and Robin R. Ali ()
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Koji M. Nishiguchi: UCL Institute of Ophthalmology
Livia S. Carvalho: UCL Institute of Ophthalmology
Matteo Rizzi: UCL Institute of Ophthalmology
Kate Powell: UCL Institute of Ophthalmology
Sophia-Martha kleine Holthaus: UCL Institute of Ophthalmology
Selina A. Azam: UCL Institute of Ophthalmology
Yanai Duran: UCL Institute of Ophthalmology
Joana Ribeiro: UCL Institute of Ophthalmology
Ulrich F. O. Luhmann: UCL Institute of Ophthalmology
James W. B. Bainbridge: UCL Institute of Ophthalmology
Alexander J. Smith: UCL Institute of Ophthalmology
Robin R. Ali: UCL Institute of Ophthalmology

Nature Communications, 2015, vol. 6, issue 1, 1-10

Abstract: Abstract The rd1 mouse with a mutation in the Pde6b gene was the first strain of mice identified with a retinal degeneration. However, AAV-mediated gene supplementation of rd1 mice only results in structural preservation of photoreceptors, and restoration of the photoreceptor-mediated a-wave, but not in restoration of the bipolar cell-mediated b-wave. Here we show that a mutation in Gpr179 prevents the full restoration of vision in rd1 mice. Backcrossing rd1 with C57BL6 mice reveals the complete lack of b-wave in a subset of mice, consistent with an autosomal recessive Mendelian inheritance pattern. We identify a mutation in the Gpr179 gene, which encodes for a G-protein coupled receptor localized to the dendrites of ON-bipolar cells. Gene replacement in rd1 mice that are devoid of the mutation in Gpr179 successfully restores the function of both photoreceptors and bipolar cells, which is maintained for up to 13 months. Our discovery may explain the failure of previous gene therapy attempts in rd1 mice, and we propose that Grp179 mutation status should be taken into account in future studies involving rd1 mice.

Date: 2015
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DOI: 10.1038/ncomms7006

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