Abstract
The absence of cyclic nucleotide-gated (CNG) channels in cone photoreceptor outer segments leads to achromatopsia, a severely disabling disease associated with the complete lack of cone photoreceptor function. In a common form, loss of the CNGA3 subunit disrupts visual transduction in cones and causes progressive degeneration. Here, we show that adeno-associated viral vector-mediated gene replacement therapy added the lacking sensual quality, cone-mediated vision, in the CNGA3−/− mouse model of the human disease. The functional rescue of cone vision was assessed at different sites along the visual pathway. In particular, we show electrophysiologically that treated CNGA3−/− mice became able to generate cone-mediated responses and to transfer these signals to bipolar and finally ganglion cells. In support, we found morphologically that expression of CNGA3 delayed cone cell death. Finally, we show in a behavioral test that treated mice acquired photopic vision suggesting that achromatopsia patients may as well benefit from gene replacement therapy.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Akimoto M, Filippova E, Gage PJ et al (2004) Transgenic mice expressing Cre-recombinase specifically in M- or S-cone photoreceptors. Invest Ophthalmol Vis Sci 45:42–47
Auricchio A, Hildinger M, O’Connor E et al (2001) Isolation of highly infectious and pure adeno-associated virus type 2 vectors with a single-step gravity-flow column. Hum Gene Ther 12:71–76
Biel M, Seeliger M, Pfeifer A et al (1999) Selective loss of cone function in mice lacking the cyclic nucleotide-gated channel CNG3. Proc Natl Acad Sci U S A 96:7553–7557
Fischer MD, Huber G, Beck SC et al (2009) Noninvasive, in vivo assessment of mouse retinal structure using optical coherence tomography. PLoS One 4:e7507
Grieger JC, Choi VW, Samulski RJ (2006) Production and characterization of adeno-associated viral vectors. Nat Protoc 1:1412–1428
Kohl S, Marx T, Giddings I et al (1998) Total colourblindness is caused by mutations in the gene encoding the alpha-subunit of the cone photoreceptor cGMP-gated cation channel. Nat Genet 19:257–259
Kohl S, Varsanyi B, Antunes GA et al (2005) CNGB3 mutations account for 50% of all cases with autosomal recessive achromatopsia. Eur J Hum Genet 13:302–308
Michalakis S, Geiger H, Haverkamp S et al (2005) Impaired opsin targeting and cone photoreceptor migration in the retina of mice lacking the cyclic nucleotide-gated channel CNGA3. Invest Ophthalmol Vis Sci 46:1516–1524
Petrs-Silva H, Dinculescu A, Li Q et al (2009) High-efficiency transduction of the mouse retina by tyrosine-mutant AAV serotype vectors. Mol Ther 17:463–471
Seeliger MW, Grimm C, Stahlberg F et al (2001) New views on RPE65 deficiency: the rod system is the source of vision in a mouse model of Leber congenital amaurosis. Nat Genet 29:70–74
Seeliger MW, Beck SC, Pereyra-Munoz N et al (2005) In vivo confocal imaging of the retina in animal models using scanning laser ophthalmoscopy. Vis Res 45:3512–3519
Tanimoto N, Muehlfriedel RL, Fischer MD et al (2009) Vision tests in the mouse: Functional phenotyping with electroretinography. Front Biosci 14:2730–2737
Acknowledgments
We thank Peter Humphries (Trinity College Dublin) for providing Rho−/− mice, James M. Wilson (Univ Pennsylvania) and Alberto Auricchio (TIGEM) for the gift of AAV plasmids. This work was supported by the Deutsche Forschungsgemeinschaft (Se837/6-1, Se837/7-1, and Bi484/4-1), the German Ministry of Education and Research (BMBF 0314106), the European Union (EU HEALTH-F2-2008-200234), and the Max Planck Society.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2012 Springer Science+Business Media, LLC
About this paper
Cite this paper
Michalakis, S. et al. (2012). Gene Therapy Restores Missing Cone-Mediated Vision in the CNGA3−/− Mouse Model of Achromatopsia. In: LaVail, M., Ash, J., Anderson, R., Hollyfield, J., Grimm, C. (eds) Retinal Degenerative Diseases. Advances in Experimental Medicine and Biology, vol 723. Springer, Boston, MA. https://doi.org/10.1007/978-1-4614-0631-0_25
Download citation
DOI: https://doi.org/10.1007/978-1-4614-0631-0_25
Published:
Publisher Name: Springer, Boston, MA
Print ISBN: 978-1-4614-0630-3
Online ISBN: 978-1-4614-0631-0
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)