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Gene Therapy Restores Missing Cone-Mediated Vision in the CNGA3−/− Mouse Model of Achromatopsia

  • Stylianos Michalakis
  • Regine Mühlfriedel
  • Naoyuki Tanimoto
  • Vidhyasankar Krishnamoorthy
  • Susanne Koch
  • M. Dominik Fischer
  • Elvir Becirovic
  • Lin Bai
  • Gesine Huber
  • Susanne C. Beck
  • Edda Fahl
  • Hildegard Büning
  • Jennifer Schmidt
  • Xiangang Zong
  • Tim Gollisch
  • Martin Biel
  • Mathias W. SeeligerEmail author
Conference paper
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 723)

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.

Keywords

CNGA3 Cyclic nucleotide-gated channel Achromatopsia ACHM2 Gene therapy rAAV Adeno-associated virus Gene replacement Rod monochromacy Cone phoroteceptor 

Notes

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.

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Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Stylianos Michalakis
    • 1
  • Regine Mühlfriedel
    • 2
  • Naoyuki Tanimoto
    • 2
  • Vidhyasankar Krishnamoorthy
    • 3
  • Susanne Koch
    • 1
  • M. Dominik Fischer
    • 2
  • Elvir Becirovic
    • 1
  • Lin Bai
    • 1
  • Gesine Huber
    • 2
  • Susanne C. Beck
    • 2
  • Edda Fahl
    • 2
  • Hildegard Büning
    • 4
  • Jennifer Schmidt
    • 1
  • Xiangang Zong
    • 1
  • Tim Gollisch
    • 3
  • Martin Biel
    • 1
  • Mathias W. Seeliger
    • 2
    Email author
  1. 1.Department of PharmacyCenter for Integrated Protein Science Munich (CIPSM), Center for Drug Research, Ludwig-Maximilians-Universität MünchenMunichGermany
  2. 2.Division of Ocular NeurodegenerationCentre for Ophthalmology, Institute for Ophthalmic Research, Eberhard Karls-UniversitätTübingenGermany
  3. 3.Visual Coding GroupMax Planck Institute of NeurobiologyMartinsriedGermany
  4. 4.Department I of Internal Medicine and Center for Molecular Medicine CologneUniversity of CologneCologneGermany

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