Transient photoreceptor deconstruction by CNTF enhances rAAV-Mediated cone functional rescue in late stage CNGB3-achromatopsia

András M. Komáromy, Jessica S. Rowlan, Amanda T.Parton Corr, Shelby L. Reinstein, Sanford L. Boye, Ann E. Cooper, Amaliris Gonzalez, Britt Levy, Rong Wen, William W. Hauswirth, William A. Beltran, Gustavo D. Aguirre

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42 Scopus citations

Abstract

Achromatopsia is a genetic disorder of cones, and one of the most common forms is a channelopathy caused by mutations in the β-subunit, CNGB3, of the cone cyclic nucleotide-gated (CNG) channel. Recombinant adeno-associated virus of serotype 5 (rAAV5)-mediated gene transfer of human CNGB3 cDNA to mutant dog cones results in functional and structural rescue in dogs <0.5 years of age, but treatment is minimally effective in dogs >1 year. We now test a new therapeutic concept by combining gene therapy with the administration of ciliary neurotrophic factor (CNTF). Intravitreal CNTF causes transient dedifferentiation of photoreceptors, a process called deconstruction, whereby visual cells become immature with short outer segments, and decreased retinal function and gene expression that subsequently return to normal. Cone function was successfully rescued in all mutant dogs treated between 14 and 42 months of age with this strategy. CNTF-mediated deconstruction and regeneration of the photoreceptor outer segments prepares the mutant cones optimally for gene augmentation therapy.

Original languageEnglish (US)
Pages (from-to)1131-1141
Number of pages11
JournalMolecular Therapy
Volume21
Issue number6
DOIs
StatePublished - Jun 2013

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ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

Cite this

Komáromy, A. M., Rowlan, J. S., Corr, A. T. P., Reinstein, S. L., Boye, S. L., Cooper, A. E., Gonzalez, A., Levy, B., Wen, R., Hauswirth, W. W., Beltran, W. A., & Aguirre, G. D. (2013). Transient photoreceptor deconstruction by CNTF enhances rAAV-Mediated cone functional rescue in late stage CNGB3-achromatopsia. Molecular Therapy, 21(6), 1131-1141. https://doi.org/10.1038/mt.2013.50