title: Transient photoreceptor deconstruction by CNTF enhances rAAV-mediated cone functional rescue in late stage CNGB3-achromatopsia.
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.
authors.affiliation: Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA. komaromy@cvm.msu.edu
authors.forename: András M
authors.initials: AM
authors.lastname: Komáromy
authors.forename: Jessica S
authors.initials: JS
authors.lastname: Rowlan
authors.forename: Amanda T Parton
authors.initials: AT
authors.lastname: Corr
authors.forename: Shelby L
authors.initials: SL
authors.lastname: Reinstein
authors.forename: Sanford L
authors.initials: SL
authors.lastname: Boye
authors.forename: Ann E
authors.initials: AE
authors.lastname: Cooper
authors.forename: Amaliris
authors.initials: A
authors.lastname: Gonzalez
authors.forename: Britt
authors.initials: B
authors.lastname: Levy
authors.forename: Rong
authors.initials: R
authors.lastname: Wen
authors.forename: William W
authors.initials: WW
authors.lastname: Hauswirth
authors.forename: William A
authors.initials: WA
authors.lastname: Beltran
authors.forename: Gustavo D
authors.initials: GD
authors.lastname: Aguirre
mesh_terms: D000818:Animals; D002874:Chromosome Mapping; D020934:Ciliary Neurotrophic Factor / Q000235:genetics / Q000378:metabolism*; D003117:Color Vision Defects / Q000235:genetics / Q000503:physiopathology / Q000628:therapy*; D054815:Cyclic Nucleotide-Gated Cation Channels / Q000235:genetics / Q000378:metabolism*; D000229:Dependovirus / Q000235:genetics; D004285:Dogs; D005260:Female; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D011994:Recombinant Proteins; D012160:Retina / Q000378:metabolism / Q000503:physiopathology; D017949:Retinal Cone Photoreceptor Cells / Q000166:cytology* / Q000378:metabolism
chemical_list: D020934:Ciliary Neurotrophic Factor; D054815:Cyclic Nucleotide-Gated Cation Channels; D011994:Recombinant Proteins