title: Restoration of cone vision in the CNGA3-/- mouse model of congenital complete lack of cone photoreceptor function.
abstract: Congenital absence of cone photoreceptor function is associated with strongly impaired daylight vision and loss of color discrimination in human achromatopsia. Here, we introduce viral gene replacement therapy as a potential treatment for this disease in the CNGA3(-/-) mouse model. We show that such therapy can restore cone-specific visual processing in the central nervous system even if cone photoreceptors had been nonfunctional from birth. The restoration of cone vision was assessed at different stages along the visual pathway. Treated CNGA3(-/-) mice were able to generate cone photoreceptor responses and to transfer these signals to bipolar cells. In support, we found morphologically that treated cones expressed regular cyclic nucleotide-gated (CNG) channel complexes and opsins in outer segments, which previously they did not. Moreover, expression of CNGA3 normalized cyclic guanosine monophosphate (cGMP) levels in cones, delayed cone cell death and reduced the inflammatory response of Müller glia cells that is typical of retinal degenerations. Furthermore, ganglion cells from treated, but not from untreated, CNGA3(-/-) mice displayed cone-driven, light-evoked, spiking activity, indicating that signals generated in the outer retina are transmitted to the brain. Finally, we demonstrate that this newly acquired sensory information was translated into cone-mediated, vision-guided behavior.
authors.affiliation: Center for Integrated Protein Science Munich (CIPSM), Department of Pharmacy-Center for Drug Research, Ludwig-Maximilians-Universität München, Munich, Germany.
authors.forename: Stylianos
authors.initials: S
authors.lastname: Michalakis
authors.forename: Regine
authors.initials: R
authors.lastname: Mühlfriedel
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Tanimoto
authors.forename: Vidhyasankar
authors.initials: V
authors.lastname: Krishnamoorthy
authors.forename: Susanne
authors.initials: S
authors.lastname: Koch
authors.forename: M Dominik
authors.initials: MD
authors.lastname: Fischer
authors.forename: Elvir
authors.initials: E
authors.lastname: Becirovic
authors.forename: Lin
authors.initials: L
authors.lastname: Bai
authors.forename: Gesine
authors.initials: G
authors.lastname: Huber
authors.forename: Susanne C
authors.initials: SC
authors.lastname: Beck
authors.forename: Edda
authors.initials: E
authors.lastname: Fahl
authors.forename: Hildegard
authors.initials: H
authors.lastname: Büning
authors.forename: François
authors.initials: F
authors.lastname: Paquet-Durand
authors.forename: Xiangang
authors.initials: X
authors.lastname: Zong
authors.forename: Tim
authors.initials: T
authors.lastname: Gollisch
authors.forename: Martin
authors.initials: M
authors.lastname: Biel
authors.forename: Mathias W
authors.initials: MW
authors.lastname: Seeliger
mesh_terms: D000818:Animals; D003001:Cloning, Molecular; D000013:Congenital Abnormalities / Q000235:genetics / Q000628:therapy*; D054815:Cyclic Nucleotide-Gated Cation Channels / Q000235:genetics*; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D017949:Retinal Cone Photoreceptor Cells / Q000378:metabolism*; D014785:Vision, Ocular / Q000235:genetics
chemical_list: D054815:Cyclic Nucleotide-Gated Cation Channels