title: Gene therapy rescues cilia defects and restores olfactory function in a mammalian ciliopathy model.
abstract: Cilia are evolutionarily conserved microtubule-based organelles that are crucial for diverse biological functions, including motility, cell signaling and sensory perception. In humans, alterations in the formation and function of cilia manifest clinically as ciliopathies, a growing class of pleiotropic genetic disorders. Despite the substantial progress that has been made in identifying genes that cause ciliopathies, therapies for these disorders are not yet available to patients. Although mice with a hypomorphic mutation in the intraflagellar transport protein IFT88 (Ift88Tg737Rpw mice, also known as ORPK mice)5 have been well studied, the relevance of IFT88 mutations to human pathology is unknown. We show that a mutation in IFT88 causes a hitherto unknown human ciliopathy. In vivo complementation assays in zebrafish and mIMCD3 cells show the pathogenicity of this newly discovered allele. We further show that ORPK mice are functionally anosmic as a result of the loss of cilia on their olfactory sensory neurons (OSNs). Notably, adenoviral-mediated expression of IFT88 in mature, fully differentiated OSNs of ORPK mice is sufficient to restore ciliary structures and rescue olfactory function. These studies are the first to use in vivo therapeutic treatment to reestablish cilia in a mammalian ciliopathy. More broadly, our studies indicate that gene therapy is a viable option for cellular and functional rescue of the complex ciliary organelle in established differentiated cells.
authors.affiliation: Department of Pharmacology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Jeremy C
authors.initials: JC
authors.lastname: McIntyre
authors.forename: Erica E
authors.initials: EE
authors.lastname: Davis
authors.forename: Ariell
authors.initials: A
authors.lastname: Joiner
authors.forename: Corey L
authors.initials: CL
authors.lastname: Williams
authors.forename: I-Chun
authors.initials: IC
authors.lastname: Tsai
authors.forename: Paul M
authors.initials: PM
authors.lastname: Jenkins
authors.forename: Dyke P
authors.initials: DP
authors.lastname: McEwen
authors.forename: Lian
authors.initials: L
authors.lastname: Zhang
authors.forename: John
authors.initials: J
authors.lastname: Escobado
authors.forename: Sophie
authors.initials: S
authors.lastname: Thomas
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Szymanska
authors.forename: Colin A
authors.initials: CA
authors.lastname: Johnson
authors.forename: Philip L
authors.initials: PL
authors.lastname: Beales
authors.forename: Eric D
authors.initials: ED
authors.lastname: Green
authors.forename: James C
authors.initials: JC
authors.lastname: Mullikin
authors.forename: Aniko
authors.initials: A
authors.lastname: Sabo
authors.forename: Donna M
authors.initials: DM
authors.lastname: Muzny
authors.forename: Richard A
authors.initials: RA
authors.lastname: Gibbs
authors.forename: Tania
authors.initials: T
authors.lastname: Attié-Bitach
authors.forename: Bradley K
authors.initials: BK
authors.lastname: Yoder
authors.forename: Randall R
authors.initials: RR
authors.lastname: Reed
authors.forename: Nicholas
authors.initials: N
authors.lastname: Katsanis
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Martens
mesh_terms: D000256:Adenoviridae; D000818:Animals; D002923:Cilia / Q000235:genetics* / Q000473:pathology*; D005816:Genetic Complementation Test; D030342:Genetic Diseases, Inborn / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D051379:Mice; D008856:Microscopy, Fluorescence; D009154:Mutation / Q000235:genetics; D018034:Olfactory Receptor Neurons / Q000166:cytology* / Q000378:metabolism; D012903:Smell / Q000235:genetics / Q000502:physiology*; D014404:Tubulin / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D015027:Zebrafish
chemical_list: C098623:IFT88 protein, human; D014404:Tubulin; D025521:Tumor Suppressor Proteins