Gene therapy rescues cilia defects and restores olfactory function in a mammalian ciliopathy model

Jeremy C. McIntyre, Erica Ellen Davis, Ariell Joiner, Corey L. Williams, I. Chun Tsai, Paul M. Jenkins, Dyke P. McEwen, Lian Zhang, John Escobado, Sophie Thomas, Katarzyna Szymanska, Colin A. Johnson, Philip L. Beales, Eric D. Green, James C. Mullikin, Aniko Sabo, Donna M. Muzny, Richard A. Gibbs, Tania Attié-Bitach, Bradley K. YoderRandall R. Reed, Elias Nicholas Katsanis, Jeffrey R. Martens*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

67 Scopus citations


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 (Ift88 Tg737Rpw mice, also known as ORPK mice) 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.

Original languageEnglish (US)
Pages (from-to)1423-1428
Number of pages6
JournalNature Medicine
Issue number9
StatePublished - Sep 2012

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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