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

TitleGene therapy rescues cilia defects and restores olfactory function in a mammalian ciliopathy model.
Publication TypeJournal Article
Year of Publication2012
AuthorsMcIntyre, JC, Davis, EE, Joiner, A, Williams, CL, Tsai, I-C, Jenkins, PM, McEwen, DP, Zhang, L, Escobado, J, Thomas, S, Szymanska, K, Johnson, CA, Beales, PL, Green, ED, Mullikin, JC, Sabo, A, Muzny, DM, Gibbs, RA, Attié-Bitach, T, Yoder, BK, Reed, RR, Katsanis, N, Martens, JR
Corporate Authors
JournalNat Med
Volume18
Issue9
Pagination1423-8
Date Published2012 Sep
ISSN1546-170X
KeywordsAdenoviridae, Animals, Cilia, Genetic Complementation Test, Genetic Diseases, Inborn, Genetic Therapy, Genetic Vectors, Humans, Mice, Microscopy, Fluorescence, Mutation, Olfactory Receptor Neurons, Smell, Tubulin, Tumor Suppressor Proteins, Zebrafish
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.

DOI10.1038/nm.2860
Alternate JournalNat. Med.
PubMed ID22941275
PubMed Central IDPMC3645984
Grant ListDK074083 / DK / NIDDK NIH HHS / United States
F32 DC011990 / DC / NIDCD NIH HHS / United States
F32 DK094578 / DK / NIDDK NIH HHS / United States
F32DC011990 / DC / NIDCD NIH HHS / United States
G0700073 / / Medical Research Council / United Kingdom
P30 DK074038 / DK / NIDDK NIH HHS / United States
R01 DK072301 / DK / NIDDK NIH HHS / United States
R01 DK075972 / DK / NIDDK NIH HHS / United States
R01 DK075996 / DK / NIDDK NIH HHS / United States
R01 EY021872 / EY / NEI NIH HHS / United States
R01 HD042601 / HD / NICHD NIH HHS / United States
R01DC004553 / DC / NIDCD NIH HHS / United States
R01DC008295 / DC / NIDCD NIH HHS / United States
R01DC009606 / DC / NIDCD NIH HHS / United States
R01DK072301 / DK / NIDDK NIH HHS / United States
R01DK075972 / DK / NIDDK NIH HHS / United States
R01DK75996 / DK / NIDDK NIH HHS / United States
R01EY021872 / EY / NEI NIH HHS / United States
R01HD04260 / HD / NICHD NIH HHS / United States
U54 HG003273 / HG / NHGRI NIH HHS / United States