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

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.

Pubmed ID: 22941275

Authors

  • McIntyre JC
  • Davis EE
  • Joiner A
  • Williams CL
  • Tsai IC
  • Jenkins PM
  • McEwen DP
  • Zhang L
  • Escobado J
  • Thomas S
  • Szymanska K
  • Johnson CA
  • Beales PL
  • Green ED
  • Mullikin JC
  • NISC Comparative Sequencing Program
  • Sabo A
  • Muzny DM
  • Gibbs RA
  • AttiĆ©-Bitach T
  • Yoder BK
  • Reed RR
  • Katsanis N
  • Martens JR

Journal

Nature medicine

Publication Data

September 5, 2012

Associated Grants

  • Agency: NIDDK NIH HHS, Id: DK074083
  • Agency: NIDCD NIH HHS, Id: F32 DC011990
  • Agency: NIDDK NIH HHS, Id: F32 DK094578
  • Agency: NIDCD NIH HHS, Id: F32DC011990
  • Agency: Medical Research Council, Id: G0700073
  • Agency: NIDDK NIH HHS, Id: P30 DK074038
  • Agency: NIDDK NIH HHS, Id: R01 DK072301
  • Agency: NIDDK NIH HHS, Id: R01 DK075972
  • Agency: NIDDK NIH HHS, Id: R01 DK075996
  • Agency: NEI NIH HHS, Id: R01 EY021872
  • Agency: NICHD NIH HHS, Id: R01 HD042601
  • Agency: NIDCD NIH HHS, Id: R01DC004553
  • Agency: NIDCD NIH HHS, Id: R01DC008295
  • Agency: NIDCD NIH HHS, Id: R01DC009606
  • Agency: NIDDK NIH HHS, Id: R01DK072301
  • Agency: NIDDK NIH HHS, Id: R01DK075972
  • Agency: NIDDK NIH HHS, Id: R01DK75996
  • Agency: NEI NIH HHS, Id: R01EY021872
  • Agency: NICHD NIH HHS, Id: R01HD04260
  • Agency: NHGRI NIH HHS, Id: U54 HG003273

Mesh Terms

  • Adenoviridae
  • 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