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Mol Ther. 2017 Apr 5;25(4):904-916. doi: 10.1016/j.ymthe.2017.02.006. Epub 2017 Feb 22.

Gene Therapeutic Reversal of Peripheral Olfactory Impairment in Bardet-Biedl Syndrome.

Author information

1
Department of Pharmacology and Therapeutics, University of Florida College of Medicine, Gainesville, FL 32610, USA; Center for Smell and Taste, University of Florida College of Medicine, Gainesville, FL 32610, USA.
2
Department of Pediatrics, University of Iowa, Iowa City, IA 52242, USA.
3
Department of Pediatrics, University of Iowa, Iowa City, IA 52242, USA; Howard Hughes Medical Institute, University of Iowa, Iowa City, IA 52242, USA.
4
Department of Pharmacology and Therapeutics, University of Florida College of Medicine, Gainesville, FL 32610, USA; Center for Smell and Taste, University of Florida College of Medicine, Gainesville, FL 32610, USA. Electronic address: martensj@ufl.edu.

Abstract

Olfactory dysfunction is a pervasive but underappreciated health concern that affects personal safety and quality of life. Patients with olfactory dysfunctions have limited therapeutic options, particularly those involving congenital diseases. Bardet-Biedl syndrome (BBS) is one such disorder, where olfactory loss and other symptoms manifest from defective cilium morphology and/or function in various cell types/tissues. Olfactory sensory neurons (OSNs) of BBS mutant mice lack the capacity to build/maintain cilia, rendering the cells incapable of odor detection. Here we examined OSN cilium defects in Bbs1 mutant mice and assessed the utility of gene therapy to restore ciliation and function in young and adult mice. Bbs1 mutant mice possessed short residual OSN cilia in which BBSome protein trafficking and odorant detection were defective. Gene therapy with an adenovirus-delivered wild-type Bbs1 gene restored OSN ciliation, corrected BBSome cilium trafficking defects, and returned acute odor responses. Finally, using clinically approved AAV serotypes, we demonstrate, for the first time, the capacity of AAVs to restore ciliation and odor detection in OSNs of Bbs1 mutants. Together, our data demonstrate that OSN ciliogenesis can be promoted in differentiated cells of young and adult Bbs1 mutants and highlight the potential of gene therapy as a viable restorative treatment for congenital olfactory disorders.

KEYWORDS:

BBS1; Bardet-Biedl syndrome; cilia; gene therapy; olfactory; olfactory sensory neuron

PMID:
28237838
PMCID:
PMC5383630
DOI:
10.1016/j.ymthe.2017.02.006
[Indexed for MEDLINE]
Free PMC Article

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