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

• Published in: Molecular therapy 2017-04, Vol.25 (4), p.904-916
• Main Authors: Williams, Corey L., Uytingco, Cedric R., Green, Warren W., McIntyre, Jeremy C., Ukhanov, Kirill, Zimmerman, Arthur D., Shively, Dana T., Zhang, Lian, Nishimura, Darryl Y., Sheffield, Val C., Martens, Jeffrey R.
• Format: Article
• Language: English
• Subjects: Adenoviruses; Alleles; Animals; Bardet-Biedl syndrome; Bardet-Biedl Syndrome - genetics; Bardet-Biedl Syndrome - physiopathology; Bardet-Biedl Syndrome - therapy; BBS1; Biosynthesis; Cilia; Cilia - metabolism; Cilia - pathology; Conflicts of interest; Cytology; Dependovirus - genetics; Disease; Disease Models, Animal; Ectopic Gene Expression; Gene Expression; Gene therapy; Gene Transfer Techniques; Genetic Therapy; Genetic Vectors - administration & dosage; Genetic Vectors - genetics; Humans; Localization; Mammals; Mice; Mice, Knockout; Microtubule-Associated Proteins - genetics; Microtubule-Associated Proteins - metabolism; Mutation; Odor; Olfaction; Olfaction disorders; olfactory; Olfactory Perception - genetics; Olfactory receptor neurons; Olfactory Receptor Neurons - metabolism; olfactory sensory neuron; Original; Phenotype; Protein Transport; Proteins; Quality of life; Recovery of function; Sensory evaluation; Sensory neurons; Serotypes; Transduction, Genetic
• ISSN: 1525-0016; 1525-0024
• DOI: 10.1016/j.ymthe.2017.02.006

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. Olfactory dysfunction is a health concern with limited therapeutic options, particularly in congenital disorders such as Bardet-Biedl syndrome (BBS). In this issue of Molecular Therapy, Williams et al. (2017) demonstrated the utility of gene therapy to restore olfactory function in young and adult mice with BBS.