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Gene therapy rescues olfactory perception in a clinically relevant ciliopathy model of Bardet–Biedl syndrome
Author(s) -
Xie Chao,
Habif Julien C.,
Uytingco Cedric R.,
Ukhanov Kirill,
Zhang Lian,
Celis Carlos,
Sheffield Val C.,
Martens Jeffrey R.
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.202100627r
Subject(s) - ciliopathy , cilium , penetrance , ciliopathies , olfactory bulb , sniffing , odor , biology , mutation , olfactory system , olfactory epithelium , bardet–biedl syndrome , genetics , neuroscience , medicine , gene , phenotype , central nervous system
Bardet–Biedl syndrome (BBS) is a hereditary genetic disorder that results in numerous clinical manifestations including olfactory dysfunction. Of at least 21 BBS‐related genes that can carry multiple mutations, a pathogenic mutation, BBS1 M390R, is the single most common mutation of clinically diagnosed BBS outcomes. While the deletion of BBS‐related genes in mice can cause variable penetrance in different organ systems, the impact of the Bbs1 M390R mutation in the olfactory system remains unclear. Using a clinically relevant knock‐in mouse model homozygous for Bbs1 M390R, we investigated the impact of the mutation on the olfactory system and tested the potential of viral‐mediated, wildtype gene replacement therapy to rescue smell loss. The cilia of olfactory sensory neurons (OSNs) in Bbs1 M390R/M390R mice were significantly shorter and fewer than those of wild‐type mice. Also, both peripheral cellular odor detection and synaptic‐dependent activity in the olfactory bulb were significantly decreased in the mutant mice. Furthermore, to gain insight into the degree to which perceptual features are impaired in the mutant mice, we used whole‐body plethysmography to quantitatively measure odor‐evoked sniffing. The Bbs1 M390R/M390R mice showed significantly higher odor detection thresholds (reduced odor sensitivity) compared to wild‐type mice; however, their odor discrimination acuity was still well maintained. Importantly, adenoviral expression of Bbs1 in OSNs restored cilia length and re‐established both peripheral odorant detection and odor perception. Together, our findings further expand our understanding for the development of gene therapeutic treatment for congenital ciliopathies in the olfactory system.