{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T23:05:09Z","timestamp":1792710309039,"version":"4.5.0"},"reference-count":73,"publisher":"Oxford University Press (OUP)","issue":"15","license":[{"start":{"date-parts":[[2020,7,4]],"date-time":"2020-07-04T00:00:00Z","timestamp":1593820800000},"content-version":"vor","delay-in-days":1,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100004339","name":"Sanofi","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004339","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,8,29]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Bardet\u2013Biedl syndrome (BBS) is a pleiotropic autosomal recessive ciliopathy affecting multiple organs. The development of potential disease-modifying therapy for BBS will require concurrent targeting of multi-systemic manifestations. Here, we show for the first time that monosialodihexosylganglioside accumulates in Bbs2\u2212\/\u2212 cilia, indicating impairment of glycosphingolipid (GSL) metabolism in BBS. Consequently, we tested whether BBS pathology in Bbs2\u2212\/\u2212 mice can be reversed by targeting the underlying ciliary defect via reduction of GSL metabolism. Inhibition of GSL synthesis with the glucosylceramide synthase inhibitor Genz-667161 decreases the obesity, liver disease, retinal degeneration and olfaction defect in Bbs2\u2212\/\u2212 mice. These effects are secondary to preservation of ciliary structure and signaling, and stimulation of cellular differentiation. In conclusion, reduction of GSL metabolism resolves the multi-organ pathology of Bbs2\u2212\/\u2212 mice by directly preserving ciliary structure and function towards a normal phenotype. Since this approach does not rely on the correction of the underlying genetic mutation, it might translate successfully as a treatment for other ciliopathies.<\/jats:p>","DOI":"10.1093\/hmg\/ddaa138","type":"journal-article","created":{"date-parts":[[2020,7,3]],"date-time":"2020-07-03T03:20:27Z","timestamp":1593746427000},"page":"2508-2522","source":"Crossref","is-referenced-by-count":13,"title":["Correction of cilia structure and function alleviates multi-organ pathology in Bardet\u2013Biedl syndrome mice"],"prefix":"10.1093","volume":"29","author":[{"given":"Herv\u00e9","family":"Husson","sequence":"first","affiliation":[{"name":"Rare and Neurologic Diseases Research, Sanofi, Framingham, MA 01701, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikolay O","family":"Bukanov","sequence":"additional","affiliation":[{"name":"Rare and Neurologic Diseases Research, Sanofi, Framingham, MA 01701, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Moreno","sequence":"additional","affiliation":[{"name":"Rare and Neurologic Diseases Research, Sanofi, Framingham, MA 01701, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mandy M","family":"Smith","sequence":"additional","affiliation":[{"name":"Rare and Neurologic Diseases Research, Sanofi, Framingham, MA 01701, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brenda","family":"Richards","sequence":"additional","affiliation":[{"name":"Translational Sciences, Sanofi, Framingham, MA 01701, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheng","family":"Zhu","sequence":"additional","affiliation":[{"name":"Translational Sciences, Sanofi, Framingham, MA 01701, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tyler","family":"Picariello","sequence":"additional","affiliation":[{"name":"Rare and Neurologic Diseases Research, Sanofi, Framingham, MA 01701, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyejung","family":"Park","sequence":"additional","affiliation":[{"name":"Pre-Development Sciences, Sanofi, Waltham, MA 02451, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bing","family":"Wang","sequence":"additional","affiliation":[{"name":"Pre-Development Sciences, Sanofi, Waltham, MA 02451, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas A","family":"Natoli","sequence":"additional","affiliation":[{"name":"Rare and Neurologic Diseases Research, Sanofi, Framingham, MA 01701, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurie A","family":"Smith","sequence":"additional","affiliation":[{"name":"Rare and Neurologic Diseases Research, Sanofi, Framingham, MA 01701, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefano","family":"Zanotti","sequence":"additional","affiliation":[{"name":"Rare and Neurologic Diseases Research, Sanofi, Framingham, MA 01701, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan J","family":"Russo","sequence":"additional","affiliation":[{"name":"Rare and Neurologic Diseases Research, Sanofi, Framingham, MA 01701, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen L","family":"Madden","sequence":"additional","affiliation":[{"name":"Translational Sciences, Sanofi, Framingham, MA 01701, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine W","family":"Klinger","sequence":"additional","affiliation":[{"name":"Translational Sciences, Sanofi, Framingham, MA 01701, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vijay","family":"Modur","sequence":"additional","affiliation":[{"name":"Rare Diseases Development, Sanofi, Cambridge, MA 02142, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oxana","family":"Ibraghimov-Beskrovnaya","sequence":"additional","affiliation":[{"name":"Rare and Neurologic Diseases Research, Sanofi, Framingham, MA 01701, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2020,7,3]]},"reference":[{"key":"2020090402222995700_ref1","doi-asserted-by":"crossref","first-page":"1039","DOI":"10.1007\/s00467-010-1731-7","article-title":"Ciliopathies: an expanding disease spectrum","volume":"26","author":"Waters","year":"2011","journal-title":"Pediatr. 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