{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,9]],"date-time":"2025-12-09T08:29:04Z","timestamp":1765268944906,"version":"3.41.2"},"reference-count":72,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2024,1,15]],"date-time":"2024-01-15T00:00:00Z","timestamp":1705276800000},"content-version":"vor","delay-in-days":18,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Healx Ltd"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,12,28]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Fragile X syndrome is a neurodevelopmental disorder caused by silencing of the fragile X messenger ribonucleotide gene. Patients display a wide spectrum of symptoms ranging from intellectual and learning disabilities to behavioural challenges including autism spectrum disorder. In addition to this, patients also display a diversity of symptoms due to mosaicism. These factors make fragile X syndrome a difficult syndrome to manage and suggest that a single targeted therapeutic approach cannot address all the symptoms. To this end, we utilized Healx\u2019s data-driven drug discovery platform to identify a treatment strategy to address the wide range of diverse symptoms among patients. Computational methods identified the combination of ibudilast and gaboxadol as a treatment for several pathophysiological targets that could potentially reverse multiple symptoms associated with fragile X syndrome. Ibudilast is an approved broad-spectrum phosphodiesterase inhibitor, selective against both phosphodiesterase 4 and phosphodiesterase 10, and has demonstrated to have several beneficial effects in the brain. Gaboxadol is a GABAA receptor agonist, selective against the delta subunit, which has previously displayed encouraging results in a fragile X syndrome clinical trial. Alterations in GABA and cyclic adenosine monophosphate metabolism have long since been associated with the pathophysiology of fragile X syndrome; however, targeting both pathways simultaneously has never been investigated. Both drugs have a good safety and tolerability profile in the clinic making them attractive candidates for repurposing. We set out to explore whether the combination of ibudilast and gaboxadol could demonstrate therapeutic efficacy in a fragile X syndrome mouse model. We found that daily treatment with ibudilast significantly enhanced the ability of fragile X syndrome mice to perform a number of different cognitive assays while gaboxadol treatment improved behaviours such as hyperactivity, aggression, stereotypy and anxiety. Importantly, when ibudilast and gaboxadol were co-administered, the cognitive deficits as well as the aforementioned behaviours were rescued. Moreover, this combination treatment showed no evidence of tolerance, and no adverse effects were reported following chronic dosing. This work demonstrates for the first time that by targeting multiple pathways, with a combination treatment, we were able to rescue more phenotypes in a fragile X syndrome mouse model than either ibudilast or gaboxadol could achieve as monotherapies. This combination treatment approach holds promise for addressing the wide spectrum of diverse symptoms in this heterogeneous patient population and may have therapeutic potential for idiopathic autism.<\/jats:p>","DOI":"10.1093\/braincomms\/fcad353","type":"journal-article","created":{"date-parts":[[2024,1,15]],"date-time":"2024-01-15T14:20:23Z","timestamp":1705328423000},"source":"Crossref","is-referenced-by-count":6,"title":["A novel combination treatment for fragile X syndrome predicted using computational methods"],"prefix":"10.1093","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1465-8180","authenticated-orcid":false,"given":"Wayne","family":"Chadwick","sequence":"first","affiliation":[{"name":"Healx Ltd. , Cambridge, CB3 0DU , UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ivan","family":"Angulo-Herrera","sequence":"additional","affiliation":[{"name":"Healx Ltd. , Cambridge, CB3 0DU , UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Patricia","family":"Cogram","sequence":"additional","affiliation":[{"name":"Department of Genetics, Faculty of Science, Institute of Ecology and Biodiversity (IEB), University of Chile , Santiago 7800024 , Chile"},{"name":"Center for Neural Circuit Mapping, UCI, School of Medicine, University of California , Irvine, CA 92617 , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert J M","family":"Deacon","sequence":"additional","affiliation":[{"name":"Department of Genetics, Faculty of Science, Institute of Ecology and Biodiversity (IEB), University of Chile , Santiago 7800024 , Chile"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel J","family":"Mason","sequence":"additional","affiliation":[{"name":"Healx Ltd. , Cambridge, CB3 0DU , UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David","family":"Brown","sequence":"additional","affiliation":[{"name":"Healx Ltd. , Cambridge, CB3 0DU , UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ian","family":"Roberts","sequence":"additional","affiliation":[{"name":"Healx Ltd. , Cambridge, CB3 0DU , UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel J","family":"O\u2019Donovan","sequence":"additional","affiliation":[{"name":"Healx Ltd. , Cambridge, CB3 0DU , UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael R","family":"Tranfaglia","sequence":"additional","affiliation":[{"name":"FRAXA Research Foundation , Newburyport, MA 01950 , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tim","family":"Guilliams","sequence":"additional","affiliation":[{"name":"Healx Ltd. , Cambridge, CB3 0DU , UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Neil T","family":"Thompson","sequence":"additional","affiliation":[{"name":"Healx Ltd. , Cambridge, CB3 0DU , UK"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2024,1,15]]},"reference":[{"issue":"5","key":"2024022920041822700_fcad353-B1","first-page":"433","article-title":"An \u201comic\u201d overview of fragile X syndrome","volume":"10","author":"Dionne","year":"2021","journal-title":"Biology (Basel)."},{"issue":"4","key":"2024022920041822700_fcad353-B2","doi-asserted-by":"crossref","first-page":"1935","DOI":"10.3390\/ijms23041935","article-title":"Fragile X syndrome: From molecular aspect to clinical treatment","volume":"23","author":"Protic","year":"2022","journal-title":"Int J Mol Sci"},{"issue":"4","key":"2024022920041822700_fcad353-B3","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1038\/s41583-021-00432-0","article-title":"The molecular biology of FMRP: New insights into fragile X syndrome","volume":"22","author":"Richter","year":"2021","journal-title":"Nat Rev 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