{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T18:28:45Z","timestamp":1787509725930,"version":"build-2736575974"},"reference-count":43,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,1,28]],"date-time":"2026-01-28T00:00:00Z","timestamp":1769558400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Curekids","award":["3914"],"award-info":[{"award-number":["3914"]}]},{"DOI":"10.13039\/501100001505","name":"Health Research Council of New Zealand","doi-asserted-by":"publisher","award":["20\/259"],"award-info":[{"award-number":["20\/259"]}],"id":[{"id":"10.13039\/501100001505","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background: Fragile X Syndrome (FXS) is an X-linked neurodevelopmental disorder characterised by intellectual disability, developmental delays, anxiety, and social and behavioural challenges. Currently, no effective treatments exist to address the root cause of FXS. Mouse models are the most widely used for studying molecular pathogenesis and conducting preclinical treatment testing. However, therapeutic interventions that show promise in rodent models have yet to succeed in clinical trials. After evaluating the current models, we have developed an ovine model to address this clinical translation gap. We expect this model to more accurately reflect the human condition in brain size, structure, and neurodevelopmental trajectory. We aim to establish this model as a valuable preclinical platform for testing therapies for FXS. Methods: To generate the sheep model, we used CRISPR-Cas9 dual-guide editing to knock out the Fragile X Messenger Ribonucleoprotein 1 (FMR1) gene in ovine embryos. Results: Two founder animals were created, one ram (male) and one ewe (female), both of which carried FMR1 gene knockouts. The ewe carries inactivating mutations on both alleles, with the edits in both animals resulting in no detectable Fragile X Messenger Ribonucleoprotein (FMRP) as expected. Both founders have undergone molecular characterisation and basic health checks, with the female founder showing increased joint flexibility, a characteristic of FXS. The ram has been used for breeding, with the successful transmission of the edited allele to his offspring. Importantly, specific lamb cohorts for postnatal treatment testing can be produced efficiently utilising accelerated breeding methods and preimplantation selection.<\/jats:p>","DOI":"10.3390\/genes17020152","type":"journal-article","created":{"date-parts":[[2026,1,28]],"date-time":"2026-01-28T17:40:22Z","timestamp":1769622022000},"page":"152","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Foundations of an Ovine Model of Fragile X Syndrome"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1376-9682","authenticated-orcid":false,"given":"Victoria","family":"Hawkins","sequence":"first","affiliation":[{"name":"Applied Translational Genetics Group, School of Biological Sciences, University of Auckland, Auckland 1010, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Skye R.","family":"Rudiger","sequence":"additional","affiliation":[{"name":"Molecular Biology and Reproductive Technology Laboratories, Livestock Innovation and Welfare, South Australian Research and Development Institute, Rosedale, SA 5350, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clive J.","family":"McLaughlan","sequence":"additional","affiliation":[{"name":"Molecular Biology and Reproductive Technology Laboratories, Livestock Innovation and Welfare, South Australian Research and Development Institute, Rosedale, SA 5350, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer M.","family":"Kelly","sequence":"additional","affiliation":[{"name":"Molecular Biology and Reproductive Technology Laboratories, Livestock Innovation and Welfare, South Australian Research and Development Institute, Rosedale, SA 5350, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Klaus","family":"Lehnert","sequence":"additional","affiliation":[{"name":"Applied Translational Genetics Group, School of Biological Sciences, University of Auckland, Auckland 1010, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessie C.","family":"Jacobsen","sequence":"additional","affiliation":[{"name":"Applied Translational Genetics Group, School of Biological Sciences, University of Auckland, Auckland 1010, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7935-2399","authenticated-orcid":false,"given":"Renee R.","family":"Handley","sequence":"additional","affiliation":[{"name":"Applied Translational Genetics Group, School of Biological Sciences, University of Auckland, Auckland 1010, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kimiora","family":"Henare","sequence":"additional","affiliation":[{"name":"Auckland Cancer Society Research Centre, University of Auckland, Auckland 1023, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul J.","family":"Verma","sequence":"additional","affiliation":[{"name":"Molecular Biology and Reproductive Technology Laboratories, Livestock Innovation and Welfare, South Australian Research and Development Institute, Rosedale, SA 5350, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8166-4014","authenticated-orcid":false,"given":"Russell G.","family":"Snell","sequence":"additional","affiliation":[{"name":"Applied Translational Genetics Group, School of Biological Sciences, University of Auckland, Auckland 1010, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"40","DOI":"10.2174\/157339608783565770","article-title":"The Fragile X Family of Disorders: A Model for Autism and Targeted Treatments","volume":"4","author":"Hagerman","year":"2008","journal-title":"Curr. 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