{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T17:54:34Z","timestamp":1785434074555,"version":"3.56.0"},"posted":{"date-parts":[[2026,5,23]]},"group-title":"Genetics","reference-count":44,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,5,23]],"date-time":"2026-05-23T00:00:00Z","timestamp":1779494400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nd\/4.0\/"}],"funder":[{"award":["3260\/21"],"award-info":[{"award-number":["3260\/21"]}],"id":[{"id":"https:\/\/ror.org\/04sazxf24","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001742","name":"United States-Israel Binational Science Foundation","doi-asserted-by":"crossref","award":["BSF 2023188"],"award-info":[{"award-number":["BSF 2023188"]}],"id":[{"id":"10.13039\/501100001742","id-type":"DOI","asserted-by":"crossref"}]},{"award":["R35GM160013"],"award-info":[{"award-number":["R35GM160013"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["T32AG052363"],"award-info":[{"award-number":["T32AG052363"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,5,23]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  Pathogenic variants in\n                  <jats:italic>ATAD3A<\/jats:italic>\n                  cause a spectrum of multisystem disorders, with a recurrent dominant-negative variant (c.1582C&gt;T; p.Arg528Trp) associated with neurodevelopmental disease. Given the tolerance of\n                  <jats:italic>ATAD3A<\/jats:italic>\n                  to heterozygous loss of function variants, allele-specific transcript reduction represents a promising therapeutic strategy. We designed and optimized allele-specific antisense oligonucleotides (ASOs) targeting the c.1582C&gt;T transcript and evaluated their efficacy and specificity in affected fibroblasts using allele-specific primers and amplicon-based next generation sequencing. Therapeutic potential was further assessed in vivo in zebrafish embryos expressing human wild-type or mutant\n                  <jats:italic>ATAD3A<\/jats:italic>\n                  transcripts. An optimized gapmer ASO selectively reduced mutant\n                  <jats:italic>ATAD3A<\/jats:italic>\n                  transcripts while relatively sparing the wild-type allele. In addition to RNase H-mediated degradation, the ASO induced exon skipping, leading to degradation of the aberrant transcript without production of a truncated protein. In zebrafish, expression of mutant human\n                  <jats:italic>ATAD3A<\/jats:italic>\n                  in embryos caused developmental abnormalities including reduced eye size, which were robustly rescued by co-injection of the optimized ASO. Our findings provide proof of concept for allele-targeted ASO therapy for dominant-negative\n                  <jats:italic>ATAD3A<\/jats:italic>\n                  variants. This work highlights the therapeutic potential of ASOs for rare dominant disorders involving genes tolerant to heterozygous loss-of-function, and establishes zebrafish as a versatile platform for in vivo ASO optimization.\n                <\/jats:p>","DOI":"10.64898\/2026.05.20.726050","type":"posted-content","created":{"date-parts":[[2026,5,23]],"date-time":"2026-05-23T23:25:13Z","timestamp":1779578713000},"source":"Crossref","is-referenced-by-count":0,"title":["Allele-specific antisense oligonucleotide treatment rescues\n                  <i>atad3-<\/i>\n                  associated phenotype in zebrafish"],"prefix":"10.64898","author":[{"given":"Shlomit","family":"Ezer","sequence":"first","affiliation":[{"name":"Department of Genetics, Hadassah Medical Organization, Jerusalem, Israel"},{"name":"Faculty of Medicine, Hebrew University of Jerusalem, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shira","family":"Yanovsky-Dagan","sequence":"additional","affiliation":[{"name":"Department of Genetics, Hadassah Medical Organization, Jerusalem, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amit","family":"Granit","sequence":"additional","affiliation":[{"name":"Department of Genetics, Hadassah Medical Organization, Jerusalem, Israel"},{"name":"Faculty of Medicine, Hebrew University of Jerusalem, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"McDougal","sequence":"additional","affiliation":[{"name":"Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taeyoung","family":"Hwang","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Israel","family":"Antman","sequence":"additional","affiliation":[{"name":"Department of Genetics, Hadassah Medical Organization, Jerusalem, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rotem","family":"Karni","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Institute for Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem, Israel"},{"name":"Department of Genetics and the RNA innovation institute, Perelman School of Medicine, University of Pennsylvania, 19104, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wan Hee","family":"Yoon","sequence":"additional","affiliation":[{"name":"Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ann","family":"Saada","sequence":"additional","affiliation":[{"name":"Department of Genetics, Hadassah Medical Organization, Jerusalem, Israel"},{"name":"Faculty of Medicine, Hebrew University of Jerusalem, Israel"},{"name":"Department of Medical Laboratory Sciences Jerusalem Multidisciplinary College, Jerusalem Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adi","family":"Inbal","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Hebrew University of Jerusalem, Israel"},{"name":"Department of Medical Neurobiology, Institute for Medical Research-Israel-Canada, Jerusalem, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tamar","family":"Harel","sequence":"additional","affiliation":[{"name":"Department of Genetics, Hadassah Medical Organization, Jerusalem, Israel"},{"name":"Faculty of Medicine, Hebrew University of Jerusalem, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026052702300642000_2026.05.20.726050v1.1","doi-asserted-by":"publisher","DOI":"10.1042\/bst0290431"},{"key":"2026052702300642000_2026.05.20.726050v1.2","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.062034"},{"key":"2026052702300642000_2026.05.20.726050v1.3","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-09291-x"},{"key":"2026052702300642000_2026.05.20.726050v1.4","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0054583"},{"key":"2026052702300642000_2026.05.20.726050v1.5","first-page":"6","article-title":"Loss of mitochondrial ATPase ATAD3A contributes to nonalcoholic fatty liver disease through accumulation of lipids and damaged mitochondria","volume":"298","year":"2022","journal-title":"J. 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