{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T11:06:51Z","timestamp":1787828811486,"version":"build-2784847793"},"reference-count":45,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2025,1,30]],"date-time":"2025-01-30T00:00:00Z","timestamp":1738195200000},"content-version":"vor","delay-in-days":37,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R44NS124351"],"award-info":[{"award-number":["R44NS124351"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000265","name":"UK Medical Research Council","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,12,24]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Congenital myasthenic syndromes are a group of inherited disorders characterized by defective neuromuscular transmission and fatigable muscle weakness. Causative mutations have been identified in over 30 genes, including DOK7, a gene encoding a post-synaptic protein crucial in the formation and stabilization of the neuromuscular junction. Mutations in this gene are one of the leading three most prevalent causes of congenital myasthenia in diverse populations across the globe. The majority of DOK7 congenital myasthenic patients experience varying degrees of disability despite receiving optimized treatment (usually salbutamol), necessitating the development of improved therapeutic approaches. Here, we executed a dose escalation pre-clinical trial using a DOK7 congenital myasthenic syndrome mouse model to assess the efficacy of AMP-101, an innovative recombinant adeno-associated viral gene replacement therapy. This mouse model harbours a duplication in the Dok7 gene that corresponds to the mutation most commonly found in DOK7 congenital myasthenia patients, c.1124-1127dupTGCC. The model has a much more severe phenotype than patients, and lives for only a few days. AMP-101 is based on AAVrh74 and contains human DOK7 cDNA under the control of a muscle-restricted promoter. Three doses of AMP-101 (2 \u00d7 1013\u2005vg\/kg, 6 \u00d7 1013\u2005vg\/kg or 1 \u00d7 1014\u2005vg\/kg) were administered intraperitoneally at 4 days of age. We show that the two higher doses of 6 \u00d7 1013\u2005vg\/kg and 1 \u00d7 1014\u2005vg\/kg generated enlarged neuromuscular junctions and rescued the very severe phenotype of the model. Treated mice became at least as strong as wild-type littermates, as demonstrated by using an inverted screen hang test, a rotarod test and a grip strength test. EMG showed that the treated model mice had decrement of compound muscle action potential on repetitive nerve stimulation, which indicates defective signalling at the neuromuscular junction. However, male models treated with 1 \u00d7 1014\u2005vg\/kg showed the least decrement that was not statistically different from wild-type littermates. Western blot analysis demonstrated robust expression of DOK7 in the diaphragm and tibialis anterior muscles. These data show that AMP-101 is an effective treatment in a mouse model for DOK7 congenital myasthenia, and suggests that AMP-101 is a promising candidate to move forward to clinic trials as a gene therapy for patients.<\/jats:p>","DOI":"10.1093\/braincomms\/fcaf046","type":"journal-article","created":{"date-parts":[[2025,1,29]],"date-time":"2025-01-29T15:19:47Z","timestamp":1738163987000},"source":"Crossref","is-referenced-by-count":4,"title":["Dose escalation pre-clinical trial of novel DOK7-AAV in mouse model of DOK7 congenital myasthenia"],"prefix":"10.1093","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2323-622X","authenticated-orcid":false,"given":"Judith","family":"Cossins","sequence":"first","affiliation":[{"name":"Neurosciences Group, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford , Oxford OX3 9DS ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Imre","family":"Kozma","sequence":"additional","affiliation":[{"name":"Neurosciences Group, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford , Oxford OX3 9DS ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Canzonetta","sequence":"additional","affiliation":[{"name":"Amplo Biotechnology , La Jolla, CA 92037 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Al","family":"Hawkins","sequence":"additional","affiliation":[{"name":"Amplo Biotechnology , La Jolla, CA 92037 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9395-7132","authenticated-orcid":false,"given":"David","family":"Beeson","sequence":"additional","affiliation":[{"name":"Neurosciences Group, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford , Oxford OX3 9DS ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricio","family":"Sepulveda","sequence":"additional","affiliation":[{"name":"Amplo Biotechnology , La Jolla, CA 92037 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8600-6988","authenticated-orcid":false,"given":"Yin Yao","family":"Dong","sequence":"additional","affiliation":[{"name":"Neurosciences Group, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford , Oxford OX3 9DS ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,1,30]]},"reference":[{"issue":"4","key":"2025021207525854000_fcaf046-B1","doi-asserted-by":"crossref","first-page":"3730","DOI":"10.3390\/ijms24043730","article-title":"Clinical and pathologic features of congenital myasthenic syndromes caused by 35 genes\u2014A comprehensive review","volume":"24","author":"Ohno","year":"2023","journal-title":"Int J Mol Sci"},{"issue":"6","key":"2025021207525854000_fcaf046-B2","doi-asserted-by":"crossref","first-page":"1677","DOI":"10.3390\/ijms19061677","article-title":"The neuromuscular junction and wide heterogeneity of congenital myasthenic syndromes","volume":"19","author":"Rodriguez Cruz","year":"2018","journal-title":"Int J Mol Sci"},{"issue":"5795","key":"2025021207525854000_fcaf046-B3","doi-asserted-by":"crossref","first-page":"1975","DOI":"10.1126\/science.1130837","article-title":"Dok-7 mutations underlie a neuromuscular junction synaptopathy","volume":"313","author":"Beeson","year":"2006","journal-title":"Science"},{"issue":"59","key":"2025021207525854000_fcaf046-B4","doi-asserted-by":"crossref","first-page":"ra7","DOI":"10.1126\/scisignal.2000113","article-title":"Dok-7 activates the muscle receptor kinase MuSK and shapes synapse formation","volume":"2","author":"Inoue","year":"2009","journal-title":"Sci Signal"},{"issue":"5781","key":"2025021207525854000_fcaf046-B5","doi-asserted-by":"crossref","first-page":"1802","DOI":"10.1126\/science.1127142","article-title":"The muscle protein Dok-7 is essential for neuromuscular synaptogenesis","volume":"312","author":"Okada","year":"2006","journal-title":"Science"},{"issue":"Pt 8","key":"2025021207525854000_fcaf046-B6","doi-asserted-by":"crossref","first-page":"2061","DOI":"10.1093\/brain\/awl200","article-title":"Pre- and post-synaptic abnormalities associated with impaired neuromuscular transmission in a group of patients with \u2018limb-girdle myasthenia\u2019","volume":"129","author":"Slater","year":"2006","journal-title":"Brain"},{"issue":"19","key":"2025021207525854000_fcaf046-B7","doi-asserted-by":"crossref","first-page":"1517","DOI":"10.1212\/WNL.0b013e3181dd43bf","article-title":"Ephedrine treatment in congenital myasthenic syndrome due to mutations in 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DOK7 gene therapy benefits mouse models of diseases characterized by defects in the neuromuscular junction","volume":"345","author":"Arimura","year":"2014","journal-title":"Science"},{"issue":"7","key":"2025021207525854000_fcaf046-B18","doi-asserted-by":"crossref","first-page":"880","DOI":"10.15252\/emmm.201607298","article-title":"DOK7 gene therapy enhances motor activity and life span in ALS model mice","volume":"9","author":"Miyoshi","year":"2017","journal-title":"EMBO Mol Med"},{"issue":"1","key":"2025021207525854000_fcaf046-B19","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1016\/j.bbrc.2020.07.031","article-title":"AAV9-DOK7 gene therapy reduces disease severity in Smn(2B\/-) SMA model mice","volume":"530","author":"Kaifer","year":"2020","journal-title":"Biochem Biophys Res Commun"},{"key":"2025021207525854000_fcaf046-B20","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1016\/j.omtn.2023.07.036","article-title":"Long-term muscle-specific overexpression of 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