{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T20:53:28Z","timestamp":1768510408718,"version":"3.49.0"},"posted":{"date-parts":[[2024,2,12]]},"group-title":"Neuroscience","reference-count":43,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,2,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Congenital myasthenic syndromes (CMS) are a group of inherited disorders characterised by defective neuromuscular transmission and fatigable muscle weakness. Mutations in\n                  <jats:italic>DOK7<\/jats:italic>\n                  , a gene encoding a post-synaptic protein crucial in the formation and stabilisation of the neuromuscular junction (NMJ), rank among the leading three prevalent causes of CMS in diverse populations globally. The majority of DOK7 CMS patients experience varying degrees of disability despite receiving optimised treatment, necessitating the development of improved therapeutic approaches. Here we executed a dose escalation pre-clinical trial using a DOK7-CMS mouse model to assess the efficacy of Amp-101, an innovative AAV gene replacement therapy. Amp-101 is based on AAVrh74 and contains human DOK7 cDNA under the control of a muscle-restricted promoter. We show that at doses 6x10\n                  <jats:sup>13<\/jats:sup>\n                  vg\/kg and 1x10\n                  <jats:sup>14<\/jats:sup>\n                  vg\/kg, Amp-101 generated enlarged NMJs and rescued the very severe phenotype of the model. Treated mice became at least as strong as WT littermates and the diaphragm and tibialis anterior muscles displayed robust expression of DOK7. This data suggests that Amp-101 is a promising candidate to move forward to clinic trials.\n                <\/jats:p>","DOI":"10.1101\/2024.02.09.579626","type":"posted-content","created":{"date-parts":[[2024,2,12]],"date-time":"2024-02-12T13:30:31Z","timestamp":1707744631000},"source":"Crossref","is-referenced-by-count":0,"title":["Dose escalation pre-clinical trial of novel DOK7-AAV in mouse model of DOK7 congenital myasthenia"],"prefix":"10.64898","author":[{"given":"Judith","family":"Cossins","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Imre","family":"Kozma","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Claudia","family":"Canzonetta","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Al","family":"Hawkins","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David","family":"Beeson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Patricio","family":"Sepulveda","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yin","family":"Dong","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2024021420050484000_2024.02.09.579626v1.1","doi-asserted-by":"crossref","unstructured":"(2020) High-dose AAV gene therapy deaths. Nat Biotechnol 38: 910","DOI":"10.1038\/s41587-020-0642-9"},{"key":"2024021420050484000_2024.02.09.579626v1.2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1250744"},{"key":"2024021420050484000_2024.02.09.579626v1.3","unstructured":"Armstrong A , 2021. Pfizer reports patient death in early-stage Duchenne gene therapy trial, halts enrollment."},{"key":"2024021420050484000_2024.02.09.579626v1.4","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1038\/s41434-020-0168-2","article-title":"Retinal gene therapy: an eye-opener of the 21st century","volume":"28","year":"2021","journal-title":"Gene Ther"},{"key":"2024021420050484000_2024.02.09.579626v1.5","doi-asserted-by":"publisher","DOI":"10.1126\/science.1130837"},{"key":"2024021420050484000_2024.02.09.579626v1.6","doi-asserted-by":"publisher","DOI":"10.1016\/j.nmd.2012.11.004"},{"key":"2024021420050484000_2024.02.09.579626v1.7","doi-asserted-by":"crossref","first-page":"231","DOI":"10.3233\/JND-170293","article-title":"Beta-2 Adrenergic Receptor Agonists Enhance AChR Clustering in C2C12 Myotubes: Implications for Therapy of Myasthenic Disorders","volume":"5","year":"2018","journal-title":"J Neuromuscul Dis"},{"key":"2024021420050484000_2024.02.09.579626v1.8","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1186\/s13023-021-02055-1","article-title":"Hepatobiliary disease in XLMTM: a common comorbidity with potential impact on treatment strategies","volume":"16","year":"2021","journal-title":"Orphanet journal of rare diseases"},{"key":"2024021420050484000_2024.02.09.579626v1.9","doi-asserted-by":"crossref","unstructured":"Dougherty JA , Dougherty KM (2023) Valoctocogene Roxaparvovec and Etranacogene Dezaparavovec: Novel Gene Therapies for Hemophilia A and B. 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