{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T14:34:51Z","timestamp":1787927691593,"version":"build-2784847793"},"reference-count":29,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2023,3,15]],"date-time":"2023-03-15T00:00:00Z","timestamp":1678838400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J of Inher Metab Disea"],"published-print":{"date-parts":[[2024,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Maple syrup urine disease (MSUD) is rare autosomal recessive metabolic disorder caused by the dysfunction of the mitochondrial branched\u2010chain 2\u2010ketoacid dehydrogenase (BCKD) enzyme complex leading to massive accumulation of branched\u2010chain amino acids and 2\u2010keto acids. MSUD management, based on a life\u2010long strict protein restriction with nontoxic amino acids oral supplementation represents an unmet need as it is associated with a poor quality of life, and does not fully protect from acute life\u2010threatening decompensations or long\u2010term neuropsychiatric complications. Orthotopic liver transplantation is a beneficial therapeutic option, which shows that restoration of only a fraction of whole\u2010body BCKD enzyme activity is therapeutic. MSUD is thus an ideal target for gene therapy. We and others have tested AAV gene therapy in mice for two of the three genes involved in MSUD,\n                    <jats:italic>BCKDHA<\/jats:italic>\n                    and\n                    <jats:italic>DBT<\/jats:italic>\n                    . In this study, we developed a similar approach for the third MSUD gene,\n                    <jats:italic>BCKDHB<\/jats:italic>\n                    . We performed the first characterization of a\n                    <jats:italic>Bckdhb<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>\u2212\/\u2212<\/jats:italic>\n                    <\/jats:sup>\n                    mouse model, which recapitulates the severe human phenotype of MSUD with early\u2010neonatal symptoms leading to death during the first week of life with massive accumulation of MSUD biomarkers. Based on our previous experience in\n                    <jats:italic>Bckdha<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>\u2212\/\u2212<\/jats:italic>\n                    <\/jats:sup>\n                    mice, we designed a transgene carrying the human\n                    <jats:italic>BCKDHB<\/jats:italic>\n                    gene under the control of a ubiquitous EF1\u03b1 promoter, encapsidated in an AAV8 capsid. Injection in neonatal\n                    <jats:italic>Bckdhb<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>\u2212\/\u2212<\/jats:italic>\n                    <\/jats:sup>\n                    mice at 10\n                    <jats:sup>14<\/jats:sup>\n                    \u2009vg\/kg achieved long\u2010term rescue of the severe MSUD phenotype of\n                    <jats:italic>Bckdhb<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>\u2212\/\u2212<\/jats:italic>\n                    <\/jats:sup>\n                    mice. These data further validate the efficacy of gene therapy for MSUD opening perspectives towards clinical translation.\n                  <\/jats:p>","DOI":"10.1002\/jimd.12604","type":"journal-article","created":{"date-parts":[[2023,3,7]],"date-time":"2023-03-07T04:57:45Z","timestamp":1678165065000},"page":"41-49","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Successful treatment of severe MSUD in\n                    <i>\n                      Bckdhb\n                      <sup>\u2212\/\u2212<\/sup>\n                    <\/i>\n                    mice with neonatal AAV gene therapy"],"prefix":"10.1002","volume":"47","author":[{"given":"Cl\u00e9ment","family":"Pontoizeau","sequence":"first","affiliation":[{"name":"Necker Hospital, APHP, Biochemistry, Metabolomics Unit University Paris Cit\u00e9  Paris France"},{"name":"Necker Hospital, APHP, Reference Center for Inborn Error of Metabolism, Pediatrics Department University Paris Cit\u00e9  Paris France"},{"name":"Inserm UMR_S1163, Institut Imagine  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clovis","family":"Gaborit","sequence":"additional","affiliation":[{"name":"Inserm UMR_S1163, Institut Imagine  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nolan","family":"Tual","sequence":"additional","affiliation":[{"name":"Inserm UMR_S1163, Institut Imagine  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcelo","family":"Simon\u2010Sola","sequence":"additional","affiliation":[{"name":"Inserm UMR_S1163, Institut Imagine  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irina","family":"Rotaru","sequence":"additional","affiliation":[{"name":"Inserm UMR_S1163, Institut Imagine  Paris 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