{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T01:51:41Z","timestamp":1783648301674,"version":"3.55.0"},"reference-count":96,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2025,10,30]],"date-time":"2025-10-30T00:00:00Z","timestamp":1761782400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100010805","name":"Fundaci\u00f3n Tatiana P\u00e9rez de Guzm\u00e1n el Bueno","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100010805","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Clinical &amp;amp; Translational Med"],"published-print":{"date-parts":[[2025,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Lafora disease is a rare and fatal form of progressive myoclonus epilepsy that typically manifests in late childhood, presenting with seizures and progressive neurological decline. It is caused by mutations in\n                      <jats:italic>EPM2A<\/jats:italic>\n                      or\n                      <jats:italic>EPM2B<\/jats:italic>\n                      genes, encoding laforin and malin, which form a complex that regulates glycogen metabolism and mitigates cellular stress. Loss of function in either gene leads to the accumulation of Lafora bodies, insoluble polyglucosan aggregates that contribute to neurodegeneration.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We previously demonstrated the efficacy of gene therapy using intracerebroventricular delivery of rAAV2\/9 vectors expressing\n                      <jats:italic>EPM2A<\/jats:italic>\n                      or\n                      <jats:italic>EPM2B<\/jats:italic>\n                      in mouse models of Lafora disease. Building on these findings, we investigated the therapeutic and translational potential of a less invasive approach using intravenous delivery of rAAV2\/9P31 vectors, which efficiently cross the blood\u2013brain barrier. Gene delivery was performed at presymptomatic stages in\n                      <jats:italic>Epm2a<\/jats:italic>\n                      <jats:sup>\u2212\/\u2212<\/jats:sup>\n                      and\n                      <jats:italic>Epm2b<\/jats:italic>\n                      <jats:sup>\u2212\/\u2212<\/jats:sup>\n                      mice.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Intravenous gene therapy with rAAV2\/9P31 vectors carrying\n                      <jats:italic>EPM2A<\/jats:italic>\n                      or\n                      <jats:italic>EPM2B<\/jats:italic>\n                      reversed neuropathological features of the disease, restored neuronal excitability and synaptic plasticity, and effectively prevented Lafora body formation. The therapeutic outcomes were comparable or superior to those achieved with intracerebroventricular administration. Long\u2010term evaluation revealed no evidence of hepatotoxicity or immunogenicity.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Our results support intravenous rAAV2\/9P31\u2013mediated gene therapy as a promising, less invasive, and safe treatment strategy for Lafora disease, with strong potential for clinical translation.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ctm2.70514","type":"journal-article","created":{"date-parts":[[2025,10,31]],"date-time":"2025-10-31T07:14:34Z","timestamp":1761894874000},"source":"Crossref","is-referenced-by-count":7,"title":["Advances in gene therapy for Lafora disease: Intravenous recombinant adeno\u2010associated virus\u2010mediated delivery of\n                    <i>EPM2A<\/i>\n                    and\n                    <i>EPM2B<\/i>\n                    genes"],"prefix":"10.1002","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1807-7538","authenticated-orcid":false,"given":"Luis","family":"Zafra\u2010Puerta","sequence":"first","affiliation":[{"name":"Laboratory of Neurology Instituto de Investigaci\u00f3n Sanitaria\u2010Fundaci\u00f3n Jim\u00e9nez D\u00edaz Universidad Aut\u00f3noma de Madrid (IIS\u2010FJD, UAM)  Madrid Spain"},{"name":"PhD Program in Neuroscience Universidad Aut\u00f3noma de Madrid\u2010Cajal Institute Madrid Spain"},{"name":"Fondazione Malattie Rare Mauro Baschirotto BIRD Onlus  Longare Vicenza Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nerea","family":"Iglesias\u2010Cabeza","sequence":"additional","affiliation":[{"name":"Laboratory of Neurology Instituto de Investigaci\u00f3n Sanitaria\u2010Fundaci\u00f3n Jim\u00e9nez D\u00edaz Universidad Aut\u00f3noma de Madrid (IIS\u2010FJD, UAM)  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miriam","family":"Sciaccaluga","sequence":"additional","affiliation":[{"name":"Fondazione Malattie Rare Mauro Baschirotto BIRD Onlus  Longare Vicenza Italy"},{"name":"Department of Life Sciences, Health, and Health Professions Link University  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Bellingacci","sequence":"additional","affiliation":[{"name":"Section of Physiology Department of Medicine and Surgery University of Perugia  Perugia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacopo","family":"Canonichesi","sequence":"additional","affiliation":[{"name":"Section of Physiology Department of Medicine and Surgery University of Perugia  Perugia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gema","family":"S\u00e1nchez\u2010Mart\u00edn","sequence":"additional","affiliation":[{"name":"Laboratory of Neurology Instituto de Investigaci\u00f3n Sanitaria\u2010Fundaci\u00f3n Jim\u00e9nez D\u00edaz Universidad Aut\u00f3noma de Madrid (IIS\u2010FJD, UAM)  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cinzia","family":"Costa","sequence":"additional","affiliation":[{"name":"Section of Neurophysiopathology S.M. 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