{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,21]],"date-time":"2026-01-21T06:21:20Z","timestamp":1768976480389,"version":"3.49.0"},"reference-count":71,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,1,20]],"date-time":"2026-01-20T00:00:00Z","timestamp":1768867200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Research Initiation Grant from Queen\u2019s University","award":["377267"],"award-info":[{"award-number":["377267"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Guanidinoacetate methyltransferase (GAMT) is an essential enzyme in the biosynthesis of creatine, an important molecule in energy recycling. GAMT loss of function leads to GAMT deficiency (GAMT-D), an autosomal recessive disorder resulting in low creatine levels and the accumulation of a toxic intermediate, guanidinoacetate (GAA). GAMT-D patients present with intellectual disability and epilepsy, emphasizing the detrimental consequences of disturbed creatine metabolisms in the central nervous system (CNS). Current treatments are not curative and may not restore creatine metabolism in the brain. Here, we present a proof-of concept study testing the first CNS-directed, Adeno-associated virus serotype 9 (AAV9)-based gene therapy for the treatment of GAMT-D. the delivery of GAMT construct to cellular models of GAMT-D effectively restored protein and mRNA expression of GAMT while increasing intracellular creatine content and decreasing GAA accumulation. In murine models of GAMT-D, treatment with scAAV9.hGAMT, delivered intrathecally, resulted in increased creatine content as well as significant decreases in GAA accumulation in the CNS and peripheral organs. Overall, we found that scAAV9.hGAMT represents a promising gene therapy for treating GAMT-D, warranting further investigation in animal models to determine an appropriate therapeutic window for both efficacy and safety that allows for translation into human patients in the future.<\/jats:p>","DOI":"10.3390\/ijms27021035","type":"journal-article","created":{"date-parts":[[2026,1,20]],"date-time":"2026-01-20T17:20:42Z","timestamp":1768929642000},"page":"1035","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A CNS-Directed, AAV9 Gene Therapy Restores Expression and Biochemical Function of Guanidinoacetate Methyltransferase in Models of GAMT Deficiency"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-8619-5343","authenticated-orcid":false,"given":"Robyn","family":"Binsfeld","sequence":"first","affiliation":[{"name":"Centre for Neuroscience Studies, Queen\u2019s University, Kingston, ON K7L 3N6, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Troy","family":"Webster","sequence":"additional","affiliation":[{"name":"Centre for Neuroscience Studies, Queen\u2019s University, Kingston, ON K7L 3N6, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ilona","family":"Tkachyova","sequence":"additional","affiliation":[{"name":"The Hospital for Sick Children, Toronto, ON M5G 1E8, Canada"},{"name":"Peter Gilgan Center for Research and Learning, Toronto, ON M5G 0A4, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Tropak","sequence":"additional","affiliation":[{"name":"The Hospital for Sick Children, Toronto, ON M5G 1E8, Canada"},{"name":"Peter Gilgan Center for Research and Learning, Toronto, ON M5G 0A4, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-1151-2524","authenticated-orcid":false,"given":"Melissa","family":"Mitchell","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Queen\u2019s University, Kingston, ON K7L 3N6, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-5602-9328","authenticated-orcid":false,"given":"Tesla","family":"Peretti","sequence":"additional","affiliation":[{"name":"Centre for Neuroscience Studies, Queen\u2019s University, Kingston, ON K7L 3N6, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8491-1095","authenticated-orcid":false,"given":"Andreas","family":"Schulze","sequence":"additional","affiliation":[{"name":"The Hospital for Sick Children, Toronto, ON M5G 1E8, Canada"},{"name":"Peter Gilgan Center for Research and Learning, Toronto, ON M5G 0A4, Canada"},{"name":"Departments of Pediatrics and Biochemistry, University of Toronto, Toronto, ON M5S 1A1, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7055-2239","authenticated-orcid":false,"given":"Jagdeep S.","family":"Walia","sequence":"additional","affiliation":[{"name":"Centre for Neuroscience Studies, Queen\u2019s University, Kingston, ON K7L 3N6, Canada"},{"name":"Department of Pediatrics, Queen\u2019s University, Kingston, ON K7L 3N6, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1016\/j.brainresbull.2008.02.035","article-title":"Functions and Effects of Creatine in the Central Nervous System","volume":"76","author":"Andres","year":"2008","journal-title":"Brain Res. 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