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Currently, patient management is based on dietary treatment preventing severe hypoglycemia and increasing the lifespan of patients. However, most of the patients develop long-term pathologies. In the past years, gene therapy for GSDI has generated proof of concept for hepatic GSDs. This resulted in a recent clinical trial of adeno-associated virus (AAV)-based gene replacement for GSDIa. However, the current limitations of AAV-mediated gene transfer still represent a challenge for successful gene therapy in GSDI and GSDIII. Indeed, transgene loss over time was observed in GSDI liver, possibly due to the degeneration of hepatocytes underlying the physiopathology of both GSDI and GSDIII and leading to hepatic tumor development. Moreover, multitissue targeting requires high vector doses to target nonpermissive tissues such as muscle and kidney. Interestingly, recent pharmacological interventions or dietary regimen aiming at the amelioration of the hepatocyte abnormalities before the administration of gene therapy demonstrated improved efficacy in GSDs. In this review, we describe the advances in gene therapy and the limitations to be overcome to achieve efficient and safe gene transfer in GSDs.<\/jats:p>","DOI":"10.1089\/hum.2019.102","type":"journal-article","created":{"date-parts":[[2019,7,19]],"date-time":"2019-07-19T02:12:55Z","timestamp":1563502375000},"page":"1263-1273","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":32,"title":["Challenges of Gene Therapy for the Treatment of Glycogen Storage Diseases Type I and Type III"],"prefix":"10.1177","volume":"30","author":[{"given":"Louisa","family":"Jauze","sequence":"first","affiliation":[{"name":"INTEGRARE, Genethon, Inserm, Universit\u00e9 d'Evry, Universit\u00e9 Paris-Saclay, Evry, France"},{"name":"Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale, U1213, Lyon, France"},{"name":"Universit\u00e9 de Lyon, Lyon, France"},{"name":"Universit\u00e9 Lyon I, Villeurbanne, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laure","family":"Monteillet","sequence":"additional","affiliation":[{"name":"Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale, U1213, Lyon, France"},{"name":"Universit\u00e9 de Lyon, Lyon, France"},{"name":"Universit\u00e9 Lyon I, Villeurbanne, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gilles","family":"Mithieux","sequence":"additional","affiliation":[{"name":"Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale, U1213, Lyon, France"},{"name":"Universit\u00e9 de Lyon, Lyon, France"},{"name":"Universit\u00e9 Lyon I, Villeurbanne, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabienne","family":"Rajas","sequence":"additional","affiliation":[{"name":"Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale, U1213, Lyon, France"},{"name":"Universit\u00e9 de Lyon, Lyon, France"},{"name":"Universit\u00e9 Lyon I, Villeurbanne, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Ronzitti","sequence":"additional","affiliation":[{"name":"INTEGRARE, Genethon, Inserm, Universit\u00e9 d'Evry, Universit\u00e9 Paris-Saclay, Evry, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2019,9,24]]},"reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2017.04.032"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.21037\/atm.2018.10.59"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.3233\/TRD-160006"},{"key":"e_1_3_3_5_2","first-page":"415","article-title":"Hepatic glycogen storage disorders: what have we learned in recent years?","volume":"18","author":"Burda P","year":"2015","unstructured":"Burda P, , Hochuli M. 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