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disease (PD) is a rare disorder caused by mutations in the acid alpha-glucosidase (GAA) gene. Most gene therapies (GT) partially rely on the cross-correction of unmodified cells through the uptake of the GAA enzyme secreted by corrected cells. In the present study, we generated isogenic murine GAA-KO cell lines resembling severe mutations from Pompe patients. All of the generated GAA-KO cells lacked GAA activity and presented an increased autophagy and increased glycogen content by means of myotube differentiation as well as the downregulation of mannose 6-phosphate receptors (CI-MPRs), validating them as models for PD. Additionally, different chimeric murine GAA proteins (IFG, IFLG and 2G) were designed with the aim to improve their therapeutic activity. Phenotypic rescue analyses using lentiviral vectors point to IFG chimera as the best candidate in restoring GAA activity, normalising the autophagic marker p62 and surface levels of CI-MPRs. Interestingly, in vivo administration of liver-directed AAVs expressing the chimeras further confirmed the good behaviour of IFG, achieving cross-correction in heart tissue. In summary, we generated different isogenic murine muscle cell lines mimicking the severe PD phenotype, as well as validating their applicability as preclinical models in order to reduce animal experimentation.<\/jats:p>","DOI":"10.3390\/ijms23116298","type":"journal-article","created":{"date-parts":[[2022,6,4]],"date-time":"2022-06-04T09:42:32Z","timestamp":1654335752000},"page":"6298","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Isogenic GAA-KO Murine Muscle Cell Lines Mimicking Severe Pompe Mutations as Preclinical Models for the Screening of Potential Gene Therapy Strategies"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2960-8672","authenticated-orcid":false,"given":"Araceli","family":"Aguilar-Gonz\u00e1lez","sequence":"first","affiliation":[{"name":"GENYO, Centre for Genomics and Oncological Research: Pfizer, University of Granada, Andalusian Regional Government PTS Granada-Avenida de la Ilustraci\u00f3n 114, 18016 Granada, Spain"},{"name":"Department of Medicinal & Organic Chemistry and Excellence Research Unit of \u201cChemistry Applied to Biomedicine and the Environment\u201d, Faculty of Pharmacy, University of Granada, Campus de Cartuja s\/n, 18071 Granada, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juan El\u00edas","family":"Gonz\u00e1lez-Correa","sequence":"additional","affiliation":[{"name":"GENYO, Centre for Genomics and Oncological Research: Pfizer, University of Granada, Andalusian Regional Government PTS Granada-Avenida de la Ilustraci\u00f3n 114, 18016 Granada, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eliana","family":"Barriocanal-Casado","sequence":"additional","affiliation":[{"name":"GENYO, Centre for Genomics and Oncological Research: Pfizer, University of Granada, Andalusian Regional Government PTS Granada-Avenida de la Ilustraci\u00f3n 114, 18016 Granada, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Iris","family":"Ramos-Hern\u00e1ndez","sequence":"additional","affiliation":[{"name":"GENYO, Centre for Genomics and Oncological Research: Pfizer, University of Granada, Andalusian Regional Government PTS Granada-Avenida de la Ilustraci\u00f3n 114, 18016 Granada, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Miguel A.","family":"Lerma-Ju\u00e1rez","sequence":"additional","affiliation":[{"name":"Instituto de Investigaci\u00f3n del Hospital Universitario La Paz, IdiPAZ, 28029 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sara","family":"Greco","sequence":"additional","affiliation":[{"name":"GENYO, Centre for Genomics and Oncological Research: Pfizer, University of Granada, Andalusian Regional Government PTS Granada-Avenida de la Ilustraci\u00f3n 114, 18016 Granada, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4741-7925","authenticated-orcid":false,"given":"Juan Jos\u00e9","family":"Rodr\u00edguez-Sevilla","sequence":"additional","affiliation":[{"name":"GENYO, Centre for Genomics and Oncological Research: Pfizer, University of Granada, Andalusian Regional Government PTS Granada-Avenida de la Ilustraci\u00f3n 114, 18016 Granada, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francisco Javier","family":"Molina-Est\u00e9vez","sequence":"additional","affiliation":[{"name":"GENYO, Centre for Genomics and Oncological Research: Pfizer, University of Granada, Andalusian Regional Government PTS Granada-Avenida de la Ilustraci\u00f3n 114, 18016 Granada, Spain"},{"name":"Fundaci\u00f3n para la Investigaci\u00f3n Biosanitaria de Andaluc\u00eda Oriental-Alejandro Otero (FIBAO), 18012 Granada, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7183-3710","authenticated-orcid":false,"given":"Valle","family":"Montalvo-Romeral","sequence":"additional","affiliation":[{"name":"G\u00e9n\u00e9thon, Integrare Research Unit UMR_S951, INSERM, Universit\u00e9 Paris-Saclay, Univ Evry, 91002 Evry, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giuseppe","family":"Ronzitti","sequence":"additional","affiliation":[{"name":"G\u00e9n\u00e9thon, Integrare Research Unit UMR_S951, INSERM, Universit\u00e9 Paris-Saclay, Univ Evry, 91002 Evry, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rosario Mar\u00eda","family":"S\u00e1nchez-Mart\u00edn","sequence":"additional","affiliation":[{"name":"GENYO, Centre for Genomics and Oncological Research: Pfizer, University of Granada, Andalusian Regional Government PTS Granada-Avenida de la Ilustraci\u00f3n 114, 18016 Granada, Spain"},{"name":"Department of Medicinal & Organic Chemistry and Excellence Research Unit of \u201cChemistry Applied to Biomedicine and the Environment\u201d, Faculty of Pharmacy, University of Granada, Campus de Cartuja s\/n, 18071 Granada, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1961-8612","authenticated-orcid":false,"given":"Francisco","family":"Mart\u00edn","sequence":"additional","affiliation":[{"name":"GENYO, Centre for Genomics and Oncological Research: Pfizer, University of Granada, Andalusian Regional Government PTS Granada-Avenida de la Ilustraci\u00f3n 114, 18016 Granada, Spain"},{"name":"Departamento de Bioqu\u00edmica y Biolog\u00eda Molecular 3 e Inmunolog\u00eda, Facultad de Medicina, Universidad de Granada, Avda. de la Investigaci\u00f3n 11, 18071 Granada, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pilar","family":"Mu\u00f1oz","sequence":"additional","affiliation":[{"name":"GENYO, Centre for Genomics and 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