Treatment of infantile-onset Pompe disease in a rat model with muscle-directed AAV gene therapy.

Autor:	Muñoz S; Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, 08193, Bellaterra, Spain; Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, 08193, Bellaterra, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, Instituto de Salud Carlos III, Spain., Bertolin J; Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, 08193, Bellaterra, Spain; Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, 08193, Bellaterra, Spain., Jimenez V; Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, 08193, Bellaterra, Spain; Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, 08193, Bellaterra, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, Instituto de Salud Carlos III, Spain., Jaén ML; Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, 08193, Bellaterra, Spain; Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, 08193, Bellaterra, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, Instituto de Salud Carlos III, Spain., Garcia M; Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, 08193, Bellaterra, Spain; Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, 08193, Bellaterra, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, Instituto de Salud Carlos III, Spain., Pujol A; Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, 08193, Bellaterra, Spain; Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, 08193, Bellaterra, Spain., Vilà L; Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, 08193, Bellaterra, Spain; Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, 08193, Bellaterra, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, Instituto de Salud Carlos III, Spain., Sacristan V; Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, 08193, Bellaterra, Spain; Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, 08193, Bellaterra, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, Instituto de Salud Carlos III, Spain., Barbon E; INTEGRARE, Genethon, INSERM UMR951, Univ Evry, Université Paris-Saclay, 91002, Evry, France., Ronzitti G; INTEGRARE, Genethon, INSERM UMR951, Univ Evry, Université Paris-Saclay, 91002, Evry, France., El Andari J; Department of Infectious Diseases/Virology, Section Viral Vector Technologies, BioQuant Center, Medical Faculty, University of Heidelberg, 69120, Heidelberg, Germany., Tulalamba W; Department of Gene Therapy & Regenerative Medicine, Vrije Universiteit Brussel (VUB), B-1090, Brussels, Belgium; Department of Cardiovascular Sciences, Center for Molecular & Vascular Biology, University of Leuven, 3000, Leuven, Belgium., Pham QH; Department of Gene Therapy & Regenerative Medicine, Vrije Universiteit Brussel (VUB), B-1090, Brussels, Belgium; Department of Cardiovascular Sciences, Center for Molecular & Vascular Biology, University of Leuven, 3000, Leuven, Belgium., Ruberte J; Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, 08193, Bellaterra, Spain; Department of Animal Health and Anatomy, School of Veterinary Medicine, Universitat Autònoma de Barcelona, 08193, Bellaterra, Spain., VandenDriessche T; Department of Gene Therapy & Regenerative Medicine, Vrije Universiteit Brussel (VUB), B-1090, Brussels, Belgium; Department of Cardiovascular Sciences, Center for Molecular & Vascular Biology, University of Leuven, 3000, Leuven, Belgium., Chuah MK; Department of Gene Therapy & Regenerative Medicine, Vrije Universiteit Brussel (VUB), B-1090, Brussels, Belgium; Department of Cardiovascular Sciences, Center for Molecular & Vascular Biology, University of Leuven, 3000, Leuven, Belgium., Grimm D; Department of Infectious Diseases/Virology, Section Viral Vector Technologies, BioQuant Center, Medical Faculty, University of Heidelberg, 69120, Heidelberg, Germany; German Center for Infection Research (DZIF) and German Center for Cardiovascular Research (DZHK), Partner site Heidelberg, Heidelberg, Germany., Mingozzi F; INTEGRARE, Genethon, INSERM UMR951, Univ Evry, Université Paris-Saclay, 91002, Evry, France., Bosch F; Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, 08193, Bellaterra, Spain; Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, 08193, Bellaterra, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, Instituto de Salud Carlos III, Spain. Electronic address: fatima.bosch@uab.es.
Jazyk:	angličtina
Zdroj:	Molecular metabolism [Mol Metab] 2024 Mar; Vol. 81, pp. 101899. Date of Electronic Publication: 2024 Feb 10.
DOI:	10.1016/j.molmet.2024.101899
Abstrakt:	Objective: Pompe disease (PD) is caused by deficiency of the lysosomal enzyme acid α-glucosidase (GAA), leading to progressive glycogen accumulation and severe myopathy with progressive muscle weakness. In the Infantile-Onset PD (IOPD), death generally occurs <1 year of age. There is no cure for IOPD. Mouse models of PD do not completely reproduce human IOPD severity. Our main objective was to generate the first IOPD rat model to assess an innovative muscle-directed adeno-associated viral (AAV) vector-mediated gene therapy. Methods: PD rats were generated by CRISPR/Cas9 technology. The novel highly myotropic bioengineered capsid AAVMYO3 and an optimized muscle-specific promoter in conjunction with a transcriptional cis-regulatory element were used to achieve robust Gaa expression in the entire muscular system. Several metabolic, molecular, histopathological, and functional parameters were measured. Results: PD rats showed early-onset widespread glycogen accumulation, hepato- and cardiomegaly, decreased body and tissue weight, severe impaired muscle function and decreased survival, closely resembling human IOPD. Treatment with AAVMYO3-Gaa vectors resulted in widespread expression of Gaa in muscle throughout the body, normalizing glycogen storage pathology, restoring muscle mass and strength, counteracting cardiomegaly and normalizing survival rate. Conclusions: This gene therapy holds great potential to treat glycogen metabolism alterations in IOPD. Moreover, the AAV-mediated approach may be exploited for other inherited muscle diseases, which also are limited by the inefficient widespread delivery of therapeutic transgenes throughout the muscular system. Competing Interests: Declaration of competing interest D.G. is a cofounder of AaviGen GmbH. F.M. works at Spark Therapeutics. D.G., J.E.A., T.V., M.K.C. and W.T. are inventors on patent applications related to this work. All other authors declare that they have no competing interests. The AAV plasmid bearing the GAA expression cassette including a full map can be obtained via an MTA from the Vrije Universiteit Brussel. The AAVMYO3 helper plasmid including a full map can easily be obtained by academic institutions via a standard non-commercial MTA from Heidelberg University Hospital. (Copyright © 2024 The Authors. Published by Elsevier GmbH.. All rights reserved.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu