Lentiviral gene therapy prevents anti-human acid α-glucosidase antibody formation in murine Pompe disease.

Autor:	Liang Q; Department of Hematology and Research Laboratory of Hematology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China.; Molecular Stem Cell Biology, Department of Clinical Genetics, Erasmus MC University Medical Center, 3015GE Rotterdam, the Netherlands.; Department of Pediatrics, Erasmus MC University Medical Center, 3015GE Rotterdam, the Netherlands.; Center for Lysosomal and Metabolic Diseases, Erasmus MC University Medical Center, 3015GE Rotterdam, the Netherlands., Vlaar EC; Molecular Stem Cell Biology, Department of Clinical Genetics, Erasmus MC University Medical Center, 3015GE Rotterdam, the Netherlands.; Department of Pediatrics, Erasmus MC University Medical Center, 3015GE Rotterdam, the Netherlands.; Center for Lysosomal and Metabolic Diseases, Erasmus MC University Medical Center, 3015GE Rotterdam, the Netherlands., Catalano F; Molecular Stem Cell Biology, Department of Clinical Genetics, Erasmus MC University Medical Center, 3015GE Rotterdam, the Netherlands.; Department of Pediatrics, Erasmus MC University Medical Center, 3015GE Rotterdam, the Netherlands.; Center for Lysosomal and Metabolic Diseases, Erasmus MC University Medical Center, 3015GE Rotterdam, the Netherlands., Pijnenburg JM; Molecular Stem Cell Biology, Department of Clinical Genetics, Erasmus MC University Medical Center, 3015GE Rotterdam, the Netherlands.; Department of Pediatrics, Erasmus MC University Medical Center, 3015GE Rotterdam, the Netherlands.; Center for Lysosomal and Metabolic Diseases, Erasmus MC University Medical Center, 3015GE Rotterdam, the Netherlands., Stok M; Molecular Stem Cell Biology, Department of Clinical Genetics, Erasmus MC University Medical Center, 3015GE Rotterdam, the Netherlands.; Department of Pediatrics, Erasmus MC University Medical Center, 3015GE Rotterdam, the Netherlands.; Center for Lysosomal and Metabolic Diseases, Erasmus MC University Medical Center, 3015GE Rotterdam, the Netherlands.; Department of Hematology, Erasmus MC University Medical Center, 3015GE Rotterdam, the Netherlands., van Helsdingen Y; Department of Hematology, Erasmus MC University Medical Center, 3015GE Rotterdam, the Netherlands., Vulto AG; Hospital Pharmacy, Erasmus MC University Medical Center, 3015GE Rotterdam, the Netherlands., Unger WWJ; Laboratory of Pediatrics, Erasmus MC University Medical Center-Sophia Children's Hospital, 3015GE Rotterdam, the Netherlands., van der Ploeg AT; Department of Pediatrics, Erasmus MC University Medical Center, 3015GE Rotterdam, the Netherlands.; Center for Lysosomal and Metabolic Diseases, Erasmus MC University Medical Center, 3015GE Rotterdam, the Netherlands., Pijnappel WWMP; Molecular Stem Cell Biology, Department of Clinical Genetics, Erasmus MC University Medical Center, 3015GE Rotterdam, the Netherlands.; Department of Pediatrics, Erasmus MC University Medical Center, 3015GE Rotterdam, the Netherlands.; Center for Lysosomal and Metabolic Diseases, Erasmus MC University Medical Center, 3015GE Rotterdam, the Netherlands., van Til NP; Department of Hematology, Erasmus MC University Medical Center, 3015GE Rotterdam, the Netherlands.
Jazyk:	angličtina
Zdroj:	Molecular therapy. Methods & clinical development [Mol Ther Methods Clin Dev] 2022 May 04; Vol. 25, pp. 520-532. Date of Electronic Publication: 2022 May 04 (Print Publication: 2022).
DOI:	10.1016/j.omtm.2022.04.016
Abstrakt:	Enzyme replacement therapy (ERT) is the current standard treatment for Pompe disease, a lysosomal storage disorder caused by deficiency of the lysosomal enzyme acid alpha-glucosidase (GAA). ERT has shown to be lifesaving in patients with classic infantile Pompe disease. However, a major drawback is the development of neutralizing antibodies against ERT. Hematopoietic stem and progenitor cell-mediated lentiviral gene therapy (HSPC-LVGT) provides a novel, potential lifelong therapy with a single intervention and may induce immune tolerance. Here, we investigated whether ERT can be safely applied as additional or alternative therapy following HSPC-LVGT in a murine model of Pompe disease. We found that lentiviral expression at subtherapeutic dose was sufficient to induce tolerance to the transgene product, as well as to subsequently administered ERT. Immune tolerance was established within 4-6 weeks after gene therapy. The mice tolerated ERT doses up to 100 mg/kg, allowing ERT to eliminate glycogen accumulation in cardiac and skeletal muscle and normalizing locomotor function. The presence of HSPC-derived cells expressing GAA in the thymus suggested the establishment of central immune tolerance. These findings demonstrate that lentiviral gene therapy in murine Pompe disease induced robust and long-term immune tolerance to GAA either expressed by a transgene or supplied as ERT. Competing Interests: A.T.v.d.P. has received consulting fees from Sanofi Genzyme and has provided consulting services, participated in advisory board meetings, and received grants for premarketing studies and research from industries via agreements between Erasmus MC and the industry. N.P.v.T. is an employee of AVROBIO (Cambridge, MA). (© 2022 The Author(s).)
Databáze:	MEDLINE
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