Multi-year enzyme expression in patients with mucopolysaccharidosis type VI after liver-directed gene therapy.

Autor:	Rossi A; Department of Translational Medicine, 'Federico II' University, 80131 Naples, Italy., Romano R; Department of Translational Medicine, 'Federico II' University, 80131 Naples, Italy., Fecarotta S; Dipartimento ad Attività Integrata Materno Infantile, 'Federico II' University Hospital, 80131 Naples, Italy., Dell'Anno M; Telethon Institute of Genetics and Medicine, 80078 Pozzuoli, Italy., Pecorella V; Telethon Institute of Genetics and Medicine, 80078 Pozzuoli, Italy., Passeggio R; Department of Translational Medicine, 'Federico II' University, 80131 Naples, Italy; Telethon Institute of Genetics and Medicine, 80078 Pozzuoli, Italy., Zancan S; Fondazione Telethon ETS, 00185 Rome, Italy., Parenti G; Department of Translational Medicine, 'Federico II' University, 80131 Naples, Italy; Telethon Institute of Genetics and Medicine, 80078 Pozzuoli, Italy., Santamaria F; Department of Translational Medicine, 'Federico II' University, 80131 Naples, Italy., Borgia F; Department of Advanced Biomedical Sciences, Divisions of Cardiology and Cardiothoracic Surgery, 'Federico II' University, 80131 Naples, Italy., Deodato F; Division of Metabolic Diseases and Hepatology, Ospedale Pediatrico Bambino Gesù, IRCCS, 00165 Rome, Italy., Funghini S; Newborn Screening, Clinical Biochemistry and Clinical Pharmacy Lab, Meyer Children's Hospital IRCCS, 50134 Florence, Italy., Rupar CA; Division of Medical Genetics, London Health Science Centre, Western University, London, ON N6G 2M1, Canada; Department of Pathology and Laboratory Medicine, London Health Sciences Centre, Western University, London, ON N6A 5C1, Canada., Prasad C; Division of Medical Genetics, London Health Science Centre, Western University, London, ON N6G 2M1, Canada., O'Callaghan M; Servicio de Neurologıa, Unidad de Enfermedades Metabolicas, Hospital Sant Joan de Deu, 08950 Barcelona, Spain., Mitchell JJ; Division of Medical Genetics and Division of Pediatric Endocrinology, McGill University Health Centre, Montreal, QC H4A 3J1, Canada., Valsecchi MG; Bicocca Bioinformatics Biostatistics and Bioimaging B4 Center, School of Medicine and Surgery, University of Milano-Bicocca, 20126 Monza, Italy; Biostatistics and Clinical Epidemiology, Fondazione IRCCS San Gerardo dei Tintori, 20900 Monza, Italy., la Marca G; Newborn Screening, Clinical Biochemistry and Clinical Pharmacy Lab, Meyer Children's Hospital IRCCS, 50134 Florence, Italy; Department of Experimental and Clinical Biomedical Sciences, University of Florence, 50134 Florence, Italy., Galimberti S; Bicocca Bioinformatics Biostatistics and Bioimaging B4 Center, School of Medicine and Surgery, University of Milano-Bicocca, 20126 Monza, Italy; Biostatistics and Clinical Epidemiology, Fondazione IRCCS San Gerardo dei Tintori, 20900 Monza, Italy., Auricchio A; Telethon Institute of Genetics and Medicine, 80078 Pozzuoli, Italy; Department of Advanced Biomedical Sciences, 'Federico II' University, 80131 Naples, Italy; Scuola Superiore Meridionale (SSM, School of Advanced Studies), Genomics and Experimental Medicine Program, University of Naples Federico II, 80138 Naples, Italy. Electronic address: auricchio@tigem.it., Brunetti-Pierri N; Department of Translational Medicine, 'Federico II' University, 80131 Naples, Italy; Telethon Institute of Genetics and Medicine, 80078 Pozzuoli, Italy; Scuola Superiore Meridionale (SSM, School of Advanced Studies), Genomics and Experimental Medicine Program, University of Naples Federico II, 80138 Naples, Italy. Electronic address: brunetti@tigem.it.
Jazyk:	angličtina
Zdroj:	Med (New York, N.Y.) [Med] 2024 Nov 14, pp. 100544. Date of Electronic Publication: 2024 Nov 14.
DOI:	10.1016/j.medj.2024.10.021
Abstrakt:	Background: Mucopolysaccharidosis type VI (MPS VI) is due to a deficiency of the lysosomal enzyme arylsulfatase B (ARSB) that results in multi-organ accumulation of glycosaminoglycans (GAGs). Limitations of current treatments prompted the development of a liver-directed gene therapy clinical trial for MPS VI. Methods: We report the long-term follow-up of patients with MPS VI who discontinued enzyme replacement therapy (ERT) and received a single intravenous infusion of high-dose (6 × 10 12 genome copies/kg) recombinant adeno-associated virus serotype 8 (AAV8) vector expressing ARSB under the control of a liver-specific promoter (ClinicalTrials.gov: NCT03173521). Primary outcomes were safety and urinary GAG excretion. Secondary outcomes were endurance and respiratory function. Findings: Median follow-up time was 45 months (n = 4, three females and one male; age range: 5-10 years). No late-emergent safety events were observed. Patients showed sustained serum ARSB activity (38%-67% of mean healthy reference values), a modest increase in urinary GAG concentrations, and no relevant changes in endurance, cardiac, or pulmonary function. In one of the four patients, ERT was restarted because of elevated urinary GAGs without decreased serum ARSB activity up to about 2.5 years after gene transfer. Liver and spleen size remained within the reference ranges. Conclusions: A single intravenous administration of AAV8.TBG.hARSB was safe and resulted in sustained ARSB expression and a modest increase in urinary GAGs in most patients, thus supporting liver-directed gene therapy for MPS VI. Funding: This study was sponsored by the Telethon Foundation ETS, the European Union, the Isaac Foundation, and the Italian Ministry of University and Research. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2024 Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu