BACKGROUND Mucopolysaccharidosis type VI (MPS VI) is an inherited multisystem lysosomal disorder due to arylsulfatase B (ARSB) deficiency that leads to widespread accumulation of glycosaminoglycans (GAG), which are excreted in increased amounts in urine. MPS VI is characterized by progressive dysostosis multiplex, connective tissue and cardiac involvement, and hepatosplenomegaly. Enzyme replacement therapy (ERT) is available but requires life-long and costly intravenous infusions; moreover, it has limited efficacy on diseased skeleton and cardiac valves, compromised pulmonary function, and corneal opacities. METHODS We enrolled nine patients with MPS VI 4 years of age or older in a phase 1/2 open-label gene therapy study. After ERT was interrupted, patients each received a single intravenous infusion of an adeno-associated viral vector serotype 8 expressing ARSB. Participants were sequentially enrolled in one of three dose cohorts: low (three patients), intermediate (two patients), or high (four patients). The primary outcome was safety; biochemical and clinical end points were secondary outcomes. RESULTS The infusions occurred without severe adverse events attributable to the vector, meeting the prespecified end point. Participants in the low and intermediate dose cohorts displayed stable serum ARSB of approximately 20% of the mean healthy value but returned to ERT by 14 months after gene therapy because of increased urinary GAG. Participants in the high-dose cohort had sustained serum ARSB of 30% to 100% of the mean healthy value and a modest urinary GAG increase that did not reach a concentration at which ERT reintroduction was needed. In the high-dose group, there was no clinical deterioration for up to 2 years after gene therapy. CONCLUSIONS Liver-directed gene therapy for participants with MPS VI did not have a dose-limiting sideeffect and adverse event profile; high-dose treatment resulted in ARSB expression over at least 24 months with preliminary evidence of disease stabilization.

Liver-Directed Adeno-Associated Virus–Mediated Gene Therapy for Mucopolysaccharidosis Type VI / Brunetti-Pierri, Nicola; Ferla, Rita; Ginocchio, Virginia Maria; Rossi, Alessandro; Fecarotta, Simona; Romano, Roberta; Parenti, Giancarlo; Yildiz, Yilmaz; Zancan, Stefano; Pecorella, Valentina; Dell’Anno, Margherita; Graziano, Mafalda; Alliegro, Marialuisa; Andria, Generoso; Santamaria, Francesca; Brunetti-Pierri, Raffaella; Simonelli, Francesca; Nigro, Vincenzo; Vargas, Maria; Servillo, Giuseppe; Borgia, Francesco; Soscia, Ernesto; Gargaro, Marco; Funghini, Silvia; Tedesco, Novella; Le Brun, Pierre Romain; Rupar, Charles A.; Prasad, Chitra; O’Callaghan, Mar; Mitchell, John J.; Danos, Olivier; Marteau, Jean-Brice; Galimberti, Stefania; Valsecchi, Maria Grazia; Veron, Philippe; Mingozzi, Federico; Fallarino, Francesca; la Marca, Giancarlo; Sivri, H. Serap; Auricchio, Alberto. - In: NEJM EVIDENCE. - ISSN 2766-5526. - ELETTRONICO. - 1:(2022), pp. 0-0. [10.1056/EVIDoa2200052]

Liver-Directed Adeno-Associated Virus–Mediated Gene Therapy for Mucopolysaccharidosis Type VI

Funghini, Silvia;la Marca, Giancarlo;
2022

Abstract

BACKGROUND Mucopolysaccharidosis type VI (MPS VI) is an inherited multisystem lysosomal disorder due to arylsulfatase B (ARSB) deficiency that leads to widespread accumulation of glycosaminoglycans (GAG), which are excreted in increased amounts in urine. MPS VI is characterized by progressive dysostosis multiplex, connective tissue and cardiac involvement, and hepatosplenomegaly. Enzyme replacement therapy (ERT) is available but requires life-long and costly intravenous infusions; moreover, it has limited efficacy on diseased skeleton and cardiac valves, compromised pulmonary function, and corneal opacities. METHODS We enrolled nine patients with MPS VI 4 years of age or older in a phase 1/2 open-label gene therapy study. After ERT was interrupted, patients each received a single intravenous infusion of an adeno-associated viral vector serotype 8 expressing ARSB. Participants were sequentially enrolled in one of three dose cohorts: low (three patients), intermediate (two patients), or high (four patients). The primary outcome was safety; biochemical and clinical end points were secondary outcomes. RESULTS The infusions occurred without severe adverse events attributable to the vector, meeting the prespecified end point. Participants in the low and intermediate dose cohorts displayed stable serum ARSB of approximately 20% of the mean healthy value but returned to ERT by 14 months after gene therapy because of increased urinary GAG. Participants in the high-dose cohort had sustained serum ARSB of 30% to 100% of the mean healthy value and a modest urinary GAG increase that did not reach a concentration at which ERT reintroduction was needed. In the high-dose group, there was no clinical deterioration for up to 2 years after gene therapy. CONCLUSIONS Liver-directed gene therapy for participants with MPS VI did not have a dose-limiting sideeffect and adverse event profile; high-dose treatment resulted in ARSB expression over at least 24 months with preliminary evidence of disease stabilization.
2022
1
0
0
Brunetti-Pierri, Nicola; Ferla, Rita; Ginocchio, Virginia Maria; Rossi, Alessandro; Fecarotta, Simona; Romano, Roberta; Parenti, Giancarlo; Yildiz, Yilmaz; Zancan, Stefano; Pecorella, Valentina; Dell’Anno, Margherita; Graziano, Mafalda; Alliegro, Marialuisa; Andria, Generoso; Santamaria, Francesca; Brunetti-Pierri, Raffaella; Simonelli, Francesca; Nigro, Vincenzo; Vargas, Maria; Servillo, Giuseppe; Borgia, Francesco; Soscia, Ernesto; Gargaro, Marco; Funghini, Silvia; Tedesco, Novella; Le Brun, Pierre Romain; Rupar, Charles A.; Prasad, Chitra; O’Callaghan, Mar; Mitchell, John J.; Danos, Olivier; Marteau, Jean-Brice; Galimberti, Stefania; Valsecchi, Maria Grazia; Veron, Philippe; Mingozzi, Federico; Fallarino, Francesca; la Marca, Giancarlo; Sivri, H. Serap; Auricchio, Alberto
File in questo prodotto:
File Dimensione Formato  
EVIDoa2200052.pdf

accesso aperto

Tipologia: Pdf editoriale (Version of record)
Licenza: Open Access
Dimensione 799.45 kB
Formato Adobe PDF
799.45 kB Adobe PDF

I documenti in FLORE sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificatore per citare o creare un link a questa risorsa: https://hdl.handle.net/2158/1302341
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus ND
  • ???jsp.display-item.citation.isi??? ND
social impact