Phase I study of liver depot gene therapy in late-onset Pompe disease.

Autor:	Smith EC; Department of Pediatrics, Duke University School of Medicine, Durham, NC, USA., Hopkins S; Asklepios Biopharmaceutical, Inc. (Askbio), Durham, NC, USA., Case LE; Department of Orthopedics, Duke University School of Medicine, Durham, NC, USA., Xu M; Department of Pediatrics, Duke University School of Medicine, Durham, NC, USA., Walters C; Department of Pediatrics, Duke University School of Medicine, Durham, NC, USA., Dearmey S; Department of Pediatrics, Duke University School of Medicine, Durham, NC, USA., Han SO; Department of Pediatrics, Duke University School of Medicine, Durham, NC, USA., Spears TG; Clinical Trials Statistics, Duke Clinical Research Institute, Durham, NC, USA., Chichester JA; Immunology Core, Gene Therapy Program, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Bossen EH; Department of Pathology, Duke University Medical Center, Durham, NC, USA., Hornik CP; Department of Pediatrics, Duke University School of Medicine, Durham, NC, USA., Cohen JL; Department of Pediatrics, Duke University School of Medicine, Durham, NC, USA., Bali D; Department of Pediatrics, Duke University School of Medicine, Durham, NC, USA., Kishnani PS; Department of Pediatrics, Duke University School of Medicine, Durham, NC, USA., Koeberl DD; Department of Pediatrics, Duke University School of Medicine, Durham, NC, USA. Electronic address: dwight.koeberl@duke.edu.
Jazyk:	angličtina
Zdroj:	Molecular therapy : the journal of the American Society of Gene Therapy [Mol Ther] 2023 Jul 05; Vol. 31 (7), pp. 1994-2004. Date of Electronic Publication: 2023 Feb 18.
DOI:	10.1016/j.ymthe.2023.02.014
Abstrakt:	Gene therapy with an adeno-associated virus serotype 8 (AAV8) vector (AAV8-LSPhGAA) could eliminate the need for enzyme replacement therapy (ERT) by creating a liver depot for acid α-glucosidase (GAA) production. We report initial safety and bioactivity of the first dose (1.6 × 10 12 vector genomes/kg) cohort (n = 3) in a 52-week open-label, single-dose, dose-escalation study (NCT03533673) in patients with late-onset Pompe disease (LOPD). Subjects discontinued biweekly ERT after week 26 based on the detection of elevated serum GAA activity and the absence of clinically significant declines per protocol. Prednisone (60 mg/day) was administered as immunoprophylaxis through week 4, followed by an 11-week taper. All subjects demonstrated sustained serum GAA activities from 101% to 235% of baseline trough activity 2 weeks following the preceding ERT dose. There were no treatment-related serious adverse events. No subject had anti-capsid T cell responses that decreased transgene expression. Muscle biopsy at week 24 revealed unchanged muscle glycogen content in two of three subjects. At week 52, muscle GAA activity for the cohort was significantly increased (p < 0.05). Overall, these initial data support the safety and bioactivity of AAV8-LSPhGAA, the safety of withdrawing ERT, successful immunoprophylaxis, and justify continued clinical development of AAV8-LSPhGAA therapy in Pompe disease. Competing Interests: Declaration of interests D.D.K. and P.S.K. have developed the technology that is being used in the study. If the technology is commercially successful in the future, the developers and Duke University may benefit financially. D.D.K. has served as a consultant for Sangamo Therapeutics and for Genzyme Sanofi, Amicus, and Vertex; has received grant support from Viking Therapeutics, Genzyme Sanofi, Roivant Rare Diseases, and Amicus; and has equity in Askbio, which is developing gene therapy for Pompe disease. E.C.S. received salary support for his role as PI on this study. S.H. is an employee of Askbio. L.E.C. has received honoraria from Genzyme Sanofi, has participated in research supported by Genzyme Sanofi, Valerion, Biomarin, and by Roivant Sciences; and is a member of the Pompe Registry North American Board of Advisors Genzyme Sanofi. D.B. has received research grant support and travel funds from Genzyme Sanofi, Baebies Inc., Biomarin, Alexion Inc., SOBI biopharma, and JCR biopharma. P.S.K. has received research/grant support from Genzyme Sanofi and Valerion Therapeutics. She received consulting fees and honoraria from Genzyme Sanofi, Amicus Therapeutics, and Vertex. She is a member of the Pompe and Gaucher Disease Registry Advisory Board for Genzyme Sanofi and on the Amicus Scientific advisory board. (Copyright © 2023 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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