Preclinical lentiviral hematopoietic stem cell gene therapy corrects Pompe disease-related muscle and neurological manifestations.

Autor:	Yoon JK; AVROBIO, Inc., Cambridge, MA 02139, USA., Schindler JW; AVROBIO, Inc., Cambridge, MA 02139, USA., Loperfido M; AVROBIO, Inc., Cambridge, MA 02139, USA., Baricordi C; AVROBIO, Inc., Cambridge, MA 02139, USA., DeAndrade MP; AVROBIO, Inc., Cambridge, MA 02139, USA., Jacobs ME; AVROBIO, Inc., Cambridge, MA 02139, USA., Treleaven C; AVROBIO, Inc., Cambridge, MA 02139, USA., Plasschaert RN; AVROBIO, Inc., Cambridge, MA 02139, USA., Yan A; AVROBIO, Inc., Cambridge, MA 02139, USA., Barese CN; AVROBIO, Inc., Cambridge, MA 02139, USA., Dogan Y; AVROBIO, Inc., Cambridge, MA 02139, USA., Chen VP; AVROBIO, Inc., Cambridge, MA 02139, USA., Fiorini C; AVROBIO, Inc., Cambridge, MA 02139, USA., Hull F; AVROBIO, Inc., Cambridge, MA 02139, USA., Barbarossa L; AVROBIO, Inc., Cambridge, MA 02139, USA., Unnisa Z; AVROBIO, Inc., Cambridge, MA 02139, USA., Ivanov D; AVROBIO, Inc., Cambridge, MA 02139, USA., Kutner RH; AVROBIO, Inc., Cambridge, MA 02139, USA., Guda S; AVROBIO, Inc., Cambridge, MA 02139, USA., Oborski C; AVROBIO, Inc., Cambridge, MA 02139, USA., Maiwald T; AVROBIO, Inc., Cambridge, MA 02139, USA., Michaud V; Lady Davis Institute for Medical Research, Jewish General Hospital, McGill University, Montreal, Quebec H3T 1E2, Canada., Rothe M; Institute of Experimental Hematology, Hannover Medical School, Carl-Neuberg-Straße 1, 30625 Hannover, Germany., Schambach A; Institute of Experimental Hematology, Hannover Medical School, Carl-Neuberg-Straße 1, 30625 Hannover, Germany; Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA., Pfeifer R; AVROBIO, Inc., Cambridge, MA 02139, USA., Mason C; AVROBIO, Inc., Cambridge, MA 02139, USA; Advanced Centre for Biochemical Engineering, University College London, London WC1E 6AE, UK., Biasco L; AVROBIO, Inc., Cambridge, MA 02139, USA; Zayed Centre for Research, University College London, London WC1N 1DZ, UK., van Til NP; AVROBIO, Inc., Cambridge, MA 02139, USA; Department of Child Neurology, Amsterdam Leukodystrophy Center, Emma Children's Hospital, Amsterdam University Medical Center, VU University, and Amsterdam Neuroscience, Cellular & Molecular Mechanisms, 1081 HV, Amsterdam, the Netherlands; Department of Integrative Neurophysiology, Center for Neurogenomics and Cognitive Research, Vrije Universiteit Amsterdam, 1081 HV, Amsterdam, the Netherlands. Electronic address: n.p.vantil@amsterdamumc.nl.
Jazyk:	angličtina
Zdroj:	Molecular therapy : the journal of the American Society of Gene Therapy [Mol Ther] 2024 Sep 17. Date of Electronic Publication: 2024 Sep 17.
DOI:	10.1016/j.ymthe.2024.09.024
Abstrakt:	Pompe disease, a rare genetic neuromuscular disorder, is caused by a deficiency of acid alpha-glucosidase (GAA), leading to an accumulation of glycogen in lysosomes, and resulting in the progressive development of muscle weakness. The current standard treatment, enzyme replacement therapy (ERT), is not curative and has limitations such as poor penetration into skeletal muscle and both the central and peripheral nervous systems, a risk of immune responses against the recombinant enzyme, and the requirement for high doses and frequent infusions. To overcome these limitations, lentiviral vector-mediated hematopoietic stem and progenitor cell (HSPC) gene therapy has been proposed as a next-generation approach for treating Pompe disease. This study demonstrates the potential of lentiviral HSPC gene therapy to reverse the pathological effects of Pompe disease in a preclinical mouse model. It includes a comprehensive safety assessment via integration site analysis, along with single-cell RNA sequencing analysis of central nervous tissue samples to gain insights into the underlying mechanisms of phenotype correction. Competing Interests: Declaration of interests All authors were former employees of AVROBIO, Inc., Cambridge, MA, USA during the conception and writing of the manuscript, except V.M., M.R., and A.S. N.P.v.T. and C.M. are inventors on patents in the field of HSC gene therapy. AVROBIO, Inc., has a preclinical gene therapy program for Pompe disease (AVR-RD-03) based on a genetically modified HSPC platform using lentiviral vectors. Collection of data and analysis was performed as part of the program. This research received no external funding and was sponsored by AVROBIO, Inc. (Copyright © 2024 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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