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

Pompe disease, a rare genetic neuromuscular disorder, is caused by a deficiency of acid alpha-glucosidase (GAA), leading to the accumulation of glycogen in lysosomes and the progressive development of muscle weakness. The current standard treatment, enzyme replacement therapy (ERT), is not curative and demonstrates poor penetration into skeletal muscle and the central and peripheral nervous systems, susceptibility to immune responses against the recombinant enzyme, and the need 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 CNS samples to gain insights into the underlying mechanisms of phenotype correction. ### Competing Interest Statement All authors are current or former employees of AVROBIO, Inc., Cambridge, MA, USA during the conception and writing of the manuscript, except VM, MR, and AS. 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.