Lentiviral vector-mediated hematopoietic stem and progenitor cell (HSPC) gene therapy may lead to increased acid alpha-glucosidase (GAA) levels in animal models, demonstrating its therapeutic potential in Pompe disease (PD), according to a recently published study in Methods and Clinical Development

Currently, enzyme replacement therapy (ERT) constitutes the standard of care for patients with PD, which has been proven to increase survival in patients with PD. However, ERT requires lifelong biweekly administration, penetrates poorly in muscle and the central nervous system, and risks recombinant enzyme immunogenicity, wrote Chris Mason, of the University College London in the United Kingdom, and colleagues.

Therefore, researchers have made efforts to assess potential alternatives to ERT. Previous attempts to perform allogeneic HSPC transplantation in patients with PD have been unsuccessful. Nevertheless, lentiviral vector-mediated HSPC gene therapy has shown promising results in clinical trials of neurometabolic diseases such as X-linked adrenoleukodystrophy, the authors noted.

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“To enhance the efficacy of treatment by HSPC gene therapy, we tested ten lentiviral vectors expressing engineered human GILT-tagged GAA sequences in vitro,” the authors wrote. 

The 11 generated lentiviral constructs included sequences with codon-optimized GAA (GAAco) sequences and an IGF2 tag fused to the N terminus of the catalytic GAA sequence (GILTco). Constructs were intravenously infused in GAA-negative mice.

The infusion of the majority of variants used in the study led to the production of supraphysiological levels of GAA in infused mice, resulting in glycogen reduction and symptom improvement. GAAco had a higher GAA activity than the GILTco variants. 

In concordance with previous studies, almost all constructs decreased heart and diaphragm glycogen deposits to almost undetectable levels; however, glycogen reduction was less dramatic in skeletal muscle. Unlike previous studies, no significant hypoglycemia occurred due to IGF2 binding to the insulin receptor (IR).

“This study demonstrated the therapeutic potential of lentiviral HSPC gene therapy exploiting optimized GAA tagged coding sequences to reverse Pompe disease pathology in a preclinical mouse model, providing promising vector candidates for further investigation,” the authors concluded. 


Dogan Y, Barese CN, Schindler JW, et al. Screening chimeric GAA variants in preclinical study results in hematopoietic stem cell gene therapy candidate vectors for Pompe diseaseMol Ther Methods Clin Dev. Published online November 4, 2022. doi:10.1016/j.omtm.2022.10.017