Lentiviral hematopoietic stem and progenitor cell gene therapy has therapeutic potential in Pompe disease, as shown in a mouse model of the disease. 

Enzyme replacement therapy is the current standard of care for Pompe disease, but the effects of the penetration of enzyme replacement therapy into skeletal muscles and the nervous system are poor. This means the treatment has to be given at a high dose and frequency, potentially leading to immunogenicity.

To overcome these drawbacks, lentiviral vector-mediated hematopoietic stem and progenitor cell gene therapy is being investigated.

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In the present study, the investigators, led by Niek van Til, PhD, from Amsterdam University Medical Centers in the Netherlands, assessed a mouse model of Pompe disease and a clinically relevant promoter driving 9 engineered acid alpha-glucosidase (GAA) coding sequences. These sequences incorporated distinct codon optimizations and peptide tags.

The team found that vectors including only tags targeting glycosylation-independent lysosomes increased secretion and improved glycogen reduction as well as myofiber and central nervous system vacuolation in key tissues. However, the levels and activity of the GAA enzyme, the enzyme that is deficient or completely missing in Pompe disease, were consistently lower compared to the native GAA enzyme. 

The researchers also found that the treatment led to genetically modified microglial cells in the brains of the animals, albeit at low levels. However, they did provide robust phenotypic correction. 

When they introduced an amino acid substitution in the tag, the researchers found that insulin receptor-mediated signaling was reduced, but this did not affect blood glucose levels. 

The researchers concluded that this study provides “promising vector candidates for further investigation.”

The study is published in the journal Molecular Therapy – Methods & Clinical Development

Pompe disease is caused by a mutation in the gene encoding for the GAA enzyme, the normal role of which is to break glycogen down to glucose.


Dogan Y, Barese C, Schindler J, et al. Screening of chimeric GAA variants in a preclinical study of Pompe disease results in candidate vectors for hematopoietic stem cell gene therapy. Mol Ther Methods Clin Dev. Published online November 3, 2022. doi:10.1016/j.omtm.2022.10.017