Lentiviral gene therapy is able to induce a robust and long-term immune tolerance to the lysosomal enzyme acid alpha-glucosidase (GAA) either expressed as a transgene or supplied via enzyme replacement therapy (ERT), a study in a mouse model of Pompe disease showed.

“This not only allows additional treatment with ERT in patients in whom gene therapy would have insufficient efficacy,” the authors of the study published in Molecular Therapy – Methods & Clinical Development wrote, “but it also prevents antibody formation, likely allowing for a better clinical response to treatment with either lentiviral gene therapy or ERT.”

ERT is the current standard treatment for Pompe disease, which has been life-saving in patients with classic infantile Pompe disease. However, the body often develops neutralizing antibodies against ERT, making the treatment ineffective.

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Hematopoietic stem and progenitor cell-mediated lentiviral gene therapy could be a potential, single-intervention, lifelong therapy that may induce immune tolerance. 

Read more about ERT for Pompe disease

Here, a team of researchers led by Niek P. van Til, PhD, investigated whether ERT could be used as an alternative or additional therapy following lentiviral gene therapy using a mouse model of Pompe disease. 

They found that the expression of the lentiviral gene therapy, even at a subtherapeutic dosage, was enough to induce tolerance to not only the transgene product, but also the ERT administered afterward. 

“Immune tolerance was established within 4-6 weeks after gene therapy,” the researchers reported, adding that the animals tolerated ERT dosages up to 100 mg/kg. This was sufficient to eliminate the accumulation of glycogen in the heart and skeletal muscle and normalize the locomotor function of the mice. 

The researchers also encountered cells derived from hematopoietic stem and progenitor cells expressing GAA in the thymus. This led them to conclude that a central immune tolerance was established.


Liang Q, Vlaar EC, Catalano F, et al. Lentiviral gene therapy prevents anti-human acid α-glucosidase antibody formation in murine Pompe disease. Mol Ther Methods Clin Dev. Published online May 4, 2022. doi:10.1016/j.omtm.2022.04.016