Targeted enzyme replacement therapy may be better than traditional enzyme replacement therapy in treating Pompe disease and other lysosomal diseases, according to a study by researchers from Regeneron Pharmaceuticals published in Molecular Therapy.

Targeted enzyme replacement therapy uses antibody-enzyme fusion proteins to target the enzyme to specific cell types in the body. In the case of lysosomal diseases, the antibody portion of the fusion protein recognizes transmembrane proteins that play a role in lysosomal trafficking and are preferentially expressed in the cells most affected by the disease.

Enzyme replacement therapy is used to treat several lysosomal diseases, including Pompe disease. However, the currently available enzyme replacement therapies cannot correct disease phenotype in all affected organs because the recombinant enzyme does not reach every cell where it is needed.

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Here, a team led by Katherine D. Cygnar, PhD, director of genome engineering technologies at Regeneron, showed that targeted enzyme replacement therapy could better treat the skeletal muscle phenotype in a mouse model of Pompe disease both as a protein replacement therapy and as a gene therapy. This therapy results in liver cells being infected with adeno-associated viruses that carry a healthy copy of the acid alpha-glucosidase enzyme (GAA) enzyme, which is mutated in Pompe disease, so that they can produce and secrete GAA and allow for continuous dosing enzyme replacement therapy.

“Swapping (or even combining) targeting antibodies to different protein targets to tune delivery to desired cell types, while avoiding other cell types, may turn out to be a significant advance in the field of enzyme therapies,” the researchers concluded.

Enzyme replacement therapy is currently the only available treatment for Pompe disease. It was first approved in 2006 to treat patients with infantile-onset Pompe disease. However, it may lead to adverse events such as allergic and immune reactions.


Baik AD, Calafati P, Zhang X, et al. Cell-type selective targeted delivery of a recombinant lysosomal enzyme for enzyme therapies. Mol Ther. Published online August 13, 2021. doi:10.1016/j.ymthe.2021.08.020