A team from Regeneron Pharmaceuticals developed an antibody-guided therapeutic able to cross the blood-brain barrier (BBB) that improved glycogen metabolism in a Pompe disease (PD) rodent model and presented their results at the 18th Annual WORLDSymposium 2022.

“The current standard-of-care enzyme replacement therapy treats the peripheral pathologies in Pompe patients, but this therapeutic requires lengthy biweekly infusions and does not cross the BBB to treat the central nervous system (CNS),” the authors explained.

Their BBB-crossing antibody-guided therapeutic, anti-transferrin receptor C (TfRC) single-chain variable fragment (scFv) acid alpha-glucosidase (GAA), could help overcome this issue since it crossed the BBB in Gaa−/− mice and completely rescued the glycogen storage phenotype in the brain and spinal cord. In contrast, untargeted GAA did not have a positive effect on glycogen storage.

Continue Reading

Read more about PD treatment

In addition, the anti-TfRCscFv:GAA was more efficient in clearing glycogen in the heart and skeletal muscle of Gaa−/− mice than untargeted GAA.

To engineer the new system, the team fused the GAA enzyme with an scFv that binds TfRC. The anti-TfRCscFv:GAA was then delivered as a single-dose treatment using an adeno-associated virus vector serotype 8 liver-depot gene therapy.

“This gene therapy eliminates the need for frequent dosing of purified GAA protein and targets both CNS and muscle with a single therapeutic in the PD mouse model,” the authors concluded.

New Engineered GAA Variants Could Overcome Shortcomings of Current ERTs

Mechanistically, the authors explained that the use of the transthyretin promoter ensured a liver-specific expression. The anti-TfRCscFv:GAA was then secreted into the bloodstream and bound TfRC in target tissues, thus facilitating uptake.


Praggastis M, Gale K, Baik A, et al. BBB-targeted GAA delivered as gene therapy treats CNS and muscle in Pompe disease model mice. Mol Genet Metab. 2022;135(2):S100. doi:10.1016/j.ymgme.2021.11.263