Can Alpha-Glucosidase Activity in Plasma or Leukocytes Serve as a Biomarker for Future Gene Therapy in Classic Infantile Pompe Disease?

We studied alpha-glucosidase activity in plasma and leukocytes after an infusion of 40 mg/kg of recombinant alglucosidase alpha in patients with classic infantile Pompe disease to assess the pharmacokinetics and identify potential surrogate efficacy markers of gene therapy in patients on enzyme replacement therapy. Samples were collected by pharmacokinetic curves (n = 5) and random samples (n = 21 patients). Alpha-glucosidase activity was measured in plasma (substrate 4-methylumbelliferyl-α-d-glucopyranoside, MU) and leukocytes (substrate glycogen, Gn, and MU). Plasma peak concentration occurred at the end of the infusion, reaching concentrations > 5000 and > 100,000 times higher than the control and untreated patient levels, with a median half-life of 3.1 h (1.3–4.2 h). In leukocytes, plasma peak concentration occurred 24 h after the start of enzyme replacement therapy; plasma peak concentration did not exceed the control level (0.7 [Gn] and 0.9 [MU] times higher than controls). The estimated half-life was 2–4 days. Seven days after enzyme replacement therapy, median enzyme activity was 1.3 times higher than the control levels in plasma and within the control range in leukocytes; after 14 days, median values in plasma and leukocytes were below the control level. These findings suggest alpha-glucosidase activity in plasma and leukocytes may serve as an efficacy marker for gene therapy studies in patients with classic infantile Pompe disease receiving enzyme replacement therapy. Similar studies with next-generation enzyme replacement therapy are advised.