New findings may help track gene therapy success in infantile Pompe
Researchers identify enzyme activity window beyond Myozyme’s influence
The activity levels of Myozyme (alglucosidase alfa) measured in blood and white blood cells may help indicate how well gene therapies are working in people with classic infantile Pompe disease who are receiving enzyme replacement therapy (ERT).
That’s according to a study that analyzed the pharmacokinetics of alglucosidase alfa — how the enzyme moves into, through, and out of the body — including how long it remains detectable after an infusion. Alglucosidase alfa is the active ingredient in Myozyme, which is marketed as Lumizyme in the U.S.
“In patients with classic infantile Pompe disease, ERT must be continued before, during, and after gene therapy, making it essential to determine a specific moment when enzyme activity can be evaluated without the influence of ERT,” the researchers wrote.
The study, “Can Alpha-Glucosidase Activity in Plasma or Leukocytes Serve as a Biomarker for Future Gene Therapy in Classic Infantile Pompe Disease?,” was published in BioDrugs.
What causes Pompe disease and how enzyme replacement therapy works
Pompe disease is caused by mutations in the GAA gene that lead to a missing or poorly functioning GAA enzyme, which normally helps break down glycogen, a complex sugar. As a result, glycogen builds up inside cells, especially muscle cells, leading to symptoms such as muscle weakness and problems with eating, hearing, and breathing.
ERT is a standard treatment for Pompe disease that involves giving a lab-made version of the working GAA enzyme. In this study, researchers in the Netherlands and Italy examined the pharmacological properties of Myozyme, the first approved ERT for Pompe disease, in five children (four girls and one boy) with classic infantile Pompe disease.
The children ranged in age from 2 to 10 at the time of the analysis. They were receiving Myozyme at a prescribed dose of 40 mg/kg, typically once weekly by intravenous (into-the-vein) infusion.
At the end of the infusion, which lasted a median of 5.1 hours, plasma levels of alpha-glucosidase peaked at 830,405 nanomol/17h/mL. This was more than 5,000 times higher than levels seen in healthy individuals and more than 100,000 times higher than in untreated patients. The median half-life, or the time needed for enzyme levels to drop by half, was 3.1 hours.
In white blood cells, also called leukocytes, the highest enzyme activity levels were reached about 24 hours after the start of ERT and did not exceed levels seen in control individuals. The estimated half-life in these cells was two to four days.
Studying how long Myozyme activity remains detectable
The researchers then examined how long enzyme activity remained detectable in blood and leukocytes after a 40 mg/kg dose, using a sample from 21 patients with classic infantile Pompe disease. Seven days after ERT, median enzyme activity was 1.3 times higher than control levels in blood and remained within the control range in leukocytes. After 14 days, median alpha-glucosidase activity in both blood and leukocytes had dropped below levels seen in control individuals.
According to the researchers, this suggests that after 14 days, GAA activity falls to a level at which any subsequent increase from gene therapy could be detected and distinguished from the effects of Myozyme.
“These findings suggest alpha-glucosidase activity in plasma and leukocytes may serve as a surrogate marker for future gene therapy studies, even for patients with classic infantile Pompe disease on ERT,” the investigators wrote.
One study limitation, the researchers said, was the limited amount of data available beyond nine days from ERT, meaning additional samples are needed to confirm the findings.
Several gene therapies are being developed for Pompe disease, aiming to restore the body’s ability to produce a functional GAA enzyme by delivering a working copy of the GAA gene.
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