Plant-based ERT May Hold Promise in Pompe Disease, Small Study Suggests
Since the study focused on muscle cells grown in the lab, further research in a whole organism, such as a mouse model, are needed to confirm the therapeutic potential of this new ERT, the researchers said.
The study, “Moss-Derived Human Recombinant GAA Provides an Optimized Enzyme Uptake in Differentiated Human Muscle Cells of Pompe Disease,” was published in the International Journal of Molecular Sciences.
Pompe disease is a lysosomal storage disorder caused by a deficiency in the acid alpha-glucosidase (GAA) enzyme. GAA breaks down glycogen — a large sugar molecule used for energy storage — within small recycling structures inside cells called lysosomes.
GAA deficiency leads to the buildup of glycogen in several tissues, resulting in widespread weakness in skeletal muscles, including those involved in breathing, and in heart muscle.
The only approved treatment for Pompe disease is an ERT, alglucosidase alfa, which delivers a lab-made version of GAA to patients once or twice a week. Alglucosidase alfa is marketed by Sanofi Genzyme as Lumizyme in the U.S., and Myozyme in the European Union.
The therapy contains a small “molecular tag” called mannose-6-phosphate (M6P) that binds to M6P receptors on the cell surface, allowing not only their entry into cells, but also direct transport to lysosomes.
While treatment with Myozyme efficiently lessens glycogen buildup and damage in cardiac muscle in most cases, the benefits in skeletal muscle and other tissues are limited. As such, there is a need for improved ERTs that may provide more stability and effectiveness.
Increasing evidence suggests that the mannose receptor (MR) may represent an effective alternative to the M6P receptor in delivering ERTs to lysosomes. MR, located on the surface of several cells (including muscle), recognizes other “tags” named mannose, fucose, and N‐acetylglucosamine.
Previous studies have shown that plant-derived enzymes with MR-directed tags were able to effectively target lysosomes. One such enzyme, produced in a type of moss, entered a clinical trial as a potential treatment of Fabry disease, another lysosomal storage disorder.
Now, researchers in Germany compared the uptake and effects of three versions of human GAA (with MR-directed tags) produced in a type of moss with that of Myozyme in myoblasts and myotubes derived from mice and four Pompe patients, and two healthy individuals.
Myoblasts are embryonic precursors of muscle cells, while myotubes are immature forms of a muscle fiber, closer to the mature muscle cell targeted by ERTs in Pompe disease.
Two of the moss-derived GAA versions (GAA-Man3 and GAA-Man5) had mannose tags, while the other (GAA-GnGn) had a N-acetylglucosamine tag, which is derived from glucose.
Results showed that, in general, GAAs’ uptake was more efficient in myoblasts than in myotubes. The most effective uptake was observed for Myozyme and moss-derived GAA-GnGn in myoblasts and for GAA-GnGn and GAA-Man5 in myotubes.
While all four treatments resulted in a significant increase in GAA activity in mouse and human myoblasts, Myozyme had the most pronounced effect.
In myotubes, GAA-GnGn treatment led to the highest increase in enzyme activity among moss-derived therapies, even though it did not reach normal activity levels.
Myozyme and GAA-GnGn also resulted in the highest levels of glycogen breakdown in myoblasts from a mouse model of Pompe disease. No significant changes were observed with GAA-Man3 and GAA-Man5.
Similar, but less pronounced, effects were observed in Pompe patients’ myoblasts.
“These initial data suggest that [M6P tags] might not always be necessary for the cellular uptake in [ERT] and indicate the potential of moss-GAA-GnGn as novel alternative drug for targeting skeletal muscle in Pompe patients,” the researchers wrote.
They said, however, that the findings need to be confirmed in a mouse model of Pompe disease to better assess treatment effectiveness.
The team also said that it is possible that another receptor may be involved in GAA-GnGn uptake, and that they plan to further explore this possibility, which could open new doors for ERTs.