Scientists at Heilbronn, Germany-based Greenovation Biotech and Dallas-based Baylor Research Institute have published results from a preclinical study in Fabry mice in the Journal of Inherited Metabolic Diseases. Results of the study imply that replacement enzymes exhibiting mannose-terminated glycosylation patterns are efficiently delivered to their subcellular targets, the lysosomes.

Lysosomal storage diseases (LSDs), like Fabry disease, are caused by inborn absence of certain degradation enzymes, leading to continuous accumulation of problematic compounds in the cells. In Fabry patients, sphingolipid accumulation leads to various symptoms like excruciating pain, heart failure and kidney failure. Enzyme replacement therapy (ERT) is a treatment option for several LSDs: Biopharmaceutical versions of the missing enzymes are intravenously infused. Once in the bloodstream, the compounds are taken up by cells either through the mannose 6-phosphate receptor (M6PR) or the mannose receptor (MR). It is generally believed that M6PR-mediated endocytosis is a key mechanism of ERT in treating patients with LSDs.

The results show that mannose receptor-mediated delivery of moss-made α-galactosidase A effectively corrects enzyme deficiency in Fabry mice. The enzymes exhibit mannose-terminated glycosylation patterns and act equally to mannose 6-phosphate-harboring enzymes in the treatment of Fabry disease, and probably other lysosomal storage disorders in which non-macrophage cells are affected.

"We are very excited about the results of this preclinical study. The findings allow the start of early clinical trials that will investigate the effect of moss-aGal in humans suffering from Fabry disease," said Greenovation CEO Dr. Thomas Frischmuth.

The therapeutic efficacy of MR-mediated uptake of mannose-terminated enzymes in patients suffering from LSDs, however, has not yet been fully evaluated. In the published study, scientists tested the effectiveness of non-phosphorylated α-galactosidase A produced in moss (referred to as moss-aGal) in vitro and Fabry mice. Endocytosis of moss-aGal was MR-dependent. Compared to agalsidase alfa, the current treatment option, moss-aGal was more efficiently targeted to kidney, whereas cellular localization of moss-aGal and agalsidase alfa in the heart was comparable. Clearance of accumulated substrate in heart and kidney by a single injection of moss-aGal was comparable to the effect of agalsidase alfa.

The results now allow the start of early clinical testing.