期刊
JOURNAL OF INHERITED METABOLIC DISEASE
卷 42, 期 3, 页码 527-533出版社
WILEY
DOI: 10.1002/jimd.12052
关键词
Agalsidase; alpha-galactosidase; Fabry disease; mannose receptor; moss; Physcomitrella
资金
- Greenovation Biotech GmbH
Moss-aGalactosidase A (moss-aGal) is a moss-derived version of human -galactosidase developed for enzyme replacement therapy in patients with Fabry disease. It exhibits a homogenous N-glycosylation profile with >90% mannose-terminated glycans. In contrast to mammalian cell produced -galactosidase, moss-aGal does not rely on mannose-6-phosphate receptor mediated endocytosis but targets the mannose receptor for tissue uptake. We conducted a phase 1 clinical trial with moss-aGal in six patients with confirmed diagnosis of Fabry disease during a 28-day schedule. All patients received a single dose of 0.2 mg/kg moss-aGal by i.v.-infusion. Primary endpoints of the trial were safety and pharmacokinetics; secondary endpoints were pharmacodynamics by analyzing urine and plasma Gb3 and lyso-Gb3 concentrations. In all patients, the administered single dose was well tolerated. No safety issues were observed. Pharmacokinetic data revealed a stable nonlinear profile with a short plasma half-life of moss-aGal of 14minutes. After one single dose of moss-aGal, urinary Gb3 concentrations decreased up to 23% 7 days and up to 60% 28days post-dose. Plasma concentrations of lyso-Gb3 decreased by 3.8% and of Gb3 by 11% 28days post-dose. These data reveal that a single dose of moss-aGal was safe, well tolerated, and led to a prolonged reduction of Gb3 excretion. As previously shown, moss-aGal is taken up via the mannose receptor, which is expressed on macrophages but also on endothelial and kidney cells. Thus, these data indicate that moss-aGal may target kidney cells. After these promising results, phase 2/3 clinical trials are in preparation.
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