After successful preclinical studies, Greenovation’s first drug candidate moss-aGal is in a phase I clinical trial.
Moss-aGal, a recombinant form of human alpha-galactosidase, has been developed by Greenovation as an enzyme replacement therapy (ERT) for patients with the genetic lysosomal storage disorder Fabry disease.
Greenovation has used its proprietary BryoTechnology®, an innovative moss gene expression system, to express the moss-aGal protein in Physcomitrella patens. The technology attaches mannose molecules to the surface of the moss aGal protein. This improves the uptake of the proteins in the human body, mediated via mannose receptors on cell surfaces.
“After very successful preclinical studies, we are excited to see our first drug candidate produced in moss entering into phase I clinical trials,” commented Dr. Thomas Frischmuth, CEO of Greenovation. “This milestone validates our BryoTechnology approach, confirming that is can serve as a production system for biopharmaceuticals.”
One dose group with 6 patients: 0.2mg/kg i. v.; single dose; clinical schedule of 28 days
Secondary (exploratory) endpoints:
- Efficiency (Gb3/lyso-Gb3 levels in plasma and urine)
For detailed study information, please visit www.clinicaltrialsregister.eu, EudrCT-No.: 2014-004325-40.
Moss-aGal for patients suffering
from Fabry Disease
Moss-aGal, our lead product, will be the first enzyme replacement treatment of Fabry disease based on moss that exhibits optimized N-glycosylation patterns of the protein alpha-galactosidase A. Studies in mice show that this translates into enhanced cellular uptake and favourable organ distribution.
Fabry disease is a rare genetic lysosomal storage disorder that is caused by deficient activity – subnormal or absent – of the lysosomal enzyme α-galactosidase A. Absence of the enzyme leads to progressive accumulation of glycosphingolipids, predominantly ceramide trihexoside (CTH or Gb3), in most tissues and cell types, particularly the vascular endothelial and smooth-muscle cells leading to various symptoms including excruciating pain, ischaemia and infarction. Fabry disease affects about 1–5 in 10,000 people worldwide.
Moss-aGal: enhanced cellular uptake into the target organ kidney
An enzyme replacement therapy, moss-aGal replaces the missing or reduced activity of the lysosomal enzyme alpha-galactosidase A in patients with Fabry disease. The kidney and heart are the organs most affected by the disease. Compared with other replacement therapies, the mannose receptor-mediated uptake of moss-aGal leads to an increased uptake of the enzyme in the kidney in mice. This has the potential for substantial improvements to patients’ quality of life.
Moss-aGal exhibits inherent N-glycan homogeneity
Treatment of Fabry disease is done by regular infusion of biotechnologically produced substitute of the missing enzyme, so called enzyme replacement therapy (ERT). The uptake of the infused enzyme into target cells from the bloodstream is mediated by glycan receptors. Therefore N-glycosylation, its pattern and homogeneity are key to the therapeutic efficacy of recombinant variants of the enzyme in treatment of Fabry disease.
Approved substitute enzymes are manufactured in mammalian cell lines (CHO or human fibroblast cells) exhibiting remarkable heterogeneity in N-glycosylation with only a minor fraction being relevant for target cell uptake.
Moss-aGal is manufactured in the moss system Physcomitrella patens and therefore benefits from the inherent N-glycan homogeneity of these organisms. Regarding its amino acid sequence moss-aGal is identical to the human enzyme. It could be demonstrated that over 95 % of the moss N-glycans are relevant for targeted uptake of the biopharmaceutical product into the cell.