Taking the bold steps needed to make the small ones possible
Oxyrane develops enhanced enzyme replacement therapies (ERTs) for the treatment of lysosomal storage diseases, with a focus on the diseases of the central nervous system.
Oxyrane’s enzyme therapies are engineered in a way to enhance their targeting and activity. This is achieved using our proprietary engineered yeast expression technology that produces proteins with defined human phosphoglycosyl structures required for effective intracellular uptake and localization.
Programs
Oxyrane is developing innovative ERT-based solutions to address the unmet clinical needs across a range of lysosomal storage diseases. Using its proprietary, engineered yeast expression host, Oxyrane can rapidly explore a number of product concepts in order to find the best possible engineered protein solution.
Oxyrane focuses on lysosomal storage diseases where the deficient enzyme can be effectively trafficked to the lysosome by interaction with the cation-independent mannose-6 phosphate receptors (CI-M6PR).
Phosphorylated mannose-6-phosphate (M6P) residues on the enzymes are recognized by specific receptors on the cell surface, increasing the internalization of the ERTs. Once inside the cell, the phosphorylated M6P targets the ERT to the lysosome, its site of action. The accumulated substrates can then be efficiently degraded by the ERT.
Gaucher disease (GD) is a lysosomal storage disease caused by mutations in the gene encoding the acid β-glucocerebrosidase (GCase), the enzyme that catalyzes the breakdown of glycolipids such as glucosylceramide (GlcCer) and glucosylsphingosine (GlcSph). This results in the accumulation of these substrates in the lysosomes of different cell types. As a result, this inherited metabolic disorder presents itself as a multi-system disease whose manifestations include anemia, thrombocytopenia, hepatosplenomegaly, bone pathology and neurological symptoms. The neuronopathic forms of Gaucher (including the acute infantile and subacute or chronic neuronopathic variant), are characterized by various degrees of systemic and neurological involvement.
OxyGCase with phosphorylated glycans is in development for neuronopathic Gaucher disease. Due to the high degree of glycan phosphorylation, OxyGCase is efficiently taken up by neuronal cells
Parkinson's disease is one of the most prevalent and debilitating neurodegenerative disorders, with a high need for disease-modifying treatments. Approximately 10% of patients with Parkinson's disease carry mutations in the GBA1 gene that encodes Glucocerebrosidase. GBA1 gene mutations constitute the most common genetic risk factor for developing Parkinson's disease. Enhancing Glucocerebrosidase activity in the brain is a promising strategy to address both motor and non-motor symptoms in Parkinson disease patients.
OxyGCase is in preclinical testing for potential application towards Parkinson's disease. This program is supported by the Michael J. Fox Foundation for Parkinson's Research
Pompe disease is a disease characterized by progressive accumulation of glycogen in tissues, particularly in the heart and skeletal muscle. It is caused by a deficiency of an enzyme called lysosomal acid alpha glucosidase (GAA) which is responsible for breaking down glycogen - a complex sugar that stores energy. When there is a deficiency of GAA, glycogen gradually accumulates in cells disrupting cell functions and impacting muscle function. The severity and age of onset of the disease varies depending on the level of residual GAA activity. Restoring GAA activity by providing recombinant enzyme is a broadly validated approach to improve outcomes in Pompe disease.
OXY2810 is a recombinant human GAA for use as an enzyme replacement therapy in Pompe disease.
Technology
Oxyrane has distinctive expertise in the engineering of a yeast expression host - Yarrowia lipolytica - to improve protein expression and to consistently produce proteins with desirable sugar structures (glycans). Oxyrane has built a world-class scientific team that has designed and developed the company's technology platform.
Mannose-6-Phosphate Glycosylation
Oxyrane’s enzymes have the potential to be significantly more effective than first generation ERTs, because of the technology’s ability to phosphorylate glycans on any glycosylation site ensuing in higher levels of mannose-6-phosphate on the enzyme, permitting more efficient uptake into cells and subsequent targeting to lysosomes.
Phosphorylated mannose-6-phosphate (M6P) residues on the enzymes are recognized by specific receptors on the cell surface, increasing the internalization of the enzymes. Once inside the cell, the phosphorylated M6P targets the enzyme to the lysosome, its site of action. The accumulated substrates can then be efficiently degraded by the enzyme.
Key advantage of the Oxyrane technology is that it leverages a molecular modification that is naturally present on the enzymes, without introducing any non-native modifications. The technology was described in a Nature Biotechnology publication.
Consistent Product
Oxyrane's engineering technology ensures batch-to-batch product consistency for the enzymes and their sugar structures, under a range of culture conditions. The resulting product yield and properties have been demonstrated to be consistent across multiple productions of up to 35,000 liter scale and implementations at different sites with a range of bioreactor configurations.
Broadly applicable platform
Oxyrane’s yeast engineering technology has produced a number of engineered proteins, including enzymes deficient in other LSDs, antibodies and other proteins. We have demonstrated consistent and reproducible results of applying our yeast engineering platform to produce different proteins with or without mannose-6-phosphate (M6P) residues.
The company is focusing on advancing its lead program with beta-glucocerebrosidase, with applications in two areas of high unmet need: neuronopathic Gaucher Disease and Parkinson’s Disease. We envision expanding our pipeline to develop enhanced enzyme therapies for other LSDs and metabolic diseases.
Leadership
Wouter
Vervecken
PhD
CEO
Hans
Preusting
PhD
Board Director
Charles
Richard
MD PhD
Board Director
Sander
Slootweg
MSc
Board Director
Somu
Subramaniam
MBA
Board Director
Len
Post
PhD
Board Director