Overview of OXY2810 Pompe ERT programme
- Pipeline ERTs
- OXY 2810
about pompe diseasePompe disease is a rare disease where the progressive accumulation of glycogen results in muscle weakness - particularly in the heart and skeletal muscle. Pompe disease 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 of the disease varies to some extent based on the level of residual GAA activity. The infantile-onset form of the disease is typically diagnosed between 4-8 months and generally involves an enlarged heart and rapidly progressive skeletal muscle weakness. If left untreated, the early-onset infantile form is uniformly fatal before 18 months. The late-onset juvenile and adult forms manifest later with variable degrees of myopathy and respiratory insufficiency. The infantile-onset form has an incidence of one in 138,000 births and the late onset form has an incidence of one in 57,000 births.
OXY2810 is a recombinant human GAA for use as an enzyme replacement therapy for Pompe disease. As a result of proprietary engineering, OXY2810 is distinguished by having unprecedented levels of the natural targeting structure required for efficient localisation to lysosomes - the subcellular compartment where the enzyme is required.
GAA is naturally produced in human cells and transported to the lysosome as a 110kDa protein which is subsequently processed to a final, more active 70kDa format. OXY2810 is produced as the naturally occurring 95 kDa format intermediate (see Figure 1) which, based on relative measurements of specificity constants (a measure of how good an enzyme is at its job), is nearly 50% better at reducing glycogen than the 110kDa format. The translational product produced within the human cell is processed to the GAA precursor which is then transported to the lysosome for further subsequent processing.
Image modified from "Lysosomal Acid a-Glucosidase Consists of Four Different Peptides Processed from a Single Chain Precursor" by Moreland et. al (J Biol Chem 2005).