Our laboratory has pioneered the design of yeast-based expression systems for the production of biopharmaceuticals that can be modified with endolysosome-targeting glycans (glycans highly substituted with mannose-6-phosphate). Furthermore, we have recently developed the GlycoDelete technology, which can convert N-glycans in pharmacokinetics-neutral small structures and which at the same time leads to enhanced secretion of lysosomal enzymes from mammalian production cell lines. When fused to protein signals that target the mannose-6-phosphate receptor, this could lead to further improved therapeutic efficacy of lysosomal Enzyme Replacement Therapies (ERTs). In this project, we will target muscle cell lysosomal defects, as we know that we can effectively deliver therapeutic enzymes to myocytes through the targeting of the cation-independent mannose-6-phosphate receptor. Our first target is the rare congenital acid alpha-glucosidase deficiency (Pompe's disease), but also a range of much more frequently occurring acquired diseases have an important 'lysosomal storage' aspect to their pathophysiology. Such is the case with sporadic inclusion body myopathy (lysosomal protein aggregate accumulation), which is the most frequent age-related muscle disease, for which therapy is presently non-existant. Using our versatile glyco-engineered platforms for lysosome targeting, we will explore the delivery of cathepsin D to skeletal muscle lysosomes as a possible therapy for this disease.