GlycoNet scientists advance screening and therapeutic treatment of lysosomal storage diseases

By Anushka Jayasuriya & Chardelle Prevatt – June 29, 2017

Glycomics research has numerous applications in the treatment of rare genetic diseases, and one is in generating therapeutic proteins. About 30% of all therapeutics proteins are glycoproteins, and the sugar residues decorating these structures play a vital role in their stability and function. Therefore, in the development of enzyme replacement therapy (ERT), carbohydrates are fundamental to influencing the therapeutic efficacy and half-life of these therapies.

As GlycoNet scientists Drs. Allison Kermode and Lorne Clarke describe, “The study of glycomics is essential not only for generating efficacious glycoproteins as therapeutics, but also to further our understanding of the pathogenesis of many diseases. For this reason, it is an immensely vital area of medical research. Together with their colleagues, the researchers focus on the area of lysosomal storage diseases (LSDs).

The lysosome is a compartment in the cell that plays a key role in the turnover and reutilization of large molecules in the cell. When lysosomal function is adversely affected, such as by mutations in the proteins critical for the breakdown of complex carbohydrates, the crucial balance between biosynthesis and degradation of these molecules is disrupted. This series of events can lead to devastating consequences according to Dr. Clarke: “It is the equilibrium between breakdown and biosynthesis that really keeps cells healthy and happy. When an enzyme deficiency occurs, these complex carbohydrates accrue in patient cells, and they cause the disease process.”

LSDs account for a considerable proportion of childhood metabolic diseases. Mucopolysaccharidosis I (MPS I), for example, results in early childhood death and is attributed to iduronidase deficiency. This enzyme is essential for degrading complex carbohydrates such as glycosaminoglycans (GAGs).

One strategy to combat MPS I is to generate iduronidase using cell cultures, and administering the purified recombinant enzyme to patients. This therapeutic regimen requires a weekly infusion of purified recombinant human lysosomal enzyme, which costs ~ $500,000 per patient, per year. The mammalian cell culture systems used to generate these enzymes are complex and expensive to maintain. Dr. Kermode’s research team has found that by using plants as hosts to express these enzymes, they can stimulate enzyme production rapidly and in a cost-effective manner. In addition, the plant cells are not subject to contamination from pathogens that affect humans.

“The potential outcomes of our research are two-fold: one is to create cost-effective enzyme therapeutics for MPS I and other LSDs, and the second is to use the plant-made iduronidase enzyme target as a reagent in newborn screening for LSDs,” explains Dr. Kermode. The latter is significant because early detection of the disease is critical to impacting the therapeutic outcome for the patient. Dr. Clarke adds, “GlycoNet has been essential in helping identify the commercialization potential of our research, particularly toward our enzyme serving as a reagent in newborn screening programs.”

“We are at an exciting phase where we can market the iduonidase enzyme created with our plant host system for use as a screening reagent,” says Dr. Kermode. “As well, the aspect of creating a therapeutic enzyme for ERT administration in patients is reaching a fruitful stage, where we are starting to look at therapeutic efficacy. Once completed, we can begin to scale up the purification of our enzyme target and develop the means to get it into clinical trials.”