Introduction to Lysosomal Storage Disease

Lysosomal storage diseases result from enzyme deficiencies which cause substrates such as lipids or glycoproteins to accumulate in the lysosome, leading to serious and often fatal systemic disease. The family of lysosomal storage diseases includes approximately forty inherited diseases such as Gaucher Disease, Fabry Disease, and the Mucopolysaccharidoses (MPS).

The Mucopolysaccharidoses

In MPS, deficiency of enzymes catalyzing the degradation of glycosaminoglycans (GAGs) causes accumulation of GAG substrates in lysosomes resulting in cell, tissue, and organ dysfunction. Depending on the specific enzyme deficiency, the chronic and progressive clinical course can include joint mobility problems, cardiovascular and respiratory complications, facial abnormalities, hearing and vision loss, profound mental retardation, spinal cord compression, and other serious symptoms with often fatal consequences [1].

Existing therapies for several MPS sub-classes have been approved and have demonstrated clinical benefits. However, a significant need exists for additional treatment options as the present therapies do not fully address the needs of clinicians and patients. Patients continue to experience debilitating and sometimes fatal symptoms [2, 3]. Additionally, existing therapies are unable to cross the blood-brain barrier preventing treatment of the neurological symptoms [4].

Zacharon’s Unique Approach: Substrate Optimization Therapy

To address the above needs, Zacharon is developing small molecule glycan inhibitors for the treatment of MPS and other lysosomal storage diseases. Zacharon’s therapeutic strategy is unique relative to historical attempts to develop small molecule therapies for these disorders. These historical attempts have sometimes targeted multiple glycan classes with the goal of reducing the amount of glycans produced (i.e., substrate reduction therapy) [5].

Zacharon’s approach is different and is designed to selectively modify the glycans to render them more readily degraded despite the presence of specific enzyme deficiencies, without altering their normal biologic function or reducing the overall amount that is produced. This strategy, termed “substrate optimization therapy”, has the potential to provide clinical efficacy without the toxicity associated with historical approaches. Importantly, this strategy also creates the potential to address the neurological symptoms and / or improve efficacy in combination with enzyme replacement therapies.

The following diagram illustrates the concept of “substrate optimization therapy.” To download a copy of the poster presentation related to our MPS therapeutic program, please visit our publications page by clicking HERE.

1. Scriver, ed. The Metabolic & Molecular Bases of Inherited Disease. 8th ed. 2001.
2. Sifuentes, M., A follow-up study of MPS I patients treated with laronidase enzyme replacement therapy for 6 years. Molecular Genetics and Metabolism, 2007(90): p. 171-180.
3. Wraith, E., Mucopolysaccharidosis type II (Hunter syndrome): a clinical review and recommendations for treatment in the era of enzyme replacement therapy. Eur J Pediatr, 2008(167): p. 267-277.
4. Wraith, E., The first 5 years of clinical experience with laronidase enzyme replacement therapy for mucopolysaccharidosis I. Expert Opin. Pharmacother., 2005. 6(3): p. 489-506.
5. Zavesca package insert. Available from: www.zavesca.com.