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Realizing the promise of glycobiology

Zacharon's Ganglioside Inhibitor Program

One of Zacharon's advanced programs involves the development of a novel small molecule inhibitor of gangliosides, a family of lipid-linked carbohydrates. This first-in-class therapy has the potential to address substantial morbidity and mortality resulting from the Gangliosidoses, a family of rare genetic diseases with no treatment options, as well as several forms of neural crest-derived tumors. Zacharon has partnered with the National Cancer Institute and the National Institute of Neurological Disorders and Stroke for financial support for this important program.

The Gangliosidoses

The Gangliosidoses include several rare diseases including Tay Sachs, Sandhoff, AB Variant, and GM-1 Gangliosidoses. These diseases have a combined incidence of 1 in 55,000 and are characterized by deficiencies in lysosomal enzymes which degrade gangliosides. Patients experience dramatic morbidity and premature death primarily resulting from lysosomal accumulation of gangliosides in the brain.

A substantial need exists for effective treatment options for the Gangliosidoses. Recombinant enzyme therapy has limited utility as the infused enzymes do not cross the blood-brain barrier, and other treatment strategies have not proven effective.

To address these needs, Zacharon is developing a small molecule inhibitor of gangliosides with excellent brain penetration to reduce the accumulation of gangliosides in the lysosome of affected patients. Importantly, by targeting the gangliosides rather than correcting the enzyme deficiency (which is specific to each class), this strategy can result in one therapy treating multiple classes of the Gangliosidoses.

Gangliosides and Neural Crest Tumors

Gangliosides also play critical roles in the growth of neural crest tumors including neuroblastoma, glioma, and melanoma. For patients with neural crest-derived tumors, this same ganglioside inhibitor can prove effective by reducing the ability of tumor cells to shed gangliosides and spread through the mechanisms described in the figure below.


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