Gangliosides are complex sialic acid-containing glycosphingolipids that are particularly enriched in the brain and are critical for brain development and function. GM3 synthase deficiency is a genetic disorder of ganglioside biosynthesis occurring primarily, but not exclusively, in the Old Order Amish. GM3, which the patients cannot synthesize, is itself not abundant in the brain; rather, it serves as the common precursor for all downstream gangliosides. Thus, patients completely lack cell-surface gangliosides. Appearing normal at birth, patients developmentally stagnate within a few months. They suffer from intractable seizures and cannot sit, stand, walk, talk, see, or hear. There is an immediate need to develop therapies for this disorder. We hypothesize that ganglioside replacement therapy represents an effective treatment strategy than can be immediately leveraged clinically. GM1 is one of the four major brain ganglioside species synthesized from GM3. There have been multiple clinical trials testing exogenous GM1 for the treatment of aging-related diseases such as Parkinson?s disease, stroke, and Alzheimer?s, for which depletion of GM1 is a common feature. These trials have shown GM1 therapy to be safe in humans. Here, we have partnered with La Jolla Pharmaceuticals who will provide semisynthetic GM3 and GM1 for pre-clinical testing.
Aim 1 will compare the two species head-to-head for their ability to repopulate cell-surface gangliosides in a patient-derived neural crest cell line and in GM3 synthase knockout mice in vivo. While we hypothesize that GM1 will be superior to GM3 in this regard, whichever species demonstrates the best normalization of cell-surface gangliosides will be tested as a therapeutic agent in Aim 2.
Aim 2 will be a longitudinal study in which ganglioside-deficient mice will be treated either at birth or at weaning with exogenous ganglioside delivered intracerebrally; the mice will be followed in a survival study with periodic neuromotor function testing. Altogether, the deliverables for this project will include: 1) a biochemical evaluation of GM1 versus GM3 for ganglioside repopulation and brain distribution; 2) the optimization of intracerebral ganglioside dosing (slow release vs. bolus injection); 3) an assessment of placental ganglioside transfer in vivo; 4) determination of the turnover rate of exogenous gangliosides in vivo; and 5) an evaluation of the therapeutic benefits of ganglioside replacement in a clinically-relevant mouse model. In summary, this high-risk R21 project may produce an immediate high-reward in the form of the pre-clinical evidence needed to fast-track ganglioside replacement therapy for the treatment of human genetic ganglioside deficiencies. Further, data from this project will fuel a future R01 proposal designed to optimize the route of delivery (peripheral versus central) and to test multimodal efficacy of ganglioside therapy with gene therapy.

Public Health Relevance

Gangliosides are specialized cell-surface lipids required for brain development and neuromotor functioning. Patients with genetic defects in ganglioside biosynthesis experience devastating neurological symptoms beginning in infancy, including deafness, blindness, developmental stagnation, and refractory seizures. The proposed research seeks to evaluate the efficacy of ganglioside replacement therapy using ganglioside-deficient mouse models and cell lines.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Exploratory/Developmental Grants (R21)
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Therapeutic Approaches to Genetic Diseases Study Section (TAG)
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Parisi, Melissa
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University of Pittsburgh
Schools of Medicine
United States
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