Infantile GM1-gangliosidosis in humans is a genetically determined glycosphingolipid storage disease for which there is currently no animal model available. It is one of several storage diseases which collectively are characterized by early childhood onset, progressive neurological impairment, variable visceral and skeletal involvement, and death at age 2-4 years. Recently, we diagnosed infantile GM1-gangliosidosis in an 8 month old English Springer Spaniel. The proband's parents were identified, rebred and a colony of the F1 offspring was established. Three groups of investigators with a common interest in this animal model will utilize clinical, pathoanatomical, biochemical and genetic methodologies to (1) fully characterize this model, (2) study its progression and (3) evaluate therapeutic approaches for correcting the enzyme defect. Physical, neurological ophthalmological, radiological and bone marrow examination will be done in normal, carrier and affected dogs. The activity of lysosomal enzymes (including acid Beta-galactosidase) in lymphocytes, mixed leukocytes and skin fibroblasts, the nature and the concentration of glycolipids and oligosaccharides in plasma, spinal fluid, amniotic fluid and urine will be determined. The glycoprotein accumulated in affected tissues and secreted in urine will be characterized, and used for monitoring the disease progression. The turnover of glycolipids and oligosaccharides will be analyzed. Light and electron microscopy and lectin histochemistry of affected tissues and controls will be done. The heritability pattern of the disease will be established. Therapeutic trials will include ligand-augmented enzyme delivery in vitro and bone marrow transplantation using normal siblings as donors. Our studies will yield data pertinent to understanding the progression of the neurovisceral and skeletal lesions in this and similar devastating storage diseases. Application of our knowledge gained from enzyme delivery in vitro and bone marrow transplantation in our animal model will facilitate the introduction of therapy to human patients.
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