• Create a specific missense point mutation in the beta chain of hexosaminidase that can be rescued by pharmacological chaperones, small molecules that selectively bind and stabilize certain point mutations, in order to test efficacy of chaperones that are being developed for Late Onset Tay-Sachs and Sandhoff.
• Compare brain levels of beta-hex, GA2, and GM2 levels in homozygous knock-in mice to determine biochemical effects of knock-in.

Impact of research: Pharmacological chaperones represent a new class of treatment for patients with diseases that result from destabilization, unfolding, or misfolding of a protein. The current GM2 mouse model is a hexosaminidase knock-out (hex-/-), which does not produce any of the target protein and therefore cannot be used to evaluate various chaperones ability to bind and stabilize the protein. Creation of a knock-in mouse with a point mutation, which is equivalent to a known human late onset mutation, will allow analysis of in vivo dosing effects of specific chaperones that have already been developed.  The mouse model will be made available for other late onset research.

This grant is made available by the Katie and Allie Buryk Research Fund.

BioStrategies LC
Lectin-assisted transnasal delivery of corrective enzyme for GM1 gangliosidosis

Investigators: David N. Radin, Carole L Cramer, Alessandra d'Azzo (SJCRH)

Executive Summary:
Genetic deficiencies in the lysosomal enzyme β-galactosidase (β-gal) lead to the neurodegenerative disease GM1 gangliosidosis. Traditional enzyme replacement therapy (ERT) approaches are ineffective because they fail to deliver sufficient enzyme to the brain. Our goal in this research, is to determine if the plant RTB lectin (sugar-binding protein) can help to carry β-gal across nasal mucosal surfaces and increase access to the brain using the mouse model of GM1. Fusion proteins linking β-gal with the RTB lectin will be produced in a plant-based protein production system and the purified protein will be administered trans-nasally to β-gal-/- mice to determine if active enzyme reaches the cells of the brain.

NTSAD is soliciting proposals for innovative research projects that involve basic research, translational studies or clinical studies in the areas of neurodegenerative disorders affecting the CNS, especially lysosomal storage disorders (such as Tay-Sachs, GM-1, Sandhoff) and pediatric leukodystrophies (such as Canavan).