The research goal is to develop an effective life-long therapy for ganglioside storage diseases. The gangliosidoses are a group of incurable autosomal recessive inborn errors of metabolism involving storage of either ganglioside GM1 or GM2 in CNS lysosomes. Accumulation of GM1 or GM2 causes wide spread inflammation and neurodegeneration. GM1 gangliosidosis arises from a genetic deficiency of the acid -galactosidase that catabolizes ganglioside GM1, whereas Sandhoff disease (SD) arises from genetic deficiency in the -hexosaminidase subunit that catabolizes ganglioside GM2. Our studies will involve diverse and complimentary approaches for disease management primarily involving substrate reduction therapy and gene therapy. The studies will be largely conducted in -gal -/-, and Hex -/- mice that accumulate GM1 and GM2, respectively. Inhibited synthesis counterbalances impaired rate of catabolism and is referred to as substrate reduction therapy. The imino sugars, NB-DNJ, and NB-DGJ, as well as the novel PDMP analogue '3h' inhibit the rate of glycosphingolipid (GSL) biosynthesis. Our recent findings show that CNS delivery and therapeutic efficacy of NB-DNJ is significantly increased when the inhibitor is administered together with the restricted high-fat, low carbohydrate ketogenic diet (KD-R). Adeno-Associated Virus (AAV) gene therapy provides the missing lysosomal enzyme thereby reducing GSL storage throughout the CNS. The proposed studies will be an extension of those conducted over the previous funding period and will involve the following specific aims.
Aim 1 will examine active and passive transport mechanisms by which the restricted ketogenic diet (KD-R) facilitates brain delivery of imino sugar and 3h to the CNS.
Aim 2 will determine the degree to which the ketogenic diet can facilitate delivery of imino sugar and 3h to neonatal mouse brain through the dam's milk.
Aim 3 will evaluate the degree to which AAV gene therapy corrects lipid abnormalities and inflammation in purified myelin, optic nerve, and retina in storage disease mice. Our preliminary studies show for the first time elevated levels of the unusual phospholipid, bis(monoacylglycerol)phosphate in the brains of human SD and in the -gal -/-, and Hex -/- mice. This lipid will be used as a novel biomarker for correction of ganglioside storage and brain inflammation. The proposed research will provide insight on novel therapeutic strategies for managing human ganglioside storage diseases.
There are currently no cures or effective treatments for patients with GM1 and GM2 ganglioside storage diseases. The goals of this research will explore novel therapeutic strategies that can help reduce ganglioside storage and accompanying inflammation in various CNS regions of mice that manifest pathology similar to that seen in the human disease. The findings can have direct translational impact to those suffering from these diseases.
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