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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
High Priority, Short Term Project Award (R56)
Project #
2R56NS055195-09
Application #
8550181
Study Section
Cellular and Molecular Biology of Glia Study Section (CMBG)
Program Officer
Morris, Jill A
Project Start
2001-03-01
Project End
2013-08-31
Budget Start
2012-09-30
Budget End
2013-08-31
Support Year
9
Fiscal Year
2012
Total Cost
$346,475
Indirect Cost
$121,475
Name
Boston College
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
045896339
City
Chestnut Hill
State
MA
Country
United States
Zip Code
02467
Heinecke, Karie A; Luoma, Adrienne; d'Azzo, Alessandra et al. (2015) Myelin abnormalities in the optic and sciatic nerves in mice with GM1-gangliosidosis. ASN Neuro 7:
Akgoc, Zeynep; Iosim, Sonia; Seyfried, Thomas N (2015) Bis(monoacylglycero)phosphate as a Macrophage Enriched Phospholipid. Lipids 50:907-12
Akgoc, Zeynep; Sena-Esteves, Miguel; Martin, Douglas R et al. (2015) Bis(monoacylglycero)phosphate: a secondary storage lipid in the gangliosidoses. J Lipid Res 56:1006-13
Ta, Nathan L; Jia, Xibei; Kiebish, Michael et al. (2014) Autosomal dominant inheritance of brain cardiolipin fatty acid abnormality in VM/DK mice: association with hypoxic-induced cognitive insensitivity. Lipids 49:113-7
Seyfried, Thomas N; Flores, Roberto E; Poff, Angela M et al. (2014) Cancer as a metabolic disease: implications for novel therapeutics. Carcinogenesis 35:515-27
Meidenbauer, Joshua J; Roberts, Mary F (2014) Reduced glucose utilization underlies seizure protection with dietary therapy in epileptic EL mice. Epilepsy Behav 39:48-54
Muthupalani, Sureshkumar; Torres, Paola A; Wang, Betty C et al. (2014) GM1-gangliosidosis in American black bears: clinical, pathological, biochemical and molecular genetic characterization. Mol Genet Metab 111:513-21
Arthur, Julian R; Wilson, Michael W; Larsen, Scott D et al. (2013) Ethylenedioxy-PIP2 oxalate reduces ganglioside storage in juvenile Sandhoff disease mice. Neurochem Res 38:866-75
Seyfried, Thomas N; Huysentruyt, Leanne C (2013) On the origin of cancer metastasis. Crit Rev Oncog 18:43-73
Huysentruyt, Leanne C; Akgoc, Zeynep; Seyfried, Thomas N (2011) Hypothesis: are neoplastic macrophages/microglia present in glioblastoma multiforme? ASN Neuro 3:

Showing the most recent 10 out of 17 publications