This gangliosidosis project will include two studies: 1) Continuation of LDN6713 Natural History of Hexosaminidase Deficiencies and Other Gangliosidoses for patients of all ages with a gangliosidosis disease;2) Syner-G treatment regimen ("synergistic enteral regimen for the gangliosidoses") for patients with infantile or juvenile forms of the gangliosidoses. Pediatric patients may simutaneously participate in both studies. The Syner-G regimen is a combination, multi-targeted combination therapy for treatment of the gangliosidoses, using FDA approved therapies that have demonstrated safety in children: miglustat, ketogenic diet to minimize gastrointestinal side effects of miglustat and optimize seizure management, and pyrimethamine for patients with mutations responsive to pyrimethamine. The infantile and juvenile forms of gangliosidosis are lethal during childhood. This gangliosidosis project provides a method for systematically gathering serial prospective, retrospective and natural history clinical data, including data on treatments tried by the patient. The ability to participate in the Syner-G treatment protocol, or other clinical treatment trials that may become available, allows for participation of patients who may otherwise be excluded from a natural history study.
Specific Aim 1 : To characterize and describe disease progression and heterogeneity in the gangliosidosis disorders. This natural history study (LDN 6713) seeks to develop quantitative methods to delineate disease progression for the gangliosidosis disorders (Tay-Sachs, Sandhoff, and GM1-gangliosidosis diseases) to better understand the natural history and heterogeneity of disease. Such quantitative methods will also be essential for evaluating any treatments that may become available in the future, such as gene therapy.
Specific Aim 2 : We hypothesize that a combination, multi-targeted therapy for pediatric gangliosidoses, using miglustat with the ketogenic dietand pyrimethamine for patients with responsive mutationswill create synergisms that improve neurodevelopmental outcomes of therapy compared to data reported in previous natural history studies, and previous studies using monotherapy with miglustat.

Public Health Relevance

Gangliosidoses are catastrophic neurodegenerative diseases with lethality during childhood in infantile and juvenile forms and for which no FDA approved treatments exist. Current knowledge of the natural history of gangliosidoses, crucial for treatment development, is limited. Monotherapy with miglustat and pyrimethamine have not shown significant clinical improvement. This project will allow continuation of natural history data collection while simultaneously providing option to participate in a synergistic combination therapy Syner-G.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
2U54NS065768-06
Application #
8907067
Study Section
Special Emphasis Panel (ZTR1-CI-8 (01))
Program Officer
Morris, Jill A
Project Start
Project End
Budget Start
2014-09-30
Budget End
2015-07-31
Support Year
6
Fiscal Year
2014
Total Cost
$63,717
Indirect Cost
$21,798
Name
University of Minnesota Twin Cities
Department
Type
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Mauer, Michael; Glynn, Emily; Svarstad, Einar et al. (2014) Mosaicism of podocyte involvement is related to podocyte injury in females with Fabry disease. PLoS One 9:e112188
Rumsey, Robin K; Rudser, Kyle; Delaney, Kathleen et al. (2014) Acquired autistic behaviors in children with mucopolysaccharidosis type IIIA. J Pediatr 164:1147-1151.e1
Schiffmann, Raphael; Forni, Sabrina; Swift, Caren et al. (2014) Risk of death in heart disease is associated with elevated urinary globotriaosylceramide. J Am Heart Assoc 3:e000394
Polgreen, Lynda E; Thomas, William; Fung, Ellen et al. (2014) Low bone mineral content and challenges in interpretation of dual-energy X-ray absorptiometry in children with mucopolysaccharidosis types I, II, and VI. J Clin Densitom 17:200-6
Polgreen, Lynda E; Thomas, William; Orchard, Paul J et al. (2014) Effect of recombinant human growth hormone on changes in height, bone mineral density, and body composition over 1-2 years in children with Hurler or Hunter syndrome. Mol Genet Metab 111:101-6
Stevenson, David A; Rudser, Kyle; Kunin-Batson, Alicia et al. (2014) Biomarkers of bone remodeling in children with mucopolysaccharidosis types I, II, and VI. J Pediatr Rehabil Med 7:159-65
Prater, Sean N; Banugaria, Suhrad G; Morgan, Claire et al. (2014) Letter to the Editors: Concerning "CRIM-negative Pompe disease patients with satisfactory clinical outcomes on enzyme replacement therapy" by Al Khallaf et al. J Inherit Metab Dis 37:141-3
Schiffmann, Raphael; Mayfield, Joan; Swift, Caren et al. (2014) Quantitative neuroimaging in mucolipidosis type IV. Mol Genet Metab 111:147-51
Wang, Raymond Y; Braunlin, Elizabeth A; Rudser, Kyle D et al. (2014) Carotid intima-media thickness is increased in patients with treated mucopolysaccharidosis types I and II, and correlates with arterial stiffness. Mol Genet Metab 111:128-32
Ahmed, Alia; Whitley, Chester B; Cooksley, Renee et al. (2014) Neurocognitive and neuropsychiatric phenotypes associated with the mutation L238Q of the *-L-iduronidase gene in Hurler-Scheie syndrome. Mol Genet Metab 111:123-7

Showing the most recent 10 out of 34 publications