Treatment modalities for lysosomal stage diseases (LSDs) with neuropathology such as Niemann-Pick Type C Disease (NPC) are currently non-existent due to the severe obstacles associated with accessing the central nervous system with proteins or genes, Also, these rare orphan disorders do not attract the interest of pharmaceutical companies, further contributing to the lack of prospects for any form of treatment of therpy. We have developed a new paradigm, termed """"""""Orphan Receptor Bypass Therapy"""""""" (ORByT), to address these disorders. This paradigm posits the existence of endogenous """"""""suppressor"""""""" proteins whose expression can dramatically improve LSD pathogenesis. The goal is the identification/discovery of small chemical compounds that can modulate the expression of these proteins and provide a new treatment modality for these devastating disorders. We have previously shown that the small GTPase protein Rab9 meets this requirement and can act as suppressor of the NPC phenotype. Thus, we propose to first carry out: * High throughput screening for identification of small molecules that upregulate Rab9 expression, utilizing the MLSCN (Molecular Libraries Screening Center Network) compound collection for drug-like small chemical molecules, and * Characterize and confirm positive hits, using in vitro assay, for their therapeutic potential in the treatment of NPC1 disease, * These studies will result in the identification of candidate compounds that will ultimately be evaluated in vivo in an NPC mouse model to determine their therapeutic potential and future drug development.

Public Health Relevance

Diseases that affect the brain are currently difficult if not impossible to treat. We have developed a novel approach to treat devastating genetic diseases with neurological involvement that are currently untreatable by utilizing molecules that can upregulate the expression of a suppressor protein.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Small Research Grants (R03)
Project #
1R03MH089537-01
Application #
7844753
Study Section
Special Emphasis Panel (ZRG1-BST-J (50))
Program Officer
Yao, Yong
Project Start
2009-11-20
Project End
2011-10-31
Budget Start
2009-11-20
Budget End
2010-10-31
Support Year
1
Fiscal Year
2010
Total Cost
$42,375
Indirect Cost
Name
Icahn School of Medicine at Mount Sinai
Department
Genetics
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029