NPC1 disease is a severe lysosomal lipidosis in which the egress of cholesterol and other lipids from the endosomal/lysosomal (E/L) system is impeded, leading to severe neurodegeneration and premature demise. At present there are no treatment options for patients with NPC1 or other lysosomal storage disorders (LSDs) that present with neurodegenerative phenotypes, mainly due to the inability of corrective proteins to cross the blood-brain barrier. Therefore, a new paradigm is needed to address the large family of LSDs with neuropathology. We hy7pothesiae that suppressor proteins can be identified for the LSDs and that the expression of these proteins can be modulated via small chemical molecules that can gain access to the central nervous system and limit the severity of these disorders. In essence, this approach bypasses the defective lysosomal protein and therefore we have termed it """"""""Orphan receptor bypass therapy"""""""" or """"""""ORByT"""""""". We will first carry out a high-throughput screen to identify pharmacologically active, for ORByT-relevant small molecules for NPC1 disease. Using Rab9 as a """"""""suppressor"""""""" candidate for NPC1, we will use the recently established high throughput screening pharmacologically active for NPC1 disease. Second, we will evaluate candidate molecules for the therapeutic potential. Small molecule compounds identified in Aim 1 will be tested for their ability to correct the NPC1 lipid transport block phenotype. Those compounds that are confirmed to restore lipid transport in NPC cells will be evaluated in vivo using an NPC mouse model to determine their therapeutic potential prior to further development to improve their potency, toxicity profile, and brain delivery. Successful identification of small molecules will provide """"""""Proof-of-principle"""""""" for the ORByt strategy and a new approach to therapy for NPC1 and other devastating neurological LSDs.

Public Health Relevance

Diseases that affect the brain are currently difficult if not impossible to treat. We are developing a novel approach to treat devastating genetic diseases with neurologic involvement that are currently untreatable.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21NS058335-01A1
Application #
7738114
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Program Officer
Tagle, Danilo A
Project Start
2009-05-15
Project End
2011-04-30
Budget Start
2009-05-15
Budget End
2010-04-30
Support Year
1
Fiscal Year
2009
Total Cost
$254,250
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