Evaluation of new therapies in Niemann-Pick type C disease

Niemann Pick type C (NPC) disease is a rare autosomal recessive neurodegenerative lysosomal storage disease caused by a mutation in the NPC1 or NPC2 genes. The functions of the proteins these genes encode are not fully understood, but are thought to be involved in free cholesterol egress from the acidic compartment. The pathogenic cascade in proposed to begin with sphingosine accumulation followed by reduction of acidic store calcium levels. This results in impairing intracellular trafficking and storage of multiple lipid substrates in the late endosome/lysosomal compartment. In this thesis, multiple potential therapies have been tested in a mouse model of NPC1 disease including neuroprotective compounds. Positive effects were observed with some compounds, as reflected by increased life span and/or improved neurological function. In the course of these studies, I discovered another factor that affects the outcome of treatment with liver metabolised drugs. In the NPC1 mouse the cytochrome P450 system is impaired as is the case in the NPC1 cats and in patients. This thesis therefore sheds light on the impairment of this system at the genetic and functional level and presents data on why this aspect of pathology must be considered when designing therapeutics for this fatal neurodegenerative disease. This defect was partially corrected with bile acid supplementation, resulting in an unexpected functional improvement suggesting benefit in the CNS. Another aspect of NPC disease investigated was Crohn's-like intestinal inflammation that occurs in some NPC patients. This has been investigated in the Npc1-/- mouse model using two colitis models showing a partial protection by the Npc1 mutation with different infection kinetics and secretory cytokine profiles. Taken together, this thesis therefore provides insights into two novel aspects of pathogenesis (Crohn's-like intestinal inflammation and a drug metabolism defect) and provides new leads on treatments that target unique aspects of the pathogenic cascade.