Niemann-Pick type c disease: pathogenesis and therapy

Thesis

Niemann-Pick disease Type C is a rare, lysosomal storage disorder caused by defects in either NPC1 (95% of cases) or NPC2, and characterized by progressive neurodegeneration that ultimately results in premature death. The function of the NPC1 protein still remains poorly understood and how the NPC1 or NPC2 proteins interact, or the functions of the pathways they regulate still remains unknown. We have found unexpected links between NPC and other human diseases - particularly Tangier disease, suggesting that the NPC cellular pathway is more broadly involved in human disease than previously suggested. To gain further insight into the function of NPC1 and proteins it interacts with we used the yeast orthologue, Ncr1p. I recreated the Δncr1 mutant and characterized the mutant using an array of systematic screens to identify different processes and pathways that may play a role in NPC pathogenesis. The screen implicated mitochondrial dysfunction, defects in metal ion homeostasis and lipid trafficking, cytoskeleton dysfunction and nutrient sensing deficiencies. These screens were validated in the Npc1^-/- mouse model, where the effects of modulating kinases also emerged as a potential therapeutic option. In addition to kinases, we examined the therapeutic potential of the FDA-approved hypertension drug, losartan. Losartan ameliorated the acidic store Ca²⁺ defect, which characterizes NPC, and all downstream pathologies as well as in combination with miglustat reduced levels of neuroinflammation in the mouse model. Furthermore, the cyclodextrin analogue Crysmeb was also examined as a novel therapy for NPC, and was found to have significant survival benefits as compared to HPβCD, the cyclodextrin compound currently in clinical trials. Taken together, in this thesis I have identified novel aspects of NPC pathogenesis, as well as mechanistic links between NPC and Tangier disease – which has led to miglustat treatment options for two patients at Addenbrooke's Hostpital, Cambridge. Additionally, taking advantage of the convergent disease mechanisms I have examined treatments (losartan/Crysmeb) that take advantage of the similarities and differences between these two disorders paving the way for potential clinical studies in the future.

Authors: Colaco, A

• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford