Evaluating the Mechanisms of 2-Hydroxypropyl-β-Cyclodextrin and Liver X Receptor Agonists as Potential Therapies for Niemann-Pick Type C Disease

Cholesterol is essential to life; therefore, the synthesis, entry, and efflux of cholesterol are tightly regulated. In some rare disease states, such as in Niemann-Pick Type C, cholesterol balance is lost leading to detrimental effects. In Niemann-Pick Type C, mutations in either of the cholesterol trafficking proteins, NPC1 or NPC2, lead to the entrapment of unesterified cholesterol within the lysosome. The accumulated cholesterol promotes increased inflammation and apoptosis throughout the body resulting in premature death, which typically occurs during adolescence in humans. Currently there are no therapies proven to halt the progression of Niemann-Pick Type C in patients; however, two separate compounds (an LXR agonist and a cyclodextrin) have been shown to increase lifespan in the Npc1-/- mouse model. Although both of these potential therapies are known to alter cholesterol dynamics in the cell, the molecular mechanism(s) through which they are able to correct the defect in Niemann-Pick Type C and ultimately to enhance survival have not been fully elucidated, which is the goal of this work. As Abcg1 is a LXR target gene and a potential mechanism through which cholesterol is trafficked from Npc1-/- cells after LXR agonist treatment, the Npc1-/-Abcg1-/- mouse was generated and evaluated. These mice die significantly earlier than Npc1-/- littermates and suggest that ABCG1 plays a vital role in reducing inflammation in Niemann-Pick Type C. In addition, comprehensive studies were done within 24 hours of cyclodextrin administration in Npc1-/- mice. These results show that cyclodextrin works in Npc1-/- mice by freeing the trapped cholesterol from the lysosome of each cell very rapidly and then releasing the cholesterol intracellularly for normal sterol processing. Finally, Npc1-/- mice were treated in combination with the LXR agonist and cyclodextrin to test if dual treatment had an additive effect on relieving Niemann-Pick Type C disease progression. The combination therapy had no further benefit over cyclodextrin alone, which implies that the two agents are acting by similar mechanism(s). Overall, this work further clarifies the molecular mechanism(s) of LXR agonists and cyclodextrins in Niemann-Pick Type C disease progression, which could lead to the development of more effective therapies for patients.