Chronic cyclodextrin treatment of murine Niemann-Pick C disease ameliorates neuronal cholesterol and glycosphingolipid storage and disease progression.

[gm1 gangliosidosis]

Niemann-Pick type C (NPC ) disease is a fatal neurodegenerative disorder caused most commonly by a defect in the NPC 1 protein and characterized by widespread intracellular accumulation of unesterified cholesterol and glycosphingolipids (GSLs ). While current treatment therapies are limited , a few drugs tested in Npc 1 (-/-) mice have shown partial benefit . During a combination treatment trial using two such compounds , N-butyldeoxynojirimycin (NB-DNJ ) and allopregnanolone , we noted increased lifespan for Npc 1 (-/-) mice receiving only 2 -hydroxypropyl-beta -cyclodextrin (CD ), the vehicle for allopregnanolone . This finding suggested that administration of CD alone , but with greater frequency , might provide additional benefit .Administration of CD to Npc 1 (-/-) mice beginning at either P 7 or P 21 and continuing every other day delayed clinical onset , reduced intraneuronal cholesterol and GSL storage as well as free sphingosine accumulation , reduced markers of neurodegeneration , and led to longer survival than any previous treatment regime . We reasoned that other lysosomal diseases characterized by cholesterol and GSL accumulation , including NPC disease due to NPC 2 deficiency , GM 1 gangliosidosis and mucopolysaccharidosis (MPS ) type IIIA , might likewise benefit from CD treatment . Treated Npc 2 (-/-) mice showed benefits similar to NPC 1 disease , however , mice with GM 1 gangliosidosis or MPS IIIA failed to show reduction in storage .Treatment with CD delayed clinical disease onset , reduced intraneuronal storage and secondary markers of neurodegeneration , and significantly increased lifespan of both Npc 1 (-/-) and Npc 2 (-/-) mice . In contrast , CD failed to ameliorate cholesterol or glycosphingolipid storage in GM 1 gangliosidosis and MPS IIIA disease . Understanding the mechanism (s ) by which CD leads to reduced neuronal storage may provide important new opportunities for treatment of NPC and related neurodegenerative diseases characterized by cholesterol dyshomeostasis .