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 .

Diseases
Validation

Diseases presenting "neurodegeneration" symptom

adrenomyeloneuropathy

alexander disease

cadasil

canavan disease

classical phenylketonuria

fabry disease

gm1 gangliosidosis

hereditary cerebral hemorrhage with amyloidosis

krabbe disease

neonatal adrenoleukodystrophy

neuralgic amyotrophy

oculocutaneous albinism

pyruvate dehydrogenase deficiency

triple a syndrome

wolf-hirschhorn syndrome

x-linked adrenoleukodystrophy

zellweger syndrome

This symptom has already been validated