Systemic administration of 2-hydroxypropyl-β-cyclodextrin to symptomatic Npc1-deficient mice slows cholesterol sequestration in the major organs and improves liver function

Adam M. Lopez, Sandi J. Terpack, Kenneth S. Posey, Benny Liu, Charina M. Ramirez, Stephen D. Turley

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

In Niemann-Pick type C (NPC) disease, loss-of-function mutations in either NPC1 or NPC2 result in progressive accumulation of unesterified cholesterol (UC) and glycosphingolipids in all organs, leading to neurodegeneration, pulmonary dysfunction and sometimes liver failure. There is no cure for this disorder. Studies using primarily NPC mouse models have shown that systemic administration of 2-hydroxypropyl-β-cyclodextrin (2HPβCD), starting in early neonatal life, diminishes UC accumulation in most organs, slows disease progression and extends lifespan. The key question now is whether delaying the start of 2HPβCD treatment until early adulthood, when the amount of entrapped UC throughout the body is markedly elevated, has any of the benefits found when treatment begins at 7 days of age. In the present study, Npc1-/- and Npc1+/+ mice were given saline or 2HPβCD subcutaneously at 49, 56, 63 and 70 days of age, with measurements of organ weights, liver function tests and tissue cholesterol levels performed at 77 days. In Npc1-/- mice, treatment with 2HPβCD from 49 days reduced whole-liver cholesterol content at 77 days from 33.0 ± 1.0 to 9.1 ± 0.5 mg/organ. Comparable improvements were seen in other organs, such as the spleen, and in the animal as a whole. There was a transient increase in biliary cholesterol concentration in Npc1-/- mice after 2HPβCD. Plasma alanine aminotransferase and aspartate aminotransferase activities in 77-day-old 2HPβCD-treated Npc1-/- mice were reduced compared with saline-treated controls. The lifespan of Npc1-/- mice given 2HPβCD marginally exceeded that of the saline-treated controls (99 ± 1.1 vs 94 ± 1.4 days, respectively; P < 0.05). Thus, 2HPβCD is effective in mobilizing entrapped cholesterol in late-stage NPC disease leading to improved liver function.

Original languageEnglish (US)
Pages (from-to)780-787
Number of pages8
JournalClinical and Experimental Pharmacology and Physiology
Volume41
Issue number10
DOIs
StatePublished - Oct 1 2014

Fingerprint

Cyclodextrins
Cholesterol
Liver
Type C Niemann-Pick Disease
Glycosphingolipids
Organ Size
Liver Function Tests
Liver Failure
Aspartate Aminotransferases
Alanine Transaminase
Disease Progression
Spleen
Lung
Mutation

Keywords

  • Biliary cholesterol
  • Brain
  • Hepatosplenomegaly
  • Lifespan
  • Lung
  • Lysosomal storage disease
  • Relative organ weight

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)
  • Pharmacology

Cite this

@article{d177b774425a4a3392a846f32b2081a4,
title = "Systemic administration of 2-hydroxypropyl-β-cyclodextrin to symptomatic Npc1-deficient mice slows cholesterol sequestration in the major organs and improves liver function",
abstract = "In Niemann-Pick type C (NPC) disease, loss-of-function mutations in either NPC1 or NPC2 result in progressive accumulation of unesterified cholesterol (UC) and glycosphingolipids in all organs, leading to neurodegeneration, pulmonary dysfunction and sometimes liver failure. There is no cure for this disorder. Studies using primarily NPC mouse models have shown that systemic administration of 2-hydroxypropyl-β-cyclodextrin (2HPβCD), starting in early neonatal life, diminishes UC accumulation in most organs, slows disease progression and extends lifespan. The key question now is whether delaying the start of 2HPβCD treatment until early adulthood, when the amount of entrapped UC throughout the body is markedly elevated, has any of the benefits found when treatment begins at 7 days of age. In the present study, Npc1-/- and Npc1+/+ mice were given saline or 2HPβCD subcutaneously at 49, 56, 63 and 70 days of age, with measurements of organ weights, liver function tests and tissue cholesterol levels performed at 77 days. In Npc1-/- mice, treatment with 2HPβCD from 49 days reduced whole-liver cholesterol content at 77 days from 33.0 ± 1.0 to 9.1 ± 0.5 mg/organ. Comparable improvements were seen in other organs, such as the spleen, and in the animal as a whole. There was a transient increase in biliary cholesterol concentration in Npc1-/- mice after 2HPβCD. Plasma alanine aminotransferase and aspartate aminotransferase activities in 77-day-old 2HPβCD-treated Npc1-/- mice were reduced compared with saline-treated controls. The lifespan of Npc1-/- mice given 2HPβCD marginally exceeded that of the saline-treated controls (99 ± 1.1 vs 94 ± 1.4 days, respectively; P < 0.05). Thus, 2HPβCD is effective in mobilizing entrapped cholesterol in late-stage NPC disease leading to improved liver function.",
keywords = "Biliary cholesterol, Brain, Hepatosplenomegaly, Lifespan, Lung, Lysosomal storage disease, Relative organ weight",
author = "Lopez, {Adam M.} and Terpack, {Sandi J.} and Posey, {Kenneth S.} and Benny Liu and Ramirez, {Charina M.} and Turley, {Stephen D.}",
year = "2014",
month = "10",
day = "1",
doi = "10.1111/1440-1681.12285",
language = "English (US)",
volume = "41",
pages = "780--787",
journal = "Clinical and Experimental Pharmacology and Physiology",
issn = "0305-1870",
publisher = "Wiley-Blackwell",
number = "10",

}

TY - JOUR

T1 - Systemic administration of 2-hydroxypropyl-β-cyclodextrin to symptomatic Npc1-deficient mice slows cholesterol sequestration in the major organs and improves liver function

AU - Lopez, Adam M.

AU - Terpack, Sandi J.

AU - Posey, Kenneth S.

AU - Liu, Benny

AU - Ramirez, Charina M.

AU - Turley, Stephen D.

PY - 2014/10/1

Y1 - 2014/10/1

N2 - In Niemann-Pick type C (NPC) disease, loss-of-function mutations in either NPC1 or NPC2 result in progressive accumulation of unesterified cholesterol (UC) and glycosphingolipids in all organs, leading to neurodegeneration, pulmonary dysfunction and sometimes liver failure. There is no cure for this disorder. Studies using primarily NPC mouse models have shown that systemic administration of 2-hydroxypropyl-β-cyclodextrin (2HPβCD), starting in early neonatal life, diminishes UC accumulation in most organs, slows disease progression and extends lifespan. The key question now is whether delaying the start of 2HPβCD treatment until early adulthood, when the amount of entrapped UC throughout the body is markedly elevated, has any of the benefits found when treatment begins at 7 days of age. In the present study, Npc1-/- and Npc1+/+ mice were given saline or 2HPβCD subcutaneously at 49, 56, 63 and 70 days of age, with measurements of organ weights, liver function tests and tissue cholesterol levels performed at 77 days. In Npc1-/- mice, treatment with 2HPβCD from 49 days reduced whole-liver cholesterol content at 77 days from 33.0 ± 1.0 to 9.1 ± 0.5 mg/organ. Comparable improvements were seen in other organs, such as the spleen, and in the animal as a whole. There was a transient increase in biliary cholesterol concentration in Npc1-/- mice after 2HPβCD. Plasma alanine aminotransferase and aspartate aminotransferase activities in 77-day-old 2HPβCD-treated Npc1-/- mice were reduced compared with saline-treated controls. The lifespan of Npc1-/- mice given 2HPβCD marginally exceeded that of the saline-treated controls (99 ± 1.1 vs 94 ± 1.4 days, respectively; P < 0.05). Thus, 2HPβCD is effective in mobilizing entrapped cholesterol in late-stage NPC disease leading to improved liver function.

AB - In Niemann-Pick type C (NPC) disease, loss-of-function mutations in either NPC1 or NPC2 result in progressive accumulation of unesterified cholesterol (UC) and glycosphingolipids in all organs, leading to neurodegeneration, pulmonary dysfunction and sometimes liver failure. There is no cure for this disorder. Studies using primarily NPC mouse models have shown that systemic administration of 2-hydroxypropyl-β-cyclodextrin (2HPβCD), starting in early neonatal life, diminishes UC accumulation in most organs, slows disease progression and extends lifespan. The key question now is whether delaying the start of 2HPβCD treatment until early adulthood, when the amount of entrapped UC throughout the body is markedly elevated, has any of the benefits found when treatment begins at 7 days of age. In the present study, Npc1-/- and Npc1+/+ mice were given saline or 2HPβCD subcutaneously at 49, 56, 63 and 70 days of age, with measurements of organ weights, liver function tests and tissue cholesterol levels performed at 77 days. In Npc1-/- mice, treatment with 2HPβCD from 49 days reduced whole-liver cholesterol content at 77 days from 33.0 ± 1.0 to 9.1 ± 0.5 mg/organ. Comparable improvements were seen in other organs, such as the spleen, and in the animal as a whole. There was a transient increase in biliary cholesterol concentration in Npc1-/- mice after 2HPβCD. Plasma alanine aminotransferase and aspartate aminotransferase activities in 77-day-old 2HPβCD-treated Npc1-/- mice were reduced compared with saline-treated controls. The lifespan of Npc1-/- mice given 2HPβCD marginally exceeded that of the saline-treated controls (99 ± 1.1 vs 94 ± 1.4 days, respectively; P < 0.05). Thus, 2HPβCD is effective in mobilizing entrapped cholesterol in late-stage NPC disease leading to improved liver function.

KW - Biliary cholesterol

KW - Brain

KW - Hepatosplenomegaly

KW - Lifespan

KW - Lung

KW - Lysosomal storage disease

KW - Relative organ weight

UR - http://www.scopus.com/inward/record.url?scp=84911033540&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84911033540&partnerID=8YFLogxK

U2 - 10.1111/1440-1681.12285

DO - 10.1111/1440-1681.12285

M3 - Article

VL - 41

SP - 780

EP - 787

JO - Clinical and Experimental Pharmacology and Physiology

JF - Clinical and Experimental Pharmacology and Physiology

SN - 0305-1870

IS - 10

ER -