2-Hydroxypropyl-β-cyclodextrin is the active component in a triple combination formulation for treatment of Niemann-Pick C1 disease

Davidson, Jessica; Molitor, Elizabeth A.; Moores, Samantha; Gale, Sarah E.; Subramanian, Kanagaraj; Jiang, Xuntian; Sidhu, Rohini; Kell, Pamela; Zhang, Jesse; Fujiwara, Hideji; Davidson, Cristin; Helquist, Paul; Melancon, Bruce J.; Grigalunas, Michael; Liu, Gang; Salahi, Farbod; Wiest, Olaf; Xu, Xin; Porter, Forbes D.; Pipalia, Nina H.; Cruz, Dana; Holson, Edward B.; Schaffer, Jean E.; Walkley, Steven U.; Maxfield, Frederick R.; Ory, Daniel S.

doi:10.1016/j.bbalip.2019.04.011

Cited by 20 publications

(23 citation statements)

References 38 publications

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“…We have recently shown that cholesterol homeostasis in cells expressing different NPC1 variants are differentially impacted by SAHA and Panobinostat (18). These results support previous observations that the most common NPC1 variant, I1061T, is sensitive to high affinity HDACi in yeast, fibroblasts and mice (59)(60)(61), although recent results challenge this observation in the context of HPCD treatment in a I1061T mouse model (62). HDACis have also been shown to provide substantial benefit in models of type II diabetes (46,63,64), cancer (65)(66)(67), rheumatoid arthritis (68), chronic lung diseases, including alpha-1-antitrypsin deficiency (AATD) (69)(70)(71)(72), chronic obstructive pulmonary disease (COPD) (72)(73)(74), asthma associated airway inflammation (75)(76)(77)(78)(79) and cystic fibrosis (CF) (80)(81)(82).…”

Section: Introductionsupporting

confidence: 86%

“…This hypothesis is supported by the report that the chronic administration of a triple combination formulation (TCF) of HPCD/SAHA/PEG400 in the nmf164 (D1005G) mouse model (D1005G) provides improved benefit to disease progression (61). While this result has been challenged by the observation that SAHA is dispensible in TCF-mediated restoration of lipid homeostasis in a different, I1061T mouse model (62), our observations that a combinatorial treatment of cyclodextrins and VPA negatively impact the HDACi-mediated correction of I1061T-NPC1 trafficking suggest that drug-drug interactions or countering effects on critical cellular pathways could account for this observation. In light of these results, the proper course of action could require a sequential rather than combinatorial treatments with HDACi to achieve benefit.…”

Section: Discussionmentioning

confidence: 97%

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Correction of Niemann-Pick type C1 disease with the histone deacetylase inhibitor valproic acid

Subramanian

Hutt

Gupta

et al. 2019

Preprint

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Niemann-Pick type C (NPC) disease is primarily caused by mutations in the NPC1 gene and is characterized by the accumulation of unesterified cholesterol and lipids in the late endosomal (LE) and lysosomal (Ly) compartments. The most prevalent disease-linked mutation is the I1061T variant of NPC1, which exhibits defective folding and trafficking from the endoplasmic reticulum to the LE/Ly compartments. We now show that the FDA-approved histone deacetylase inhibitor (HDACi) valproic acid (VPA) corrects the folding and trafficking defect associated with I1061T-NPC1 leading to restoration of cholesterol homeostasis, an effect that is largely driven by a reduction in HDAC7 expression. The VPA-mediated trafficking correction is in part associated with an increase in the acetylation of lysine residues in the cysteine-rich domain of NPC1. The HDACi-mediated correction is synergistically improved by combining it with the FDA-approved anti-malarial, chloroquine, a known lysosomotropic compound, which improved the stability of the LE/Ly-localized fraction of the I1061T variant. We posit that combining the activity of VPA, to modulate epigentically the cellular acetylome, with chloroquine, to alter the lysosomal environment to favor stability of the trafficked I1061T variant protein, can have a significant therapeutic benefit in patients carrying at least one copy of the I1061T variant of NPC1, the most common disease-associated mutation leading to NPC disease. Given its ability to cross the blood brain barrier, we posit VPA provides a potential mechanism to improve the response to 2hydroxypropyl--cyclodextrin, by restoring functional NPC1 to cholesterol managing compartment as an adjunct therapy. the LE/Ly compartments (9-12) where it works in tandem with NPC2 to ensure cholesterol distribution between all cellular and subcellular membranes (13)(14)(15). Like most rare diseases, genetic variation in the clinic contributes differentially to disease onset and progression (1,16). We have shown that variants triggering NPC1 disease are differentially responsive to both proteostasis regulators (17) and the HDAC inhibitor, SAHA (18), suggesting a potential route to manipulate the variant challenged NPC1 misfolding by stabilizing its fold.NPC1 disease progression is primarily a consequence of neuronal dysfunction in the hippocampus (19-23), The most common disease-associated mutation leading to NPC is the I1061T-NPC1, which accounts for 15-20% of all clinical cases (24,25). Disease presentation is characterized by the aberrant accumulation of unesterified cholesterol (CH), glycosphingolipids (GSL), sphingomyelin and sphingosine in the LE/Ly compartments (26) resulting in either a toxic accumulation of CH in the LE/Ly compartment or depletion of accessible CH by other cellular compartments (27) culminating in the progressive loss of Purkinje (PK) cells in the cerebellum. The loss of PK neurons causes ataxia, dysarthria, vertical supranuclear gaze palsy and a decline of neurological functions (27,28), phenotypic hallmarks of NPC1 d...

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Section: Introductionsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 97%

Correction of Niemann-Pick type C1 disease with the histone deacetylase inhibitor valproic acid

Subramanian

Hutt

Gupta

et al. 2019

Preprint

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“…Mechanistically, whether HDACi sensitive events are due to direct alteration of the acetylation balance of Lys residues in the NPC1 polypeptide chain 41,56 , more indirectly through transcriptional and/or post-translational mechanisms affecting HDAC-sensitive proteostasis pathways as shown herein 24,43,57,58 , and/or other HDAC-sensitive events facilitating endomembrane trafficking (ER-Golgi-LE/Ly) compartment function 24,59 , remains to be determined. Recent controversial results 60–64 of HDACi effects in mouse models emphasize the need for use of the human genome sequence and patient related models as captured herein, to point the way 1 , particularly in response to epigenetic modifications that are sensitive to the evolutionary trajectory and the local environment. Consistent with this prediction, from a natural history perspective, we have shown that epigenetic-sensitive SCV relationships can predict residues that are more likely to be responsive to HDACi in human clinical disease.…”

Section: Discussionmentioning

confidence: 99%

Quantitating the epigenetic transformation contributing to cholesterol homeostasis using Gaussian process

et al. 2019

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To understand the impact of epigenetics on human misfolding disease, we apply Gaussian-process regression (GPR) based machine learning (ML) (GPR-ML) through variation spatial profiling (VSP). VSP generates population-based matrices describing the spatial covariance (SCV) relationships that link genetic diversity to fitness of the individual in response to histone deacetylases inhibitors (HDACi). Niemann-Pick C1 (NPC1) is a Mendelian disorder caused by >300 variants in the NPC1 gene that disrupt cholesterol homeostasis leading to the rapid onset and progression of neurodegenerative disease. We determine the sequence-to-function-to-structure relationships of the NPC1 polypeptide fold required for membrane trafficking and generation of a tunnel that mediates cholesterol flux in late endosomal/lysosomal (LE/Ly) compartments. HDACi treatment reveals unanticipated epigenomic plasticity in SCV relationships that restore NPC1 functionality. GPR-ML based matrices capture the epigenetic processes impacting information flow through central dogma, providing a framework for quantifying the effect of the environment on the healthspan of the individual.

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“…A first study using intra-peritoneal or intra-thecal injection in NPC1-deficient mice failed to show a positive effect [362]. However, subsequent reports revealed that CD prolongs the life span, slows down neurologic disease progression, and halts the degeneration of Purkinje cells in the mouse and cat model [177][178][179][180][181]363,364]. Intra-thecal injections were required, as CD cannot pass the blood-brain barrier [365].…”

Section: Models Mattering For Therapy Developmentmentioning

confidence: 99%

“…A first in vivo study using Npc1 mutant mice claimed that repeated intra-peritoneal injections of vorinostat, an HDAC inhibitor, together with polyetheylene-glycol and CD slow down neurologic disease progression, but some controls were missing [387]. A subsequent report on mice attributed the effects on neurologic symptoms to CD [363]. Repeated intra-peritoneal injections of vorinostat in NPC1 mutant mice improved liver function but did not slow down weight loss or increase life span [194] probably because the drug cannot enter the central nervous system [363].…”

Section: Models Mattering For Therapy Developmentmentioning

confidence: 99%

Understanding and Treating Niemann–Pick Type C Disease: Models Matter

Pallottini

Pfrieger

2020

IJMS

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Biomedical research aims to understand the molecular mechanisms causing human diseases and to develop curative therapies. So far, these goals have been achieved for a small fraction of diseases, limiting factors being the availability, validity, and use of experimental models. Niemann–Pick type C (NPC) is a prime example for a disease that lacks a curative therapy despite substantial breakthroughs. This rare, fatal, and autosomal-recessive disorder is caused by defects in NPC1 or NPC2. These ubiquitously expressed proteins help cholesterol exit from the endosomal–lysosomal system. The dysfunction of either causes an aberrant accumulation of lipids with patients presenting a large range of disease onset, neurovisceral symptoms, and life span. Here, we note general aspects of experimental models, we describe the line-up used for NPC-related research and therapy development, and we provide an outlook on future topics.

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2-Hydroxypropyl-β-cyclodextrin is the active component in a triple combination formulation for treatment of Niemann-Pick C1 disease

Cited by 20 publications

References 38 publications

Correction of Niemann-Pick type C1 disease with the histone deacetylase inhibitor valproic acid

Correction of Niemann-Pick type C1 disease with the histone deacetylase inhibitor valproic acid

Quantitating the epigenetic transformation contributing to cholesterol homeostasis using Gaussian process

Understanding and Treating Niemann–Pick Type C Disease: Models Matter

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