Measuring the Effect of Histone Deacetylase Inhibitors (HDACi) on the Secretion and Activity of Alpha-1 Antitrypsin

Wang, Chao; Bouchecareilh, Marion; Balch, William E.

doi:10.1007/978-1-4939-7163-3_18

Cited by 8 publications

(9 citation statements)

References 29 publications

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“…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: 78%

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: 78%

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

Subramanian

Hutt

Gupta

et al. 2019

Preprint

Self Cite

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“…How HDAC-regulated epigenomic programs translate genetic diversity found in the genome into a functional proteome to contribute to health and disease of each CF individual remains enigmatic. There is now considerable interest in the use of HDAC inhibitors (HDACi) to improve the management of numerous rare protein-folding diseases including CF, Niemann-Pick C1 (43)(44)(45)(46), Alpha-1-AntiTrypsin Deficiency (47)(48)(49) and lysosomal storage disorders (24,(50)(51)(52)(53)(54)(55)(56)(57)(58)(59)(60)(61)(62)(63)(64)(65). Moreover, there is an ever-growing body of evidence that HDACi could play a crucial therapeutic role in complex familial and somatic disease including lung fibrosis, Chronic Obstructive Pulmonary Disease (66), arthritis, hypertension, septic shock and neurodegenerative disease including Alzheimer's, Huntington's and Parkinson's (67)(68)(69).…”

Section: Introductionmentioning

confidence: 99%

“…To address the role of the epigenome in CF biology, we now examine the impact of a rapidly expanding Class of HDACi on mitigation of CF etiology (43,(47)(48)(49)(71)(72)(73)(74). While the vast majority of these compounds are under investigation as anti-cancer therapeutics, where they are used to kill cells, we focus on their potential beneficial effects given the wellrecognized role of HDACs in promoting normal development, differentiation and response to stress and the environment (75).…”

Section: Introductionmentioning

confidence: 99%

HDAC inhibitors rescue multiple disease-causing CFTR variants

Anglès

Hutt

Balch

2019

Human Molecular Genetics

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Understanding the role of the epigenome in protein-misfolding diseases remains a challenge in light of genetic diversity found in the worldwide population revealed by human genome sequencing efforts and the highly variable response of the disease population to therapeutics. An ever-growing body of evidence has shown that histone deacetylase (HDAC) inhibitors (HDACi) can have significant benefit in correcting protein-misfolding diseases that occur in response to both familial and somatic mutation. Cystic fibrosis (CF) is a familial autosomal recessive disease, caused by genetic diversity in the CF transmembrane conductance regulator (CFTR) gene, a cyclic Adenosine MonoPhosphate (cAMP)-dependent chloride channel expressed at the apical plasma membrane of epithelial cells in multiple tissues. The potential utility of HDACi in correcting the phenylalanine 508 deletion (F508del) CFTR variant as well as the over 2000 CF-associated variants remains controversial. To address this concern, we examined the impact of US Food and Drug Administration-approved HDACi on the trafficking and function of a panel of CFTR variants. Our data reveal that panobinostat (LBH-589) and romidepsin (FK-228) provide functional correction of Class II and III CFTR variants, restoring cell surface chloride channel activity in primary human bronchial epithelial cells. We further demonstrate a synergistic effect of these HDACi with Vx809, which can significantly restore channel activity for multiple CFTR variants. These data suggest that HDACi can serve to level the cellular playing field for correcting CF-causing mutations, a leveling effect that might also extend to other protein-misfolding diseases.

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“…How HDAC-regulated epigenomic programs translate genetic diversity in the genome into a functional proteome to contribute differentially to health and disease over the lifespan of each CF individual remains a challenge to understand. There is now considerable interest in the use of HDACi to improve the management of numerous protein folding diseases including CF, Niemann-Pick C1 (NPC1) [43][44][45][46], Alpha-1-AntiTrypsin Deficiency (AATD) [47][48][49], as well as lysosomal disorders [24,[50][51][52][53][54][55][56][57][58][59][60][61][62][63][64][65]. Moreover, there is an ever-growing body of evidence that HDACi could play a crucial therapeutic role in somatic/complex disease including lung fibrosis/Chronic Obstructive Pulmonary Disease (COPD) [66], arthritis, hypertension, septic shock, and neurodegenerative disease including Alzheimer's, Huntington, and Parkinson's [67][68][69].…”

Section: Introductionmentioning

confidence: 99%

“…To address the role of the epigenome in the genomic to phenomic transformation driving CF biology, we have now examined the impact of a rapidly expanding class of HDAC inhibitors (HDACi) on mitigation of CFTR functional etiology [43,[47][48][49][71][72][73][74]. While the vast majority of these compounds are under investigation as anti-cancer therapeutics where they are used to kill cells, we focus on their potential beneficial effects given the well-recognized role of HDACs in promoting development and differentiation.…”

Section: Introductionmentioning

confidence: 99%