HDAC Inhibitors Rescue Multiple Disease-Causing CFTR Variants

Anglès, Frédéric; Hutt, Darren M.; Balch, William E.; McGuckian, Mary

doi:10.1101/399451

Cited by 2 publications

(1 citation statement)

References 109 publications

(168 reference statements)

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“…A number of other strategies to correct biosynthesis of misfolded CFTR are currently under investigation Recent screening efforts identified the translation initiation factor 3a (eIF3a) as a potentially druggable central hub for the biogenesis of CFTR (Hutt et al, 2018). FDA-approved histone deacetylase (HDAC) inhibitors such as panobinostat (LBH-589) and romidepsin (FK-228) can help to correct misfolded CFTR, particularly in combination with other correctors such as VX809 (Angles et al, 2018). Promising results were also obtained with combinations of pharmacological chaperones with different sites of action, such as VX-809, RDR1, and MCG1516A (Carlile et al, 2018).…”

Section: Correcting and Potentiating Cftrmentioning

confidence: 99%

TMEM16A in Cystic Fibrosis: Activating or Inhibiting?

et al. 2019

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The inflammatory airway disease cystic fibrosis (CF) is characterized by airway obstruction due to mucus hypersecretion, airway plugging, and bronchoconstriction. The cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel is dysfunctional in CF, leading to defects in epithelial transport. Although CF pathogenesis is still disputed, activation of alternative Cl− channels is assumed to improve lung function in CF. Two suitable non-CFTR Cl− channels are present in the airway epithelium, the Ca2+ activated channel TMEM16A and SLC26A9. Activation of these channels is thought to be feasible to improve hydration of the airway mucus and to increase mucociliary clearance. Interestingly, both channels are upregulated during inflammatory lung disease. They are assumed to support fluid secretion, necessary to hydrate excess mucus and to maintain mucus clearance. During inflammation, however, TMEM16A is upregulated particularly in mucus producing cells, with only little expression in ciliated cells. Recently it was shown that knockout of TMEM16A in ciliated cells strongly compromises Cl− conductance and attenuated mucus secretion, but does not lead to a CF-like lung disease and airway plugging. Along this line, activation of TMEM16A by denufosol, a stable purinergic ligand, failed to demonstrate any benefit to CF patients in earlier studies. It rather induced adverse effects such as cough. A number of studies suggest that TMEM16A is essential for mucus secretion and possibly also for mucus production. Evidence is now provided for a crucial role of TMEM16A in fusion of mucus-filled granules with the apical plasma membrane and cellular exocytosis. This is probably due to local Ca2+ signals facilitated by TMEM16A. Taken together, TMEM16A supports fluid secretion by ciliated airway epithelial cells, but also maintains excessive mucus secretion during inflammatory airway disease. Because TMEM16A also supports airway smooth muscle contraction, inhibition rather than activation of TMEM16A might be the appropriate treatment for CF lung disease, asthma and COPD. As a number of FDA-approved and well-tolerated drugs have been shown to inhibit TMEM16A, evaluation in clinical trials appears timely.

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Section: Correcting and Potentiating Cftrmentioning

confidence: 99%

TMEM16A in Cystic Fibrosis: Activating or Inhibiting?

et al. 2019

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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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HDAC Inhibitors Rescue Multiple Disease-Causing CFTR Variants

Abstract: All rights reserved. No reuse allowed without permission.(which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.

Cited by 2 publications

References 109 publications

TMEM16A in Cystic Fibrosis: Activating or Inhibiting?

TMEM16A in Cystic Fibrosis: Activating or Inhibiting?

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

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