Reduced histone deacetylase 7 activity restores function to misfolded CFTR in cystic fibrosis

Abstract

Chemical modulation of histone deacetylase (HDAC) activity by HDAC inhibitors (HDACi) is an increasingly important approach to modify the etiology of human disease. Loss-of-function diseases arise as a consequence of protein misfolding and degradation leading to system failures. The ΔF508 mutation in cystic fibrosis transmembrane conductance regulator (CFTR) results in the absence of the cell surface chloride channel and a loss of airway hydration, leading to premature lung failure and reduced lifespan responsible for cystic fibrosis (CF). We now show that the HDACi suberoylanilide hydroxamic acid (SAHA) restores surface channel activity in human primary airway epithelia to levels that are 28% of wild-type CFTR. Biological silencing of all known class I and II HDACs reveals that HDAC7 plays a central role in restoration of ΔF508 function. We suggest that the tunable capacity of HDACs can be manipulated by chemical biology to counter the onset of CF and other human misfolding disorders.

Correction of the F508del-CFTR protein processing defect in vitro by the investigational drug VX-809

“…These included drugs approved for non-CF indications [e.g., 4-phenylbutyrate, miglustat, sildenafil, suberoylanilide hydroxamic acid (SAHA)] (19,(30)(31)(32) and compounds identified through high-throughput screening (e.g., corr-4a, VRT-325) (18,19). The cultured F508del-HBE cells were preincubated with each compound at the maximally effective concentration and treatment duration (Fig.…”

“…Several CFTR correctors have been previously reported to be active in vitro, including drugs approved for non-CF indications (e.g., 4-phenylbutyrate, miglustat, sildenafil, SAHA) (19,(30)(31)(32) and compounds identified through high-throughput screening (e.g., corr-4a, VRT-325) (18,19). Therapies for CF have not advanced from these efforts, possibly due to insufficient restoration of CFTR function and/or poor selectivity for processing of CFTR compared with other proteins and other off-target actions.…”

“…First, VX-809 increased the efficiency of F508del-CFTR ER export, suggesting , and VRT-325 (6.7 μM) for 8 d with 1 μM SAHA or 2 to 4 h with 100 μM miglustat. The concentration and treatment duration for each compound were based on the maximally effective experimental conditions published for the previously described CFTR corrector (18,30,43,44). Asterisks indicate significant (P < 0.05; paired t test) increase in I T vs. untreated levels.…”

Managing the Adaptive Proteostatic Landscape: Restoring Resilience in Alpha-1 Antitrypsin Deficiency

“…Specifi cally, we have shown that the pan Class I/II/IV HDACi suberoylanilide hydroxamic acid (SAHA) restores the secretion and activity of Z-AAT to ~50 % of the level that observed in WT AAT [ 27 ]. Currently, this correction appears to be mainly through inhibition of HDAC7, which is the same HDAC target that can be modifi ed by SAHA to correct the folding of the most common mutation found in cystic fi brosis, F508del [ 249 ]. Incubation with SAHA or silencing of HDAC7 improves AATD through multiple pathways.…”

“…Given the above, it is therefore not surprising that HDAC inhibitors (HDACi) have been shown to have benefi cial effects for ma ny protein misfolding diseases, such as cystic fi brosis [ 249 ], Gauchers disease [ 250 ], muscle atrophy [ 251 ], Niemann-Pick C [ 252 , 253 ], and neurodegenerative diseases [ 254 -258 ]. Specifi cally, we have shown that the pan Class I/II/IV HDACi suberoylanilide hydroxamic acid (SAHA) restores the secretion and activity of Z-AAT to ~50 % of the level that observed in WT AAT [ 27 ].…”