Cystic fibrosis is an autosomal recessive disease in which mutations in the CFTR gene lead to a reduced life expectancy in carriers, partly due to the rapid loss of respiratory functions. CFTR-F508del is the most frequent mutation, leading to a mislocalized and non-functional CFTR protein. The tri-therapy Elexacaftor/Tezacaftor/Ivacaftor is now given to patients carrying CFTR-F508del mutation, but some biological defaults of this mutation are still not addressed. Among CFTR interactors, we have previously identified COMMD1 as a potential therapeutic target, which overexpression favors the plasma membrane expression of CFTR. In 2013, a cell-penetrating peptide named CIGB-552 was discovered as a COMMD1 protein stabilizer. We evaluate the therapeutic potential of CIGB-552 in cystic fibrosis context. FITC Tagged version of CIGB-552 was used to evaluate its uptake on cell models cultured submerged or in air-liquid interface. HS-eYFP assay was performed for measuring CFTR quenching ratio. Short-circuit current was recorded to evaluate specific chloride flux through CFTR channel. Western blot was used to evaluate CFTR maturation and COMMD1 expression. We demonstrate that CIGB-552 is non-toxic and preferentially enters CFTR-F508del expressing cells without modifying COMMD1 expression or localization in our cystic fibrosis cell models. CIGB-552 is not a potentiator nor a corrector but acts synergistically with Elexacaftor/Tezacaftor/Ivacaftor in improving chloride efflux and increasing transepithelial potential difference of CFTR-F508del cells. The mechanism implied by CIGB-552 with the COMMD1 protein in this positive effect are still undeciphered. CIGB-552 synergy with the tri-therapy to modulate CFTR-F508del function is still a promising strategy to improve cystic fibrosis treatment.

Background and Purpose: Limb-girdle muscular dystrophy type R3 (LGMD R3) is a rare genetic disorder characterized by a progressive proximal muscle weakness and caused by mutations in the SGCA gene encoding alpha-sarcoglycan (α-SG). Here, we report the results of a mechanistic screening ascertaining the molecular mechanisms involved in the degradation of the most prevalent misfolded R77C-α-SG protein. Experimental Approach: We performed a combinatorial study to identify drugs potentializing the effect of a low dose of the proteasome inhibitor bortezomib on the R77C-α-SG degradation inhibition. Key Results: Analysis of the screening associated to artificial intelligence-based predictive ADMET characterization of the hits led to identification of the HDAC inhibitor givinostat as potential therapeutical candidate. Functional characterization revealed that givinostat effect was related to autophagic pathway inhibition, unveiling new theories concerning degradation pathways of misfolded SG proteins. Conclusion and Implications: Beyond the identification of a new therapeutic option for LGMD R3 patients, our results shed light on the potential repurposing of givinostat for the treatment of other genetic diseases sharing similar protein degradation defects such as LGMD R5 and cystic fibrosis.