COMBINING TRANSLATION READTHROUGH INDUCING DRUGS AND NONSENSE MEDIATED DECAY PATWHAY INHIBITION TO THE CFTR RESCUEIN CYSTIC FIBROSIS CELL MODEL SYSTEM

Risultato della ricerca: Meeting Abstractpeer review

Abstract

Nonsense mutations affect 10% of patients with cysticfibrosis and produce a premature termination codon in CFTR(Cystic Fibrosis Transmembrane Conductance Regulator)mRNA causing early termination of translation and leading tolack of CFTR function. A potential therapy for nonsense mutations provides the use of small molecules able to overcome thepremature stop codon (PTC) by a readthrough mechanism thatlead to synthesis a complete CFTR protein. Despite the goodresults obtained from this approach, TRIDs efficiency is considerably reduced by the poor amount of target transcript, that isthe mRNA containing the PTC. The readthrough, indeed, doesnot occur on the totality of target transcripts because of theirdegradation due to the nonsense mediated decay pathway(NMD). This pathway provides the degradation of mRNA harboring premature stop codon to prevent the production ofaltered polypeptides. In contrast, the activity of this pathwayinterferes with the effectiveness of the readthrough drugs, limiting the mRNA concentration of the target protein. Thus, apromising strategy for nonsense mutation treatment is a combined use of readthrough agents and factors that attenuate thenonsense mRNA decay. By silencing the UPF1 mRNA/protein, the activity of the NMD pathway was reduced, in FRTcells CFTR W1282X. Alternatively, caffeine was used as specificinhibitor of the UPF1 activity, to increase the efficiency ofreadthrough molecules (NV848 and NV914) in FRT cellsCFTRW1282X cells. In both cases, the combined treatment:NV848 or NV914/caffeine and NV848 orNV914/UPF1siRNA caused an increase of CFTRW1282XmRNA level followed by the rescue of the CFTR expressionand functionality. However, unexpectedly, despite the higherCFTRW1282X mRNA level in caffeine treated samples, bothexpression and functionality CFTR rescue resulted slightlylower than the recovery achieved by UPF1 silencing. Ourresults indicate that modulation of NMD pathway, althoughstill to be optimized, could be a promising approach in orderto increase TRIDs effects in presence of stop mutations.
Lingua originaleEnglish
pagine (da-a)56-57
Numero di pagine2
RivistaJOURNAL OF BIOLOGICAL RESEARCH
VolumeVolume 94
Stato di pubblicazionePublished - 2021

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