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Antisense RNA Technology and its Applications
(09-26-2013, 08:07 PM)mtwalsh01 Wrote: RNA interference and Cystic Fibrosis

Part of the challenge of targeting antisense RNA and small interfering RNA is the individual cell and tissue environments which need to be targeted in different diseases. Cystic fibrosis is a devastating autosomal recessive disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. It affects most notably the lungs, but also the liver, pancreas and intestines. It involves a defect in epithelial transport of sodium and chlorine. In this context, hyperactivity of epithelial sodium channels (ENaC) has been implicated in CF pathogenesis due to dysregulation of fluid and electrolytes in the airways.

A study from Erasmus MC, Rotterdam in The Netherlands addressed the possibility of targeting ENaC by RNA interference techniques as a possible addition to the armoury of CF therapeutic agents. A proof-of-principle study was performed using lentiviral-mediated RNA interference cells including immortalised normal (H441) and CF mutant (CFBE) airway cells, and differentiated human bronchial epithelial cells in air-liquid interface culture (HBEC-ALI). Air-liquid interface culture more accurately mimics in vivo conditions than solid phase culture. The cells were transduced with a vesicular stomatitis virus G glycoprotein pseudotyped lentiviral (LV) vector which was engineered to express a short hairpin RNA (shRNA) designed to interfere with the α subunit of ENaC (ENaCα). A marker gene was included to allow verification of transduction efficiency, which was confirmed at close to 100% efficiency of H441, CFBE and HBEC-ALI before differentiation and polarization. The study confirmed that ENaCα mRNA was inhibited by shRNA transduction, as was antigen expression. ENaC-dependent short circuit current and fluid transport was proportionally decreased while transepithelial resistance or cAMP-induced secretion responses were unaffected in HBEC-ALI. Off-target effects mediated by Toll-like receptor 3 or RNA-induced silencing complex were ruled out. The study concluded that the generic method to down-regulate ENaCα by lentiviral shRNA expression vectors has potential therapeutic value in CF treatment.


AARBIOU, J. et al., 2012. Lentiviral small hairpin RNA delivery reduces apical sodium channel activity in differentiated human airway epithelial cells. The journal of gene medicine, 14(12), pp. 733-745

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