Small interfering RNA against ENaC and cystic fibrosis
The use of small interfering RNA technology is being considered in a number of different pathological conditions. Cystic fibrosis is a devastating autosomal recessive disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. CF incidence is about 1 in 2000-3000 new births in the European Union; incidence in Ireland is the highest in the world. Incidence in the USA is approximately 1 in 3500 births while in Asia the disease is severely underdiagnosed according to WHO, although existing evidence indicates that it is low. It affects most notably the lungs but also the liver, pancreas and intestines and involves a defect in epithelial transport of sodium and chlorine. Dehydration of the airway surface liquid and build-up of a thick layer of mucus provide the ideal conditions for bacterial biofilm formation. Common bacterial strains found in these biofilms are notably Pseudomonas aeruginosa and also Staphylococcus aureus. The epithelial surface of the airways becomes dehydrated, partially due to hyperactivity of epithelial sodium channels (ENaC), which has been implicated in CF pathogenesis. Patients are locked in a cycle of infection and antibiotic treatment and life expectancy is approximately 40 years. Research into new therapies is urgently needed.
A recent study from the Therapeutic Oligonucleotide Discovery Performance Unit of GlaxoSmithKline (GSK) has identified screened a series of chemically modified 21-mer siRNAs targeting human ENaC . The study identified a siRNA called GSK2225745 which potently inhibited ENaCα mRNA and protein levels in A549 human lung carcinoma cells. GSK2225745 was further tested and shown to exert prolonged inhibition of expression and function of ENaCα in a number of cell lines relevant to CF pathology including bronchial epithelial and nasal epithelial cells. In vivo studies on mice used nanoparticle technology to deliver GSK2225745 to the airways, resulting again in potent inhibition of ENaCα. Further testing of GSK2225745 as a therapeutic agent for cystic fibrosis is indicated.
Sources
CLARK, K.L. et al., 2013. Pharmacological Characterization of a Novel ENaCα siRNA (GSK2225745) With Potential for the Treatment of Cystic Fibrosis. United States: Nature Pub. Group
http://www.who.int/genomics/public/genet...ndex2.html
http://www.cfireland.ie/
The use of small interfering RNA technology is being considered in a number of different pathological conditions. Cystic fibrosis is a devastating autosomal recessive disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. CF incidence is about 1 in 2000-3000 new births in the European Union; incidence in Ireland is the highest in the world. Incidence in the USA is approximately 1 in 3500 births while in Asia the disease is severely underdiagnosed according to WHO, although existing evidence indicates that it is low. It affects most notably the lungs but also the liver, pancreas and intestines and involves a defect in epithelial transport of sodium and chlorine. Dehydration of the airway surface liquid and build-up of a thick layer of mucus provide the ideal conditions for bacterial biofilm formation. Common bacterial strains found in these biofilms are notably Pseudomonas aeruginosa and also Staphylococcus aureus. The epithelial surface of the airways becomes dehydrated, partially due to hyperactivity of epithelial sodium channels (ENaC), which has been implicated in CF pathogenesis. Patients are locked in a cycle of infection and antibiotic treatment and life expectancy is approximately 40 years. Research into new therapies is urgently needed.
A recent study from the Therapeutic Oligonucleotide Discovery Performance Unit of GlaxoSmithKline (GSK) has identified screened a series of chemically modified 21-mer siRNAs targeting human ENaC . The study identified a siRNA called GSK2225745 which potently inhibited ENaCα mRNA and protein levels in A549 human lung carcinoma cells. GSK2225745 was further tested and shown to exert prolonged inhibition of expression and function of ENaCα in a number of cell lines relevant to CF pathology including bronchial epithelial and nasal epithelial cells. In vivo studies on mice used nanoparticle technology to deliver GSK2225745 to the airways, resulting again in potent inhibition of ENaCα. Further testing of GSK2225745 as a therapeutic agent for cystic fibrosis is indicated.
Sources
CLARK, K.L. et al., 2013. Pharmacological Characterization of a Novel ENaCα siRNA (GSK2225745) With Potential for the Treatment of Cystic Fibrosis. United States: Nature Pub. Group
http://www.who.int/genomics/public/genet...ndex2.html
http://www.cfireland.ie/
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