Safety of Antisense RNA Oligonucleotides in Treatment of Cystic Fibrosis




Robinson, Elizabeth

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Cystic fibrosis (CF) is a deadly, heritable lung disorder. Patients with CF lack activity in (or lack altogether) the cystic fibrosis transmembrane regulator (CFTR), a chloride ion channel responsible for keeping lung mucus moist—without proper moisture, the lungs develop breathing difficulties and frequent infections (Boyd et al., 2020). Because it is a genetic disorder, research conventionally focuses on creating gene therapies to supply CFTR DNA. While gene therapies are effective, they often cause adverse side-effects from integrating into unpredictable areas of the genome. Gene vectors may accidentally place the CFTR DNA into a tumor suppressor gene, putting patients at risk for developing cancers (Boyd et al., 2020). Recently, researchers have looked into RNA therapies, such as antisense oligonucleotides (ASO), for combating cystic fibrosis without need for integration. Unlike gene therapies, ASOs cannot integrate into the cell’s DNA, and therefore are much less likely to interrupt a proto-oncogene and cause cancer. ASOs are small RNA molecules that block mRNA translation by physically binding to the mRNA (Boyd et al., 2020). Therefore, they can downregulate expression of genes that may cause or exacerbate CF symptoms. For instance, the epithelial sodium channel (ENaC) remains active while the CF patient’s missing chloride channel is inactive, contributing to unbalanced moisture in the lungs (Crosby et al., 2017). ASOs targeted at genes encoding ENaC, such as Scnn1a, might therefore alleviate or even reverse CF symptoms (Crosby et al., 2017). Conversely, ASOs can be used to block translation regulation elements in the mRNA for CFTR itself, therefore upregulating CFTR translation levels (Boyd et al., 2020). CFTR upregulation through ASOs has advanced into the clinical stage, where researchers are assessing its tolerable dose and adverse side-effects (Drevinek et al., 2020). Due to the low incidence and severity of adverse side-effects in clinical trials, antisense oligonucleotide therapy for treating cystic fibrosis offers a far safer alternative to conventional gene therapy.


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