Using oligonucleotides against 2019-nCoV RNA genome
Beyond targeting the surface proteins of 2019-nCoV, one could also target the RNA genome itself for degradation. This RNA genome sequence of 2019-nCoV was recently published (GenBank: MN908947.3), and one strategy that could be considered then, is the use of small interfering RNA (siRNA) or antisense oligonucleotides (ASO) to combat the virus by targeting its RNA genome 23. The challenge with this strategy is multi-fold. First, the conserved RNA sequence domains of CoV-2019 are not known. Identifying conserved sequences is essential in order to optimize siRNA targeting and avoid viral escape of the oligonucleotide strategy. One could look at genome homology of 2019-nCoV to the SARS virus for comparison of conserved sequences, but this would still be guesswork. A second challenge is how the oligonucleotides would be delivered into the lungs. Advances have been made into delivery vehicles such as lipid nanoparticles that can mediate some delivery into the lungs 24. It is unknown, however, if enough siRNA’s or ASO’s would be effectively delivered within the lungs to stop the infection or make a difference in its clinical course. For example, if 25% of alveolar epithelial cells in the lung had siRNA or ASO in them, that efficiency might be a great success for traditional gene therapy, but would hardly make any difference in a viral infection. Such an explanation is also likely why siRNA candidates against Ebola failed in trials 25, despite significant success in preclinical animal models 26, 27. Lastly, even if one assumed that siRNA was effective clinically, there is a limited ability to scale up manufacturing of siRNA drugs to a large infected population. Current siRNA and ASO therapies are manufactured for rare diseases, and there are no available resources existing to manufacture the medications quickly.