Develop novel inhaled neutralizing RNA therapeutics against COVID-19

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Project Abstract Despite various antiviral agents or symptom-alleviating interventions under development, unfortunately no effective drug treatment for COVID-19 have been readily identified so far. Given the desperate need for and willingness to try new therapeutic approaches during the COVID-19 pandemic, RNA-based therapeutics could prove to be an attractive option due to their rational design and relatively faster speed of development compared to conventional strategies. Utilizing our extensive experience and expertise in nucleic acid aptamer technology, we will seek to design and develop RNA aptamer-based drug candidates that can provide immediate neutralizing protection against SARS-CoV-2 infection. The SARS-CoV-2 binds to human angiotensin I converting enzyme 2 (ACE2) through its trimeric spike protein (S protein) on the virion, where after fusion of the viral membrane and host cell membrane occurs. Subsequently, the RNA virus will replicate its genome inside the cells and ultimately make new virions that will be secreted to infect other host cells. The S protein is the key target for the development of neutralizing antibodies (Abs), vaccine and therapeutics. The immediate objective of our project is to develop novel inhaled RNA aptamers that specifically bind to the conserved and functional essential elements of SARS-CoV-2 S protein, as viral neutralizing agents, to prevent viral entry and infection. Our central hypothesis is that the inhaled neutralizing RNA intervention will have utility for both pre-exposure prophylaxis and immediate post-exposure treatment to provide a 1st line of defense against SARS-CoV-2 and/or future SARS-CoV stains. In addition to their utility as stand-alone antagonists, the aptamer can also be formulated as cocktailed format or multivalent modality to maximize neutralization potency and breadth. The inhalation administration will further maximize delivery to the epithelial cilial cells of the upper and lower respiratory tract, the tissue sites of initial viral attachment and infection. To the end, we expect successful completion to lead to a translational stage and justify the use of inhaled neutralizing RNA therapeutics immediately in the clinic to protect 1st line health care workers and others at high risk of SARS-CoV-2 exposure. The proposed research is both significant and innovative, and could change current paradigms in the treatment of SARS-CoV-2 infection. The knowledge gained from this study can be rapidly deployed for combating a future strain evolution of SARS that may emerge as a human healthcare threat.