mRNA Therapeutic Against the SARS-CoV-2 Spike Protein

Background

Vaccines have shown great efficacy against SARS-CoV-2, the pathogen of COVID-19; however, methods of treatment are required for patients suffering from COVID‑19.

More than 15 million cases with over 600,000 deaths have resulted from the ongoing coronavirus disease 2019 (COVID-19). SARS-CoV-2, the pathogen of COVID-19, is a β-coronavirus that primarily enters through the airways and lungs. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters through the airways and infects the lungs, causing lethal pulmonary damage in vulnerable patients. This virus contains spike proteins on its envelope that binds to human angiotensin-converting enzyme 2 (hACE2) expressed on the surface of airway cells, enabling entry of the virus for causing infection. In severe cases, the virus enters the circulatory system, contributing to multiorgan failure.

Technology Overview

The invention is a method to produce soluble (secreted) forms of angiotensin-converting enzyme 2 (ACE2) as therapeutic molecules for the treatment of virus infection as well as hypertension.

Soluble forms of ACE2 are produced from synthetic messenger RNA (mRNA) intracellularly delivered. The synthetic mRNAs encode the human soluble ACE2 variants. The mRNA is packaged in lipid-based nanoparticles (LNPs). LNP-delivered mRNA is translated into soluble ACE2 protein forms inside cells. Produced soluble ACE2 is secreted extracellularly and exerts its pharmacological effects. Here, we engineered synthetic mRNA to encode a soluble form of hACE2 (hsACE2) to prevent viral infection. Novel lipid nanoparticles (LNPs) were used to package mRNA and transfect mammalian cells for enhanced production of secreted proteins. Intravenously administered LNP led to hepatic delivery of the mRNA. This elicited secretion of hsACE2 into the blood circulation within 2 h, and levels of circulating hsACE2 peaked at 6 h and gradually decreased over several days. Through co-immunoprecipitation, we found that mRNA-generated hsACE2 was able to bind with the receptor-binding domain of the SARS-CoV-2 spike protein. Furthermore, hsACE2 was able to strongly inhibit (over 90%) SARS-CoV-2 pseudovirus infection. Our proof of principle study shows that mRNA-based nanotherapeutics can be potentially deployed for pulmonary and extrapulmonary neutralization of SARS-CoV-2 and open new treatment opportunities for COVID-19.

Benefits

mRNA-based nanotherapeutics can be potentially deployed for pulmonary and extrapulmonary neutralization of SARS-CoV-2
New treatment opportunities for COVID-19