Alternative splicing of ACE2 possibly generates variants that may limit the entry of SARS-CoV-2: A potential therapeutic approach using SSOs

Abstract

Angiotensin-converting enzyme 2 (ACE2) plays an essential role in maintaining the balance of the renin-angiotensin system and also serves as a receptor for the SARS-CoV-2, SARS-CoV, and HCoV-NL63. Following the recent outbreak of SARS-CoV-2 infection, there has been an urgent need to develop therapeutic interventions. ACE2 is a potential target for many treatment approaches for the SARS-CoV-2. With the help of bioinformatics, we have predicted several novel exons of the human ACE2 gene. The inclusion of novel exons located in the 5'UTR/intronic region in the mature transcript may remove the critical ACE2 residues responsible for the interaction with the receptor-binding domain (RBD) of SARS-CoV-2, thus preventing their binding and entry into the cell. Additionally, inclusion of a novel predicted exons located in the 3'UTR by alternative splicing may remove the C-terminal transmembrane domain of ACE2 and generate soluble ACE2 isoforms. Splice-switching antisense oligonucleotides (SSOs) have been employed effectively as a therapeutic strategy in several disease conditions. Alternative splicing of the ACE2 gene could similarly be modulated using SSOs to exclude critical domains required for the entry of SARS-CoV-2. Strategies can also be designed to deliver these SSOs directly to the lungs in order to minimize the damage caused by SARS-CoV-2 pathogenesis.