Antisense Oligonucleotides Reducing ACE2 Expression for Viral Infection
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Solution Overview
Problem
Current therapeutic approaches for COVID-19, such as inhibiting viral RNA polymerase with Remdesivir, do not prevent pandemic spread or provide immunization, and vaccines take time to develop and may lose efficacy due to viral mutations, highlighting the need for alternative therapeutic methods to reduce ACE2 expression and inhibit viral infection.
Innovation Solution
Development of oligonucleotides that hybridize with ACE2 mRNA or pre-mRNA, specifically targeting the enzymatically active domain of ACE2, reducing its expression by up to 99% using modified nucleotides like LNA, ENA, or 2'Fluoro modifications, which can be administered alone or in combination with other antiviral agents.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If vaccines are developed to prevent SARS-CoV-2 infection, then immunity can be provided to the population, but it takes several months to years for production and may lose efficacy due to viral mutations
Solution Approach 1:
The patent applies preliminary action by using antisense oligonucleotides to reduce ACE2 expression before viral infection occurs. This pre-emptive approach blocks the viral entry mechanism in advance, providing immediate protection without waiting for vaccine-induced immunity to develop. The oligonucleotides are administered directly to reduce cellular ACE2 levels, creating a preliminary defensive barrier against SARS-CoV-2 entry.
2Productivity
If therapeutic approaches like Remdesivir are used to inhibit viral RNA polymerase, then viral propagation can be reduced in infected subjects, but they do not prevent pandemic spread or provide immunization
Solution Approach 1:
The patent applies the extraction principle by specifically removing or reducing the ACE2 receptor expression on host cells using antisense oligonucleotides. By extracting the critical entry point (ACE2) that the virus needs to infect cells, the invention prevents viral attachment and entry at the source, thereby stopping both replication in infected subjects and spread to new hosts, addressing both treatment and prevention needs.
3Reliability
If siRNAs are used to target viral RNA, then viral propagation can be inhibited, but delivery systems are required and applicability is limited to specific cell types
Solution Approach 1:
The patent applies this principle by using naked antisense oligonucleotides that can be directly administered without complex delivery systems. These oligonucleotides are designed to be stable enough to reach their target but are replaced and re-administered as needed. The simplicity of the oligonucleotide structure itself, combined with its ability to function without specialized delivery vehicles, reduces device complexity while maintaining reliable viral RNA degradation through RNase H recruitment.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The oligonucleotides effectively reduce ACE2 expression in various cell types, including nasal and lung epithelial cells, thereby inhibiting viral entry and replication, providing a promising therapeutic approach for preventing and treating COVID-19 with minimal side effects and resistance risks.
Implementation Method 1
an oligonucleotide hybridizing with ACE2 of SEQ ID NO.1 and/or 2 to reduce the level of ACE2, ACE2 mRNA, ACE2 pre-mRNA
Implementation Method 2
The modification of the nucleotide is for example selected from the group consisting of a bridged nucleic acid such as LNA, ENA, a 2′Fluoro modified nucleotide
Data Source
AI summary
The present invention refers to oligonucleotides comprising 10 to 25 nucleotides, wherein at least one of the nucleotides is modified, and the oligonucleotide hybridizes with mRNA of angiotensin-converting enzyme 2 (ACE2) of SEQ ID NO.1 and/or with pre-mRNA of ACE2 of SEQ ID NO.2 resulting in a reduction of the level of ACE2, ACE2 mRNA, ACE2 pre-mRNA or a combination thereof of 30 to 99% compared to an untreated control. The invention is further directed to a pharmaceutical composition comprising such oligonucleotide. The oligonucleotide and the pharmaceutical composition are used in a method of preventing and/or treating a viral disease.