Lipophilic dsRNA Compositions for TMPRSS2 Gene Silencing
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Solution Overview
Problem
There is an urgent need for an agent that can selectively and efficiently silence the TMPRSS2 gene using the cell's own RNAi machinery to inhibit coronavirus infection, particularly for severe diseases like SARS-CoV-2, SARS-CoV, and MERS-CoV, as current treatments are lacking.
Innovation Solution
Development of double-stranded ribonucleic acid (dsRNA) agents conjugated to lipophilic moieties, which form an RNA-induced silencing complex to target and cleave TMPRSS2 mRNA, inhibiting its expression and viral entry into cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional RNAi agents are used to silence TMPRSS2 gene, then gene expression can be inhibited, but the agents lack in vivo stability and cellular uptake efficiency
Solution Approach 1:
The patent applies composite materials by combining RNAi agents with lipid moieties to create lipophilic conjugates. This composite structure enhances in vivo stability and cellular uptake while maintaining gene silencing efficacy. The lipid component provides membrane interaction capability and protection against degradation, resolving the contradiction between efficacy and stability.
Solution Approach 2:
The patent modifies the chemical parameters of RNAi agents by conjugating them with lipid moieties of varying chain lengths and structures. This parameter change transforms the physical-chemical properties of the agents, improving their stability in biological environments without compromising their ability to silence the TMPRSS2 gene.
2Reliability
If conventional RNAi agents are used to silence TMPRSS2 gene, then gene expression can be inhibited, but the agents have poor cellular uptake efficiency
Solution Approach 1:
The patent changes the lipophilicity parameter of RNAi agents through conjugation with lipid moieties. This parameter modification enables the agents to interact with cell membranes and be internalized by cells, thereby improving cellular uptake efficiency while preserving gene silencing function.
Solution Approach 2:
The lipid moiety acts as an intermediary that facilitates the entry of RNAi agents into cells. The lipophilic conjugate serves as a mediator that bridges the hydrophilic RNAi agent and the hydrophobic cell membrane, enabling efficient cellular uptake while maintaining the agent's biological activity.
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 dsRNA agents effectively inhibit TMPRSS2 gene expression, reducing viral entry and replication, providing a therapeutic approach for coronavirus infections and associated disorders.
Implementation Method 1
double-stranded ribonucleic acid (dsRNA) agents conjugated to lipophilic moieties, which form an RNA-induced silencing complex to target and cleave TMPRSS2 mRNA
Implementation Method 2
effect the RNA-induced silencing complex (RISC)-mediated cleavage of RNA transcripts of a gene encoding Transmembrane Serine Protease 2 (TMPRSS2)
Data Source
AI summary
The present invention relates to RNAi agents, e.g., dsRNA agents, targeting the transmembrane serine protein 2 (TMPRSS2) gene. The invention also relates to methods of using such RNAi agents to inhibit expression of a TMPRSS2 gene and to methods of treating or preventing a TMPRSS2-associated disease, e.g., COVID-19, in a subject.