Self-amplifying mRNA with Interferon Antagonists
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Solution Overview
Problem
Current methods for delivering mRNA or self-replicating RNA into cells often induce an interferon response, which can interfere with the function of the gene of interest and is not easily modulated, posing challenges in therapeutic applications where a controlled immune response is needed.
Innovation Solution
Development of mRNAs and self-amplifying mRNAs comprising specific sequences that encode heterologous polypeptide interferon effectors, such as VP35, NS1, E3, and PB1-F2, to modulate the interferon response, either suppressing or enhancing it depending on the therapeutic goal, using non-viral delivery systems for efficient delivery.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If self-replicating mRNA is used to deliver therapeutic genes, then gene expression efficiency is improved, but interferon response is enhanced which interferes with therapeutic function
Solution Approach 1:
The patent incorporates viral interferon antagonists (such as influenza NS1, Ebola VP35, or vaccinia E3) into the self-replicating mRNA construct. These antagonists convert the harmful interferon response into a beneficial controlled response by specifically binding to and neutralizing interferon molecules, thereby allowing the therapeutic gene to be expressed efficiently without unwanted immune interference
Solution Approach 2:
The patent creates a composite RNA construct that combines multiple functional elements: a self-replicating RNA backbone (providing high expression efficiency), therapeutic gene sequences (providing therapeutic function), and interferon antagonist sequences (providing immune modulation). This composite structure integrates the benefits of self-replication while mitigating the harmful interferon response through the incorporated antagonist proteins
2Quantity of substance
If mRNA replication is enabled for amplification, then therapeutic protein yield is increased, but immune system activation is intensified
Solution Approach 1:
The patent introduces interferon antagonist proteins as intermediary molecules that mediate between the self-replicating mRNA and the host immune system. These antagonists act as buffers that specifically bind to interferon molecules produced during mRNA replication, preventing them from activating immune cells while allowing the replication process to continue and produce high yields of therapeutic protein
Data Source
AI summary
Compounds useful as components of immunogenic compositions for the induction of an immunogenic response in a subject against infection, methods for their use in treatment, and processes for their manufacture are provided herein. The compounds comprise a nucleic acid construct comprising a sequence which encodes an interferon effector.