Self-Circularizing RNA Structure for Stable Therapeutic Expression
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Solution Overview
Problem
Existing mRNA-based therapeutic agents face challenges due to their instability and short half-life in vivo, limiting their effectiveness.
Innovation Solution
A self-circularization RNA construct is developed with a structure of 5′-IGS-ribozyme-gene of interest-target site-3′, forming a P1 helix through complementary binding, allowing for self-targeting and splicing to create a circRNA that includes a bulge, which enhances stability and expression of therapeutic agents.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Duration of action of moving object
If mRNA is used as a therapeutic agent, then gene expression can be achieved, but stability and half-life are limited
Solution Approach 1:
The patent applies circularization of the RNA molecule, transforming the linear mRNA structure into a circular form. This curvature eliminates the exposed 5′ and 3′ ends that are susceptible to degradation, thereby improving stability and extending half-life while maintaining gene expression capability
Solution Approach 2:
The patent modifies the structural parameters of the RNA molecule by introducing specific sequence elements (IGS and target site) that enable self-circularization. This parameter change from linear to circular topology fundamentally alters the degradation kinetics and stability profile of the therapeutic RNA
2Reliability
If poly(A) tail is attached to mRNA, then stability is improved, but the structure becomes more complex
Solution Approach 1:
The patent merges the functions of stability enhancement and structural organization into a single circularized architecture. Instead of adding separate elements like poly(A) tails, the circular structure itself provides both stability through end-protection and organizational simplicity through its closed-loop design
Solution Approach 2:
The patent extracts the vulnerable 5′ and 3′ ends from the RNA structure by circularizing it, removing the sites that require additional protective elements. This extraction eliminates the need for poly(A) tails and other end-protection mechanisms
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 self-circularization RNA construct achieves stable and efficient expression of therapeutic agents like miRNA, shRNA, and mRNA vaccines by forming circRNA, ensuring high stability within cells and rapid peptide or protein production.
Implementation Method 1
a P1 helix is a helix structure formed through a complementary binding between the nucleotide sequence linked to the front end (5′ direction) of the ribozyme and the nucleotide sequence in the 3′ direction of the transcript
Implementation Method 2
the self-circularization RNA construct... may form a P1 helix including a bulge... forming a circRNA through self-targeting and splicing
Data Source
AI summary
A self-circularized RNA structure of the present invention can be expressed in a DNA vector and, at the same time, form circRNA by being circularized through a self-targeting and splicing reaction, wherein the circRNA consists of only a gene of interest. The gene of interest includes an IRES region, an initiation codon and a termination codon, and thus enables the rapid expression of a peptide and a protein.