shRNA Molecules with Kinked Stem for RIG-I Activation
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Solution Overview
Problem
Current pharmaceutical approaches primarily target viral pathogens rather than host immune responses, limiting their effectiveness against broad-spectrum viral infections and cancer, as they can become sensitive to virus adaptive mutations. There is a need for immune-modulatory molecules that activate the retinoic acid inducible gene I (RIG-I) receptor to stimulate innate immune responses.
Innovation Solution
Development of small hairpin RNA (shRNA) molecules with specific structures that modulate RIG-I mediated immune responses, including a 5' to 3' orientation with nucleotide sequences forming a double-stranded stem structure and a loop region, featuring a nucleotide insertion that creates a kink, which binds specifically to the human retinoic acid-inducible gene 1 receptor (RIG-I).
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If pharmaceutical drugs target viral pathogens and their essential enzymes, then they can treat specific viral infections, but they become sensitive to virus adaptive mutations and have limited effectiveness against broad-spectrum viral infections
Solution Approach 1:
Instead of targeting the virus directly, the invention inverts the approach by targeting the host's immune response system. The shRNA molecules are designed to activate the host's RIG-I receptor, which then triggers the innate immune response against viral infections. This host-targeting approach reduces sensitivity to viral mutations and provides broad-spectrum protection.
Solution Approach 2:
The shRNA molecules with specific structural features (5' triphosphate, double-stranded stem with kink, loop region) are designed to universally activate the RIG-I receptor regardless of the specific virus type. This multi-functional design enables a single therapeutic approach to protect against multiple different viral infections.
2Reliability
If small hairpin RNA molecules are designed with specific structural features to activate RIG-I, then they can stimulate innate immune responses, but their structural complexity increases
Solution Approach 1:
The shRNA molecule is segmented into distinct functional domains: a 5' triphosphate group, a double-stranded stem region with specific length and pairing, a loop region with defined nucleotide composition, and a 3' end structure. Each segment contributes specifically to RIG-I activation, allowing systematic optimization while maintaining overall manageability.
Solution Approach 2:
The invention systematically varies key parameters of the shRNA structure, including stem length (10-30 nucleotides), loop size (1-10 nucleotides), nucleotide composition (AU-rich sequences), and phosphorylation state (5' triphosphate). These parameter changes enable optimization of immune activation while maintaining structural feasibility.
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
These shRNA molecules effectively stimulate RIG-I mediated immune responses, acting as potent adjuvants and antiviral agents, capable of activating type I interferon production and enhancing immune activation against viral infections, including dengue virus, while also showing potential in cancer immunotherapy.
Implementation Method 1
binds specifically to the human retinoic acid-inducible gene 1 receptor (RIG-I)
Implementation Method 2
capable of activating type I interferon production and enhancing immune activation against viral infections
Data Source
AI summary
The present invention generally relates to specific immune-modulatory RNA species that have a small hairpin structure (shRNA), and that can bind to retinoic acid inducible gene I receptor (RIG-I). In particular, said RNA species comprise a nucleotide insertion to create a kink in the stem region. Also encompassed are compositions comprising such shRNA, for use as antiviral or anticancer medication, or as adjuvants in vaccine.