Oncoselective mRNA Constructs for Targeted Immunogenic Cell Death
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Solution Overview
Problem
Current therapies for cellular diseases, such as cancer, lack effective methods to induce targeted cell death and generate an immune response, limiting treatment options.
Innovation Solution
Development of translatable nucleic acid constructs, specifically in-vitro transcribed mRNAs encoding constitutively active cell death polypeptides, which are designed for controlled expression in target cells, including those with oncoselective readthrough elements to ensure cancer cell specificity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If translatable nucleic acid constructs encoding cell death polypeptides are administered, then cell death and immune response are induced, but specificity to target cells must be ensured to spare healthy cells
Solution Approach 1:
The patent applies local quality by incorporating oncoselective readthrough elements at specific locations within the nucleic acid construct (between the cap and coding sequence) that enable cancer cell-specific translation. This ensures the cell death polypeptide is expressed only in target cancer cells with defective translation machinery, while healthy cells with normal translation fidelity do not express the toxic payload, thus resolving the contradiction between therapeutic efficacy and off-target toxicity.
2Productivity
If constitutively active cell death polypeptides are expressed, then potent cell death is achieved, but controlled expression in specific cell types and physiological states is required
Solution Approach 1:
The patent applies dynamics by creating a translation system that is dynamically regulated based on cellular context. The oncoselective readthrough element remains dormant in healthy cells with functional translation termination, but becomes active in cancer cells with defective termination mechanisms, enabling conditional expression of the cell death polypeptide only when and where needed, thus achieving both potent cell death and controlled expression.
3Productivity
If nucleic acid constructs are designed for high expression, then effective cell death is achieved, but delivery and stability of nucleic acids must be optimized
Solution Approach 1:
The patent applies composite materials by constructing a complex nucleic acid molecule that integrates multiple functional elements: a 5' cap structure for stability and translation initiation, an oncoselective readthrough element for cancer cell specificity, a coding sequence for the cell death polypeptide, and a poly-A tail for stability. This composite structure achieves high expression levels while incorporating necessary elements for delivery, stability, and specificity within a single RNA molecule.
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 constructs induce immunogenic cell death in cancer cells, promoting an adaptive immune response and demonstrating dose-responsive killing, while sparing healthy cells, thus offering a potent therapeutic approach for treating cancer.
Implementation Method 1
These constructs induce immunogenic cell death in cancer cells, promoting an adaptive immune response
Implementation Method 2
Delivery of translatable RNA molecules... expression of an encoded cell death polypeptide
Data Source
AI summary
The present disclosure provides, among other things, methods and compositions useful for induction of cell death. The present disclosure provides translatable nucleic acids encoding constitutively active payloads capable of inducing cell death. Payloads of the present disclosure are particularly useful in induction of immunogenic cell death.