Immune Checkpoint miRNA Composition for Selective mRNA Silencing
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Solution Overview
Problem
Bioactive molecules such as immune checkpoint molecules are often overexpressed or misexpressed, leading to homeostatic imbalance and associated diseases, necessitating therapies to regulate their production and function.
Innovation Solution
Compositions comprising recombinant plasmids that encode miRNA sequences targeting the mRNA of immune checkpoint molecules like PD-1, PD-L1, PD-L2, CTLA4, or IDO1, administered to upregulate miRNA production within cells, thereby downregulating the expression of these molecules.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If immune checkpoint molecules are overexpressed or misexpressed, then homeostatic control is lost and disease occurs, but increasing their expression for therapeutic benefit creates harmful effects
Solution Approach 1:
The patent introduces miRNA as an intermediary molecule that mediates the regulation of immune checkpoint molecules. The recombinant plasmid delivers miRNA sequences that specifically target and bind to mRNA of immune checkpoint molecules (PD-1, PD-L1, PD-L2, CTLA-4, IDO-1), forming an RNA-RNA hybrid that triggers mRNA degradation or translational repression, thereby indirectly controlling protein expression levels and restoring homeostasis without directly manipulating the checkpoint molecules themselves.
Solution Approach 2:
The patent changes the expression parameter of immune checkpoint molecules by introducing exogenous miRNA sequences that specifically target their mRNA. The recombinant plasmid system allows controlled variation of miRNA expression levels, which in turn modulates the abundance of target mRNA and protein, effectively adjusting the expression parameter from pathological overexpression to physiological levels.
2Reliability
If recombinant plasmids are administered to upregulate miRNA production, then expression of immune checkpoint molecules is downregulated, but this may affect normal immune function
Solution Approach 1:
The patent applies local quality by designing miRNA sequences with high specificity for particular immune checkpoint molecules. Each miRNA is engineered to recognize and bind only to its complementary target mRNA sequence, ensuring that the regulatory effect is localized to specific overexpressed molecules rather than globally affecting all immune functions. This specificity allows selective downregulation of pathological molecules while preserving normal immune regulation.
Solution Approach 2:
The patent implements a feedback mechanism where miRNA expression is controlled by promoters that respond to the expression levels of target immune checkpoint molecules. When checkpoint molecules are overexpressed, the promoter activity increases, leading to higher miRNA production that subsequently reduces checkpoint molecule expression, creating a negative feedback loop that maintains expression within physiological ranges and prevents both overexpression and underexpression.
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 compositions effectively decrease the bioavailability of immune checkpoint molecules, restoring homeostasis and potentially treating associated diseases by inducing endogenous production of miRNA that degrades or inactivates the target mRNA, thus reducing the expression of these molecules.
Implementation Method 1
The sequences of miRNA may be complimentary to a sequence of target messenger RNA (mRNA) that encodes for translation of a target biomolecule and the miRNA can cause the target mRNA to be degraded or inactivated
Implementation Method 2
a backbone sequence of nucleic acids that facilitates introduction of the one or more insert sequences into one or more of a subject's cells where it is expressed and/or replicated
Data Source
AI summary
Embodiments of the present disclosure relate to a composition that comprises a recombinant plasmid (RP) with a sequence of nucleic acids. The sequence comprise a start region, an end region and an insert positioned between the start region and the end region. The insert encodes for a sequence of micro interfering ribonucleic acid (miRNA) that may be complimentary to a sequence of target messenger RNA (mRNA) that encodes for translation of a target biomolecule. The miRNA can cause the target mRNA to be degraded or inactivated, thereby causing a decrease in bioavailability of the target biomolecule because it is degraded or inactivated by the miRNA, thereby decreasing the bioavailability of the target biomolecule. In some embodiments of the present disclosure, the target biomolecule is an immune checkpoint protein.