LNP mRNA Therapeutics with Binding Element for Expression Stability
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Solution Overview
Problem
Current mRNA therapeutics face limitations in achieving maximum potency and duration of expression, as existing approaches primarily focus on modifying mRNAs themselves without fully exploiting RNA biology to enhance peak and duration of expression.
Innovation Solution
The development of lipid nanoparticle (LNP) compositions that include a first polynucleotide encoding a therapeutic payload and a binding element, along with a second polynucleotide encoding an effector molecule that binds to the binding element, to modulate mRNA and protein levels, activities, and subcellular localization, thereby enhancing expression and stability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If mRNA therapeutics are modified with end-protection (modified caps and tails), then resistance to cellular degradation is improved, but peak and duration of expression are not maximized
Solution Approach 1:
The patent introduces a binding element as an intermediary component that mediates between the mRNA and cellular machinery. This binding element specifically interacts with RNA-binding proteins or other cellular factors to enhance mRNA stability and expression duration without directly modifying the mRNA structure itself, thereby resolving the contradiction between degradation resistance and expression duration
Solution Approach 2:
The invention creates a composite system consisting of mRNA combined with a binding element that has specific affinity for cellular targets. This composite approach allows the mRNA to benefit from both its inherent coding capability and the stabilizing properties of the binding element, achieving both degradation resistance and extended expression duration simultaneously
2Productivity
If mRNA sequence design is optimized for UTRs and ORFs, then canonical linear mRNA potency is improved, but maximum possible potency is not achieved
Solution Approach 1:
The patent segments the mRNA system into two functional components: the canonical linear mRNA for coding and the separate binding element for enhancement. This segmentation allows optimization of each component independently - the mRNA maintains its simple, well-understood structure while the binding element provides the additional potency-boosting function, avoiding the need to complicate the mRNA structure itself
3Quantity of substance
If higher doses of mRNA therapeutics are administered, then expression level is increased, but toxicity increases
Solution Approach 1:
The invention changes the quality parameter of the mRNA system by introducing a binding element with specific cellular interactions, rather than simply increasing the quantity of mRNA. This parameter change (from quantity to quality enhancement) allows achieving higher expression levels through improved stability and translation efficiency rather than through dose escalation, thereby avoiding the toxicity associated with higher doses
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
This approach significantly increases the level and duration of expression of therapeutic payloads, improving mRNA stability and protein translation, potentially reducing dosing requirements and toxicity, while maintaining sustained expression levels.
Implementation Method 1
a second polynucleotide comprising a sequence encoding: (1) an effector molecule, and/or (2) a polypeptide that binds to, e.g., recognizes the binding element
Data Source
AI summary
The disclosure features LNP compositions and systems comprising a therapeutic payload or prophylactic payload, a binding element, a tether molecule and/or an effector molecule and uses thereof. The LNP compositions or systems of the present disclosure comprise: (a) a first polynucleotide (e.g., mRNA) comprising: (1) a sequence encoding a therapeutic payload or prophylactic payload, and (2) a binding element; and (b) a second polynucleotide (e.g., mRNA) comprising a sequence encoding: (1) an effector molecule, and/or (2) a polypeptide that recognizes the binding element (a tether molecule). Such compositions or systems can: increase the level and/or activity of the therapeutic payload or prophylactic payload, e.g., increase the level, stability and/or activity of the mRNA encoding the therapeutic payload or prophylactic payload. Also disclosed herein are methods of treating a disorder, or for modulating an immune response in a subject using the disclosed LNP compositions or systems.