Optimized ACE2 mRNA Sequences for Scalable Viral Neutralization
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Solution Overview
Problem
Existing treatments for viral infections using soluble ACE2 proteins are laborious, costly, and do not scale easily, while mRNA therapies face challenges in optimizing delivery and expression for effective viral neutralization.
Innovation Solution
Optimized nucleotide sequences encoding the extracellular domain of human ACE2 protein and lipid nanoparticles (LNPs) are developed to enhance mRNA delivery and expression, ensuring high affinity binding and prolonged presence of ACE2 proteins to neutralize viruses like SARS-CoV-2.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If soluble recombinant ACE2 proteins are administered to block viral binding, then viral neutralization is achieved, but the production process becomes laborious and costly with limited scalability
Solution Approach 1:
The patent uses mRNA as a template to instruct cells to produce ACE2 proteins endogenously, rather than administering pre-made recombinant proteins. This copying approach allows the body's own cellular machinery to generate the therapeutic protein, enabling scalable production through mRNA synthesis while maintaining the desired biological activity and neutralization efficacy
Solution Approach 2:
The mRNA therapy enables cells to self-produce the ACE2 protein through their own translational machinery. The administered mRNA encodes the extracellular domain of ACE2, which cells then translate and secrete autonomously, eliminating the need for complex external protein production and purification processes while achieving sustained therapeutic levels
2Productivity
If mRNA therapies are used to express soluble ACE2 proteins, then production scalability is improved, but delivery efficiency and protein expression levels remain challenging to optimize
Solution Approach 1:
The patent optimizes multiple parameters of the mRNA molecule including codon composition (using codons preferred by human cells), nucleotide sequence modifications, 5' cap structure, 3' poly(A) tail length, and untranslated regions to enhance translation efficiency, stability, and protein expression levels while maintaining scalability of production
Solution Approach 2:
The patent employs lipid nanoparticles as intermediary carriers to deliver the mRNA into target cells. These LNPs protect the mRNA from degradation, facilitate cellular uptake through endocytosis, and enable efficient cytoplasmic delivery, thereby bridging the gap between scalable mRNA production and effective intracellular expression
3Reliability
If high levels of soluble ACE2 protein are administered, then viral neutralization is enhanced, but the complexity of maintaining sustained expression increases
Solution Approach 1:
The mRNA therapy establishes continuous protein production by delivering stable mRNA molecules that persist in cells and are continuously translated. The optimized mRNA structure ensures sustained expression over time, maintaining therapeutic ACE2 levels without requiring repeated administrations or complex delivery systems, thereby achieving both high efficacy and operational simplicity
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 optimized mRNA and LNP system achieves enhanced expression and duration of ACE2 proteins, effectively preventing and neutralizing viral infections, particularly in vulnerable populations.
Implementation Method 1
lipid nanoparticles (LNPs) encapsulating such mRNAs
Implementation Method 2
mRNAs comprising optimized nucleotide sequences encoding such polypeptides
Implementation Method 3
block the binding of the viral surface spike (S) glycoprotein to the genuine ACE2 receptors
Data Source
AI summary
The present invention provides compositions that are useful in treating or preventing an infection in a subject caused by a virus which uses human angiotensin-converting enzyme 2 (ACE2) protein for cellular entry. Such compositions act by neutralizing the virus, preventing it from binding to the human ACE2 protein and gaining cellular entry. In particular, the invention provides an mRNA comprising an optimized nucleotide sequence encoding a polypeptide comprising the extracellular domain of ACE2 protein or a portion thereof, which binds to a viral surface protein. The mRNA may be encapsulated in lipid nanoparticles (LNPs) for delivery to a subject in vivo. Typically, compositions comprising the LNPs are delivered to a subject either intravenously or as an aerosol, for example via nebulization.