Nuclease-Resistant mRNA via Stabilizing Oligonucleotide Hybridization
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Solution Overview
Problem
Current gene therapies for protein or enzyme deficiencies face challenges such as immunological responses, inefficient cellular uptake, and high costs due to the use of recombinantly-prepared proteins, and the poor stability of exogenous polynucleotides like mRNA, which leads to reduced therapeutic efficacy.
Innovation Solution
Development of nuclease-resistant polynucleotides and compositions that encode functional proteins or enzymes, where a complementary stabilizing oligonucleotide hybridizes with the non-coding region of the polynucleotide to enhance stability and resistance to degradation, allowing for improved expression and production of therapeutic proteins or enzymes.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If exogenous polynucleotides (e.g., mRNA) are administered for therapeutic purposes, then treatment of protein or enzyme deficiencies is achieved, but stability of the polynucleotide is poor leading to reduced therapeutic efficacy
Solution Approach 1:
The patent applies parameter changes by chemically modifying the polynucleotide structure through phosphorothioate backbone modifications and 2'-O-methyl ribose modifications. These chemical parameter changes increase resistance to nuclease degradation while maintaining the ability to encode functional proteins, thereby improving therapeutic efficacy without sacrificing stability
Solution Approach 2:
The patent creates composite polynucleotide structures by combining modified nucleotides (2'-O-methyl ribose) with phosphorothioate linkages. This composite approach produces a hybrid polynucleotide that exhibits both enhanced stability against degradation and retained translational capability, resolving the contradiction between stability and therapeutic efficacy
2Duration of action of moving object
If nuclease degradation occurs in vivo, then circulatory half-life of the polynucleotide is shortened, but this leads to inefficient translation and reduced protein production
Solution Approach 1:
The patent modifies the chemical parameters of the polynucleotide backbone by introducing phosphorothioate linkages and 2'-O-methyl ribose modifications. These parameter changes extend circulatory half-life by protecting against nuclease degradation while preserving the polynucleotide's ability to be translated into functional protein, thereby simultaneously improving duration of action and productivity
3Ease of operation
If viral vectors are used to deliver exogenous polynucleotides, then delivery to host cells is achieved, but serious immunological and inflammatory responses are elicited
Solution Approach 1:
The patent extracts the problematic viral delivery component and replaces it with chemically modified polynucleotides that can be delivered without viral vectors. By removing the viral vector element while retaining the therapeutic polynucleotide function through chemical modifications, the patent achieves delivery efficiency without triggering immunological responses
Solution Approach 2:
The patent introduces chemically modified polynucleotides as intermediaries that facilitate delivery without requiring viral vectors. The phosphorothioate and 2'-O-methyl modifications act as protective intermediaries that enable non-viral delivery while maintaining therapeutic function and reducing immunogenicity
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 nuclease-resistant polynucleotides demonstrate increased stability and translational efficiency, leading to enhanced production of therapeutic proteins or enzymes, potentially providing viable treatments or cures for protein or enzyme-related diseases with reduced immunogenicity and lower costs.
Implementation Method 1
a complementary stabilizing oligonucleotide hybridizes with the non-coding region of the polynucleotide to enhance stability and resistance to degradation
Data Source
AI summary
The invention provides, among other things, methods of stabilizing mRNA and nuclease resistant mRNA prepared in accordance with such methods. hi certain embodiments, the nuclease resistant mRNA encodes a functional protein, such as enzyme, and is characterized by its resistance to nuclease digestion, increased half-life and/or its ability to produce increased amounts of the functional protein (e.g., enzyme) encoded thereby.