Modified Polyribonucleotides for ABCA3 Gene Expression
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Solution Overview
Problem
Current methods for delivering exogenous RNAs into cells are inefficient due to immune recognition and stability issues, leading to inadequate expression and translation, particularly for genes associated with conditions like respiratory distress syndrome.
Innovation Solution
A modified polyribonucleotide composition optimized for translation within cells, incorporating specific codon sequences and nucleotide modifications, formulated in nanoparticles or other delivery systems to enhance stability and reduce immune response, targeting genes such as ABCA3 for improved expression and treatment of associated diseases.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If exogenous RNA is delivered into cells, then therapeutic protein expression can be achieved, but the immune system recognizes the RNA as foreign and triggers inactivation responses
Solution Approach 1:
The patent uses modified nucleotides (such as pseudouridine, 5-methylcytidine, and other chemically modified bases) to replace standard RNA nucleotides. These modifications allow the RNA to evade immune system detection while maintaining its ability to be translated into therapeutic proteins, effectively converting the harmful immune recognition into a beneficial evasion mechanism that preserves therapeutic function.
Solution Approach 2:
The patent systematically changes the chemical parameters of RNA nucleotides by incorporating modified bases and sugar modifications. These parameter changes alter the physical and chemical properties of the RNA molecule, including its stability, immunogenicity, and translation efficiency, thereby resolving the contradiction between immune recognition and therapeutic expression.
2Reliability
If exogenous RNA is delivered into cells, then protein translation can occur, but the RNA lacks sufficient stability for adequate expression within the host cell
Solution Approach 1:
The patent employs multiple nucleotide modifications including 2'-O-methyl modifications, pseudouridine, and other chemically altered nucleotides that increase the thermal and enzymatic stability of the RNA molecule. These parameter changes enhance the RNA's resistance to degradation while preserving its ability to function as a template for protein synthesis.
Solution Approach 2:
The patent creates composite RNA structures by combining multiple types of modified nucleotides within a single RNA molecule. This composite approach integrates different modification types (base modifications, sugar modifications, backbone modifications) to achieve both enhanced stability and maintained translation capability simultaneously.
3Productivity
If standard codon sequences are used in exogenous RNA, then translation can occur, but translation efficiency is insufficient for adequate therapeutic expression
Solution Approach 1:
The patent optimizes codon usage by selecting and arranging codons based on the host cell's tRNA abundance and translation machinery characteristics. This codon optimization changes the sequence parameters of the RNA to match the host cell's translational preferences, thereby maximizing translation efficiency and therapeutic protein expression levels.
Solution Approach 2:
The patent designs the RNA sequence to be self-optimizing for the host cell system by incorporating codons that naturally align with the host's translational capabilities. The RNA sequence itself serves to enhance its own translation efficiency through strategic codon selection, reducing the need for external optimization factors.
Data Source
AI summary
Polynucleotides encoding peptides, proteins, enzymes, and functional fragments thereof are disclosed. The polynucleotides of the disclosure can be effectively delivered to an organ, such as the lung, and expressed within cells of the organ. The polyribonucleotides of the disclosure can be used to treat a disease or condition associated with a gene of the ATP-binding cassette (ABC) family, such as ABCA3.