Nucleic Acid-Polypeptide Conjugates for Exon Skipping Delivery
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Solution Overview
Problem
Current therapies for modulating RNA processing to treat diseases caused by incorrectly spliced mRNA transcripts, such as muscular dystrophy, are inadequate in effectively inducing exon skipping or inclusion to produce functional proteins.
Innovation Solution
Development of polynucleic acid molecule conjugates, comprising 2′ modified nucleotides, modified internucleotide linkages, or inverted abasic moieties, that are conjugated to cell-targeting binding moieties to induce insertion, deletion, or alteration in incorrectly spliced mRNA transcripts, promoting exon skipping or inclusion to generate fully processed mRNA transcripts encoding functional proteins.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional oligonucleotides are used to modulate RNA processing, then some RNA function modulation is achieved, but the effectiveness in inducing exon skipping or inclusion is inadequate
Solution Approach 1:
The patent modifies the chemical parameters of oligonucleotides by incorporating 2′ modified nucleotides (such as 2′-O-methyl, 2′-O-methoxyethyl, locked nucleic acid) and modified internucleotide linkages (such as phosphorothioate, phosphorodithioate). These parameter changes enhance the stability, affinity, and specificity of the oligonucleotides for target pre-mRNA, thereby significantly improving their effectiveness in inducing exon skipping or inclusion to produce functional proteins
Solution Approach 2:
The patent creates composite oligonucleotide structures by combining different modified nucleotides and linkages within single molecules. These composite structures integrate the benefits of various modifications - such as enhanced stability from phosphorothioate linkages combined with improved affinity from locked nucleic acid residues - to achieve superior therapeutic effectiveness in correcting splicing defects
2Reliability
If oligonucleotides are administered to treat diseases with incorrectly spliced mRNA, then some treatment effect is achieved, but the therapeutic efficacy is insufficient
Solution Approach 1:
The patent employs cell-penetrating peptides and targeting moieties as intermediaries to facilitate the delivery of modified oligonucleotides into target cells. These intermediary components enable the oligonucleotides to overcome cellular barriers and reach their intracellular targets effectively, thereby significantly enhancing therapeutic efficacy while simplifying the delivery process
3Ease of manufacture
If standard oligonucleotide structures are used, then manufacturing is relatively simple, but the ability to correct splicing defects is limited
Solution Approach 1:
The patent modifies specific parameters of oligonucleotide structures - such as incorporating locked nucleic acid residues at particular positions and using phosphorodithioate linkages at terminal regions - to enhance splicing correction accuracy. These targeted parameter changes maintain reasonable manufacturing complexity while significantly improving the precision of splicing defect correction
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 polynucleic acid molecule conjugates effectively induce exon skipping or inclusion, leading to the production of functional proteins and thereby treating diseases like muscular dystrophy, including Duchenne muscular dystrophy, by correcting mRNA splicing defects.
Implementation Method 1
hybridizing the polynucleic acid molecule to the incorrectly spliced mRNA transcript within the target cell
Data Source
AI summary
Disclosed herein are molecules and pharmaceutical compositions that induce an insertion, deletion, duplication, or alteration in an incorrectly spliced mRNA transcript to induce exon skipping or exon inclusion. Also described herein include methods for treating a disease or disorder that comprises a molecule or a pharmaceutical composition that induces an insertion, deletion, duplication, or alteration in an incorrectly spliced mRNA transcript to induce exon skipping or exon inclusion.