Morpholino dsRNA with Cationic Linkages for Nuclease Resistance
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Solution Overview
Problem
Current siRNA molecules face challenges in stability and specificity while targeting disease-causing genes, requiring improved pharmacologic properties such as stability in vivo, membrane permeability, and sequence specificity without compromising sequence selectivity.
Innovation Solution
Development of double-stranded RNA (dsRNA) molecules comprising morpholino subunits with modified intersubunit linkages and terminal groups, specifically cationic linkages and peptide transport moieties, to enhance stability and cellular uptake while maintaining sequence specificity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If standard phosphodiester linkages are used in siRNA molecules, then the molecules can be synthesized and delivered, but they exhibit poor stability in vivo due to nuclease degradation
Solution Approach 1:
The patent applies parameter changes by modifying the chemical structure of the backbone linkages from standard phosphodiester to phosphorodiamidate and morpholino intersubunit linkages. This chemical parameter change confers resistance to nuclease degradation while maintaining the functional integrity of the siRNA molecule, directly resolving the contradiction between deliverability and stability in vivo.
Solution Approach 2:
The patent employs composite materials by creating hybrid oligomer structures that combine morpholino subunits with modified backbone linkages. This composite approach integrates the nuclease resistance of morpholino structures with the base-pairing capabilities of traditional nucleic acids, achieving both stability and functionality simultaneously.
2Ease of operation
If oligonucleotides are modified to enhance cellular uptake, then membrane permeability improves, but sequence specificity may be compromised
Solution Approach 1:
The patent applies local quality by introducing peptide transport moieties at specific terminal positions of the oligomer rather than uniformly modifying the entire structure. This localized modification enhances cellular uptake at the ends of the molecule while preserving the sequence-specific base-pairing regions, thus maintaining specificity while improving uptake efficiency.
Solution Approach 2:
The patent segments the oligomer into distinct functional regions: morpholino subunits with modified linkages for stability, central base-pairing regions for sequence specificity, and terminal peptide moieties for cellular uptake. This segmentation allows each region to optimize its specific function without interfering with other regions, resolving the contradiction between uptake and specificity.
Data Source
AI summary
Morpholino oligomers containing modified intersubunit linkages and/or terminal groups are provided for use within dsRNA molecules. The oligomers are oligonucleotide analogs containing predetermined sequences of base-pairing moieties. Also provided are such oligomers conjugated to peptide transporter moieties, where the transporters are preferably composed of arginine subunits, or arginine dimers, alternating with neutral amino acid subunits.