Multimeric Oligonucleotides With Cleavable Linkers for Plasma Stability
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Solution Overview
Problem
Natural phosphodiester-backbone oligonucleotides are susceptible to nuclease degradation in plasma, limiting their effectiveness as therapeutics, and existing modifications do not fully address the need for favorable pharmacokinetic and pharmacodynamic properties.
Innovation Solution
Development of multimeric oligonucleotide compounds with cleavable linkers that are more susceptible to enzymatic cleavage, allowing for controlled release of monomeric units in target tissues and enhanced pharmacokinetic and pharmacodynamic properties.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of operation
If natural phosphodiester-backbone oligonucleotides are used, then they are taken up by cells efficiently, but they are highly susceptible to nuclease degradation in plasma
Solution Approach 1:
The patent combines multiple oligonucleotide units with different properties into a multimeric structure. Specifically, it links oligonucleotides with modified backbones (resistant to plasma nucleases) to oligonucleotides with natural phosphodiester backbones (efficiently taken up by cells) through cleavable linkers, creating a composite therapeutic agent that leverages the advantages of both components
Solution Approach 2:
The cleavable linker serves as an intermediary element between the stable oligonucleotide units and the cell-uptake-efficient oligonucleotide units. This linker is designed to be stable in plasma but cleavable by cellular nucleases, mediating the transition from the stable multimeric form in circulation to the active monomeric form inside cells
2Reliability
If modified nucleotides and backbone modifications are used to improve stability, then stability in plasma is improved, but favorable pharmacokinetic and pharmacodynamic properties are not fully achieved
Solution Approach 1:
The patent segments the oligonucleotide therapeutic into multiple distinct units linked together, where each unit can have different modifications optimized for specific functions (plasma stability, cell uptake, target binding). This segmentation allows independent optimization of each component's properties
Solution Approach 2:
Different regions of the multimeric oligonucleotide are assigned different local properties: some units have modified backbones for plasma stability, others have natural backbones for cell uptake efficiency, and linkers have cleavable bonds for controlled activation. Each local region is optimized for its specific functional requirement
3Duration of action of moving object
If multimeric oligonucleotides with cleavable linkers are used, then higher levels are achieved in target tissues with longer-lasting knockdown, but device complexity increases
Solution Approach 1:
The patent merges multiple oligonucleotide units into a single multimeric molecule that functions as one therapeutic agent. This merging provides several advantages: increased plasma stability through the modified backbone units, enhanced cell uptake through the natural backbone units, and prolonged duration of action through the sustained release of active monomeric units from the multimeric structure
Solution Approach 2:
The multimeric oligonucleotide is pre-assembled with cleavable linkers in a stable configuration before administration. This preliminary assembly allows the therapeutic to circulate in a protected, stable form and only undergoes cleavage and activation after reaching the target tissue, where cellular nucleases trigger the release of active monomeric units
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
Multimeric oligonucleotides achieve higher levels in target tissues and longer-lasting target mRNA knockdown, with reduced clearance and lower effective concentrations compared to monomeric forms, effectively addressing stability and delivery issues.
Implementation Method 1
a linker that links at least two Xs and that is more susceptible to cleavage in a mammalian extract than each X
Implementation Method 2
the targeting oligonucleotides hybridize to a target nucleic acid encoded by a genomic target sequence and inhibit the function and/or effect degradation of the target nucleic acid
Data Source
AI summary
The disclosure provides multimeric oligonucleotide compounds, comprising two or more target-specific oligonucleotides (e.g., antisense oligonucleotides (ASOs)), each being resistant to cleavage, and linked together by a cleavable linker. In particular, two or more linked target-specific oligonucleotides, each to a different target, allows concomitant inhibition of multiple genes' expression levels, while exhibiting favorable pharmacokinetic and pharmacodynamic properties. Methods of making and uses of the described compounds are also provided.