Multimeric Oligonucleotides with Cleavable Linkers
Find Innovative SolutionsGenerate Solutions
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 modulating pharmacokinetic and pharmacodynamic properties, enabling simultaneous knockdown of multiple targets with improved stability and delivery.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of operation
If natural phosphodiester-backbone oligonucleotides are used, then cell uptake efficiency is improved, but nuclease degradation in plasma increases
Solution Approach 1:
The oligonucleotide is divided into multiple monomeric units connected by cleavable linkers to form multimeric structures. This segmentation allows the molecule to achieve both efficient cell uptake (through the oligonucleotide backbone) and nuclease resistance (through the protective multimeric structure that releases stable monomers in target cells).
Solution Approach 2:
The patent modifies the chemical structure by introducing cleavable linkers with specific properties (e.g., disulfide bonds, ester linkages) that change the degradation parameters. These linkers are designed to be stable in plasma but cleavable in target cells, transforming the pharmacokinetic profile while maintaining cell uptake efficiency.
2Reliability
If oligonucleotide modifications (LNAs, phosphorothioates, methylphosphonates) are applied, then nuclease degradation resistance is improved, but pharmacokinetic and pharmacodynamic properties are not fully optimized
Solution Approach 1:
The patent introduces dynamic elements through cleavable linkers that can change their structure based on environmental conditions (plasma stability vs. cellular cleavage). This dynamic behavior allows the molecule to adapt its pharmacokinetic properties during circulation while maintaining stable monomer release in target tissues for optimized pharmacodynamic effects.
Solution Approach 2:
The multimeric structure with cleavable linkers serves multiple functions simultaneously: it provides nuclease resistance during circulation, enables controlled release in target cells, and allows simultaneous targeting of multiple genes. This multi-functionality optimizes both pharmacokinetic and pharmacodynamic properties that single modifications cannot achieve.
3Productivity
If multimeric oligonucleotide compounds with cleavable linkers are used, then monomeric unit release in target tissue is improved, but linker stability in plasma must be controlled
Solution Approach 1:
The patent applies local quality by making the linker properties tissue-specific. The cleavable linkers (e.g., disulfide bonds, ester linkages) are designed to be stable in the plasma environment but susceptible to cleavage in target cell cytosol. This local differentiation of stability ensures controlled monomer release only where needed while maintaining circulation stability.
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, providing effective and sustained target mRNA knockdown with reduced clearance, enhancing therapeutic efficacy and duration of action.
Implementation Method 1
multimeric oligonucleotide compounds with cleavable linkers that are more susceptible to enzymatic cleavage, allowing for controlled release of monomeric units in target tissues
Implementation Method 2
each targeting oligonucleotide has a region complementary to a target region of a genomic target sequence. In some embodiments, the targeting oligonucleotides hybridize to a target nucleic acid encoded by a genomic target sequence
Implementation Method 3
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.