Multimeric Oligonucleotides Using Covalent Linkers to Reduce Kidney Clearance
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Solution Overview
Problem
Existing oligonucleotide therapeutics face challenges in delivery to target cells due to poor targeting, toxicity, and inefficient delivery methods, necessitating high dosages and increased costs.
Innovation Solution
Development of multimeric oligonucleotides with a molecular weight of at least 45 kD, joined by covalent linkers, to reduce kidney clearance and enhance in vivo circulation half-life, combined with targeting ligands for improved delivery and activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Duration of action of stationary object
If oligonucleotide molecular weight is increased to at least 45 kD through multimeric construction, then kidney clearance is reduced and circulation half-life is extended, but delivery efficiency to target cells deteriorates
Solution Approach 1:
The oligonucleotide is divided into multiple monomeric subunits (e.g., 2-17 subunits) that are covalently linked to form a multimeric structure. This segmentation increases the overall molecular weight to at least 45 kD, reducing kidney clearance and extending circulation half-life while maintaining functional activity through the modular design of subunits
Solution Approach 2:
The invention creates a composite oligonucleotide structure by covalently linking multiple monomeric subunits with specific sequences and structures. This composite multimeric design combines the benefits of increased molecular weight for reduced clearance with the functional capabilities of individual oligonucleotide subunits for target cell delivery
2Object-affected harmful factors
If GalNAc ligand is used for targeting hepatocytes, then toxicological profile is improved, but delivery efficiency deteriorates necessitating increased dosages
Solution Approach 1:
The invention merges the GalNAc targeting ligand with multimeric oligonucleotide subunits to create a multi-conjugate structure. This combination leverages the low toxicity of GalNAc while the multimeric design increases payload capacity, allowing improved delivery efficiency without requiring increased dosages
3Ease of operation
If Lipid Nanoparticles are used for delivery, then internalization is facilitated, but targeting precision and toxicity profile deteriorate
Solution Approach 1:
The invention extracts the delivery facilitation function from lipid nanoparticles and implements it through the multimeric oligonucleotide structure itself. By taking out the need for nanoparticle carriers and using the multimeric design with increased molecular weight and potential ligand conjugation, the system achieves internalization without the toxicity and poor targeting associated with LNPs
Data Source
AI summary
The present invention relates to methods of administering to a subject multimeric oligonucleotides having monomeric subunits joined by linkers. The multimeric oligonucleotides have a molecular weight of at least about 45 kD and other characteristics, such that their clearance due to glomerular filtration is reduced. The present invention also relates to such multimeric oligonucleotides and methods of synthesizing such multimeric oligonucleotides.