Small Molecules Enhancing Oligonucleotide Intracellular Delivery
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Solution Overview
Problem
Oligonucleotide-based therapies face challenges in accessing their sites of action within cells, leading to inefficient delivery and potential toxicity due to reliance on complex delivery systems like cationic lipids or polymers, which can cause biodistribution problems.
Innovation Solution
Concurrent administration of an active agent that enhances the delivery and activity of oligonucleotides by influencing intracellular trafficking, allowing for increased cytosolic and nuclear accumulation and activity of oligonucleotides such as antisense, siRNA, and splice switching oligonucleotides.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If complex delivery systems such as cationic lipid or polymer nanoparticles are used to deliver oligonucleotides, then oligonucleotide delivery efficiency is improved, but toxicity and biodistribution problems are introduced
Solution Approach 1:
The patent uses clathrin-mediated endocytosis as a natural cellular intermediary mechanism to deliver oligonucleotides into cells. By harnessing this endogenous pathway rather than introducing external complex delivery systems, the invention achieves efficient oligonucleotide delivery while avoiding the toxicity and biodistribution issues associated with cationic lipids or polymer nanoparticles. The clathrin-mediated endocytosis pathway serves as a biocompatible mediator that facilitates oligonucleotide internalization without the harmful effects of synthetic delivery vehicles.
2Reliability
If large doses of oligonucleotides are administered to attain therapeutic effects, then pharmacological activity is improved, but drug-related toxicities increase
Solution Approach 1:
The patent changes the delivery parameter from passive diffusion/uptake to active clathrin-mediated endocytosis. This parameter change in the delivery mechanism dramatically improves oligonucleotide internalization efficiency, allowing therapeutic effects to be achieved at much lower doses. By optimizing the delivery pathway parameter rather than increasing the dose parameter, the invention maintains reliable pharmacological activity while minimizing drug-related toxicities.
3Ease of operation
If oligonucleotides are internalized via endocytosis and traffic through membrane-bound vesicular compartments, then cellular uptake is achieved, but most oligonucleotides remain sequestered in endomembrane vesicles and are pharmacologically inert
Solution Approach 1:
The patent applies preliminary action by using clathrin-mediated endocytosis to directly deliver oligonucleotides to appropriate intracellular destinations, bypassing the problematic sequestration in endomembrane vesicles. This preliminary routing action ensures that oligonucleotides are positioned correctly for pharmacological activity from the outset, rather than becoming trapped in inert compartments. The clathrin pathway pre-establishes the correct trafficking route to avoid vesicular sequestration.
Data Source
AI summary
Methods of administering an oligonucleotide of interest into a cell in vitro or in vivo are described. In the methods, a small organic compound active agent is concurrently administered to the cell in an amount effective to increase the delivery of the oligonucleotide into the cell, and/or increase the activity of said oligonucleotide in the cell. Compositions useful for carrying out the method are also described.