Antisense Oligonucleotide Duplexes for Extrahepatic Delivery
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Solution Overview
Problem
Current antisense oligonucleotide therapeutics face challenges in achieving efficient delivery to extrahepatic tissues and reducing toxicity, limiting their potency and efficacy due to difficulties in cellular uptake and distribution beyond the liver.
Innovation Solution
The development of compounds comprising a first nucleic acid strand interacting with a nucleic acid target and a second complementary strand that alters the secondary structure to mimic double-stranded DNA, enhancing cell surface receptor interaction and subsequent uptake, while the second strand is designed to be less stable and dissociate upon entry, allowing the first oligonucleotide to interact with the target RNA.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If single-stranded antisense oligonucleotides are used, then they can bind to target RNA, but they show poor cellular uptake and limited delivery to extrahepatic tissues
Solution Approach 1:
The patent employs a composite structure consisting of a first oligonucleotide strand (antisense sequence) hybridized with a second oligonucleotide strand (carrier sequence), forming a duplex structure. This composite material combines the target-binding capability of the antisense strand with the enhanced cellular uptake properties of the duplex structure, thereby improving delivery to extrahepatic tissues while maintaining RNA binding efficiency
Solution Approach 2:
The patent changes the structural parameter of the oligonucleotide from single-stranded to duplex form. This parameter change fundamentally alters the physical and chemical properties of the molecule, including its stability, recognition by cellular receptors, and uptake efficiency, thereby resolving the contradiction between binding capability and cellular delivery
2Stability of the object's composition
If phosphorothioate linkages are used in antisense oligonucleotides, then stability is improved, but acute toxicity occurs
Solution Approach 1:
The patent segments the oligonucleotide structure into two functional strands: the first strand (antisense) that binds to target RNA and the second strand (carrier) that provides stability and facilitates uptake. This segmentation allows the carrier strand to bear the stability-function while the antisense strand maintains its binding function, reducing the toxic effects associated with phosphorothioate linkages in the overall molecule
Solution Approach 2:
The second oligonucleotide strand acts as an intermediary or carrier that mediates the delivery of the first antisense strand into cells. This intermediary structure provides the necessary stability and cellular uptake properties while allowing the antisense strand to perform its specific binding function with minimal toxicity
3Reliability
If chemical modifications are made to improve cellular delivery, then delivery is enhanced, but complexity of the compound increases
Solution Approach 1:
The second oligonucleotide strand serves multiple functions simultaneously: it acts as a carrier for cellular uptake, provides structural stability to the duplex, and facilitates delivery to target tissues. This multi-functionality reduces the need for multiple separate chemical modifications, thereby enhancing delivery while limiting complexity increase
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
This approach significantly improves the activity of antisense compounds in extrahepatic tissues, reducing toxicity and enhancing delivery and efficacy by altering the secondary structure for better cellular interaction and stability, leading to improved patient compliance and safety.
Implementation Method 1
a first oligonucleotide strand (i) having a nucleobase sequence that is complementary to a nucleic acid target
Implementation Method 2
a second oligonucleotide strand (ii) having a nucleobase sequence that is complementary to the nucleobase sequence of the first oligonucleotide strand
Data Source
AI summary
The present invention relates to a compound comprising a first oligomeric compound and a second oligomeric compound, wherein the first oligomeric compound comprises a first oligonucleotide and said second oligomeric compound comprises a second oligonucleotide, wherein said first oligonucleotide has a nucleobase sequence that is complementary to a nucleic acid target, and wherein preferably said first oligonucleotide is an antisense oligonucleotide; and wherein said second oligonucleotide has a nucleobase sequence that is complementary to the nucleobase sequence of the first oligonucleotide; and wherein the affinity of said first oligonucleotide to said second oligonucleotide is lower than the affinity of said first oligonucleotide to the fully complementary unmodified RNA oligonucleotide of said first oligonucleotide; or wherein the biostability of said second oligonucleotide is lower than the biostability of said first oligonucleotide.