Conjugated Half-Duplex Antisense Compounds for CNS Delivery
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Solution Overview
Problem
Existing antisense compounds face challenges in efficiently delivering oligomeric compounds to extra-hepatic tissues such as CNS and muscle tissues, and overcoming the blood-brain barrier for systemic modulation of nucleic acids.
Innovation Solution
Development of half duplex oligomeric compounds comprising a first modified oligonucleotide and a second modified oligonucleotide, with specific nucleobase sequences and lengths, potentially enhanced by conjugate groups, to improve uptake and activity in extra-hepatic tissues and penetrate the blood-brain barrier.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If traditional antisense compounds are administered, then good functional uptake into liver tissue is achieved, but delivery to extra-hepatic tissues such as CNS and muscle tissues is insufficient
Solution Approach 1:
The antisense compound is divided into two separate oligonucleotides that form a half-duplex structure. The first oligonucleotide (14-30 nucleotides) provides liver targeting, while the second oligonucleotide (6-12 nucleotides) provides extra-hepatic tissue targeting. This segmentation allows each component to be optimized for specific tissue uptake, resolving the contradiction between liver uptake and extra-hepatic delivery.
Solution Approach 2:
The half-duplex structure combines multiple functions into a single compound: the first oligonucleotide provides liver targeting and the second oligonucleotide provides extra-hepatic tissue targeting and blood-brain barrier penetration. This multi-functionality allows the compound to achieve both good liver uptake and effective delivery to CNS and muscle tissues simultaneously.
2Adaptability or versatility
If antisense compounds are designed to penetrate the blood-brain barrier, then CNS target modulation is enabled, but the compound structure becomes more complex
Solution Approach 1:
The blood-brain barrier penetration function is assigned to the second oligonucleotide (6-12 nucleotides), which is structurally simpler than the first oligonucleotide. By segmenting the compound into two functional parts, the overall structure remains manageable while achieving CNS penetration capability through the optimized second oligonucleotide.
Solution Approach 2:
Different regions of the half-duplex structure have different properties: the first oligonucleotide is optimized for liver uptake with specific nucleotide sequences and modifications, while the second oligonucleotide is optimized for blood-brain barrier penetration and extra-hepatic tissue delivery. This local optimization allows each region to perform its specific function effectively without requiring the entire compound to be complex.
3Productivity
If higher doses of antisense compounds are used to improve efficacy, then target modulation is enhanced, but toxicity increases
Solution Approach 1:
The compound is segmented into two oligonucleotides with different functional roles. The first oligonucleotide (14-30 nucleotides) provides the bulk of the target modulation efficacy through strong binding to the target mRNA, while the second oligonucleotide (6-12 nucleotides) provides tissue-specific delivery and reduces off-target effects. This segmentation allows for lower overall doses to achieve the same efficacy while reducing toxicity.
Solution Approach 2:
The first oligonucleotide is designed with high affinity for the target mRNA to maximize modulation efficacy at low concentrations, while the second oligonucleotide is designed with specific sequences that target extra-hepatic tissues and reduce non-specific binding. This local optimization of properties allows for reduced overall dosing while maintaining high efficacy and minimizing toxicity.
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
Enhanced delivery and activity of antisense compounds in CNS and muscle tissues, with improved safety profiles and increased ability to modulate target nucleic acids, including penetration of the blood-brain barrier.
Implementation Method 1
the first modified oligonucleotide is 14-30 linked nucleosides and has a nucleobase sequence complementary to the nucleobase sequence of the second oligomeric compound and to a nucleic acid target
Implementation Method 2
the systemically delivered oligomeric compound crosses the blood-brain barrier and modulates a nucleic acid target in the CNS
Implementation Method 3
RNase H-based degradation of the target RNA upon hybridization with a DNA-like antisense compound
Implementation Method 4
RNAi refers to antisense-mediated gene silencing through a mechanism that utilizes the RNA-induced silencing complex (RISC)
Implementation Method 5
The binding of an antisense compound to a microRNA prevents that microRNA from binding to its messenger RNA targets, and thus interferes with the function of the microRNA
Data Source
AI summary
The present disclosure provides half duplex compounds comprising a first oligomeric compound and a second, shorter, oligomeric compound, wherein the first oligomeric compound is complementary to a target nucleic acid and the second oligomeric compound is complementary to the first oligomeric compound. In certain embodiments, the compounds disclosed herein are useful for modulating the expression of extra-hepatic target nucleic acids.