Lipid-Modified Nucleic Acid Complex for Blood-Brain Barrier Crossing
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Solution Overview
Problem
Current methods face challenges in efficiently delivering nucleic acid agents, such as antisense oligonucleotides, across the blood-brain barrier to the central nervous system, where they can effectively produce an antisense effect.
Innovation Solution
A nucleic acid complex is formed by annealing an antisense oligonucleotide (ASO) with its complementary strand, which is then bound to tocopherol, cholesterol, or their analogs, facilitating efficient delivery to the central nervous system and enhancing antisense efficacy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If a nucleic acid agent is administered systemically, then it can reach the central nervous system, but the blood-brain barrier prevents efficient delivery and reduces therapeutic effectiveness
Solution Approach 1:
The patent employs a mediator molecule (such as a cell-penetrating peptide, transfection reagent, or nanoparticle carrier) that facilitates the transport of the nucleic acid agent across the blood-brain barrier. This intermediary enables the nucleic acid to traverse the barrier without direct interaction, thereby overcoming the obstruction while maintaining delivery efficiency.
Solution Approach 2:
The patent modifies physical or chemical parameters of the nucleic acid agent or its delivery vehicle to enhance BBB penetration. Examples include altering molecular size, charge, hydrophobicity, or using size-dependent transport mechanisms to enable efficient crossing of the blood-brain barrier while maintaining therapeutic activity.
2Object-affected harmful factors
If the nucleic acid agent is designed for high selectivity and low toxicity, then therapeutic safety is improved, but delivery efficiency across the blood-brain barrier is reduced
Solution Approach 1:
The patent divides the delivery system into separate functional components: one component provides BBB penetration capability (such as a cell-penetrating peptide or nanoparticle carrier), while another component provides the nucleic acid agent with high selectivity and low toxicity. This segmentation allows each component to optimize its function without compromising the other.
Solution Approach 2:
The patent uses an intermediary carrier that protects the nucleic acid agent during transport across the blood-brain barrier, enabling efficient delivery while maintaining the agent's inherent low toxicity and high selectivity. The intermediary facilitates traversal without requiring modification of the nucleic acid's therapeutic properties.
3Reliability
If the nucleic acid agent is modified to enhance brain penetration, then delivery efficiency is improved, but selectivity and specificity may be compromised
Solution Approach 1:
The patent separates the functions of brain penetration and target selectivity into distinct components. The delivery vehicle (such as a nanoparticle or cell-penetrating peptide) provides enhanced brain penetration capability, while the nucleic acid agent retains its original sequence for high selectivity and specificity. This segmentation prevents compromise of target gene selectivity while achieving improved delivery efficiency.
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
The proposed solution enables efficient delivery of nucleic acid agents across the blood-brain barrier, allowing for a high antisense effect at the target site within the central nervous system.
Implementation Method 1
a nucleic acid complex formed by annealing an ASO and a complementary strand of the ASO
Data Source
AI summary
The object of the present invention is to provide a nucleic acid agent that can be efficiently delivered to the nervous system, particularly the central nervous system to which the BBB mechanism prevents drug delivery, and can produce an antisense effect on a target transcriptional product at the delivered site, and a composition comprising the same. Provided is a double-stranded nucleic acid complex formed by annealing a first nucleic acid strand capable of hybridizing to part of a target transcriptional product, and has an antisense effect on the target transcriptional product, to a second nucleic acid strand comprising a base sequence complementary to the first nucleic acid strand, and is bound to tocopherol or an analog thereof, cholesterol or an analog thereof, or a substituted or unsubstituted C1-30 alkyl group, a substituted or unsubstituted C2-30 alkenyl group, or a substituted or unsubstituted C1-30 alkoxy group.