Lipid-Conjugated Antisense Duplex for BBB Crossing
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Solution Overview
Problem
The blood-brain barrier (BBB) prevents efficient delivery of nucleic acid agents, such as antisense oligonucleotides (ASOs), to the central nervous system, hindering their antisense effects on target transcriptional products.
Innovation Solution
A nucleic acid complex is formed by annealing an ASO with a complementary strand bound to a cholesterol analog, enabling efficient delivery across the BBB and producing a high antisense effect in the central nervous system.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If a nucleic acid agent is administered systemically, then the agent can reach the bloodstream, but the blood-brain barrier prevents efficient delivery to the central nervous system
Solution Approach 1:
The patent employs a cholesterol analog (such as 24,25-dihydrocholesterol or 25-hydroxycholesterol) as an intermediary molecule conjugated to the antisense oligonucleotide. This cholesterol analog acts as a mediator that enables the nucleic acid agent to interact with and cross the blood-brain barrier, which normally blocks such molecules. The cholesterol moiety facilitates transport through the BBB while the antisense oligonucleotide maintains its gene-silencing function, thus resolving the contradiction between systemic administration and CNS delivery efficiency.
Solution Approach 2:
The invention creates a composite molecule by chemically conjugating a cholesterol analog to an antisense oligonucleotide. This composite structure combines the lipid-soluble properties of cholesterol (which can cross the BBB) with the nucleic acid component (which provides the antisense effect). The resulting hybrid molecule simultaneously achieves blood-brain barrier penetration and target gene silencing in the central nervous system, overcoming the barrier effect that would otherwise prevent efficient delivery.
2Object-affected harmful factors
If the BBB mechanism is strengthened to better protect the brain, then protection from toxic substances is improved, but drug delivery to the brain becomes more difficult
Solution Approach 1:
The cholesterol analog serves as a protective intermediary that is already accepted by the BBB mechanism. By conjugating the antisense oligonucleotide to this BBB-accepted molecule, the invention bypasses the barrier's protective function without compromising it. The cholesterol analog acts as a Trojan horse that the BBB allows through, while carrying the therapeutic nucleic acid payload, thus maintaining brain protection while enabling drug delivery.
Solution Approach 2:
The invention converts the BBB's barrier function, which normally blocks drug delivery, into a benefit by utilizing the cholesterol analog's natural ability to cross the BBB. The cholesterol moiety's lipophilic properties, which would normally be seen as a barrier to nucleic acid delivery, are transformed into an advantage that facilitates CNS penetration. This approach maintains the BBB's protective role while creating a pathway for therapeutic delivery.
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 nucleic acid complex effectively crosses the BBB and regulates target transcriptional products in the central nervous system, providing a potent antisense effect.
Implementation Method 1
a first nucleic acid strand and a second nucleic acid strand, in which the first nucleic acid strand is annealed to the second nucleic acid strand
Data Source
Figure 1(a)~1(d)
Figure 2
Figure 3
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.