Cholesterol-Conjugated Antisense Oligonucleotide for Blood-Brain Barrier Delivery
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Solution Overview
Problem
Current methods face challenges in efficiently delivering nucleic acid agents, such as antisense oligonucleotides, to the central nervous system due to the blood-brain barrier, limiting their therapeutic potential for neurological disorders.
Innovation Solution
A nucleic acid complex is developed, where an antisense oligonucleotide is annealed with a tocopherol- or cholesterol-conjugated complementary strand, enabling efficient delivery to the central nervous system and retina, and exhibiting a high antisense effect.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If a nucleic acid agent is administered to treat neurological disorders, then the therapeutic effect is desired, but the blood-brain barrier prevents efficient delivery to the central nervous system
Solution Approach 1:
The patent uses tocopherol or cholesterol conjugated to the antisense oligonucleotide as an intermediary that facilitates transport across the blood-brain barrier. These lipid conjugates act as mediators that enable the nucleic acid agent to cross the barrier while maintaining its antisense activity, thus resolving the contradiction between therapeutic effect and delivery efficiency.
Solution Approach 2:
The patent modifies the chemical parameters of the antisense oligonucleotide by conjugating it with tocopherol or cholesterol groups. This parameter change alters the physicochemical properties of the molecule, enabling it to cross the blood-brain barrier while retaining its biological activity, thereby improving both delivery efficiency and therapeutic effect.
2Object-affected harmful factors
If the blood-brain barrier mechanism is maintained to protect the brain from harmful substances, then brain protection is improved, but drug delivery to the brain is hindered
Solution Approach 1:
The tocopherol or cholesterol conjugates serve as intermediaries that are recognized by the blood-brain barrier transport mechanisms. These mediators allow the antisense oligonucleotide to pass through the barrier without compromising the barrier's protective function, as the conjugates themselves are natural components that the barrier is designed to transport.
Solution Approach 2:
The patent converts the restrictive nature of the blood-brain barrier into a benefit by designing the conjugate structure to mimic natural substrates that the barrier transports. The tocopherol and cholesterol groups are naturally present in brain tissue, so the barrier's selective transport mechanism actually facilitates rather than hinders the delivery of the conjugated antisense oligonucleotide.
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 reduces the expression of target transcription products in the central nervous system and retina, providing a promising approach for treating neurological diseases by overcoming the blood-brain barrier.
Implementation Method 1
the first nucleic acid strand comprises base sequence capable of hybridizing with at least part of the target transcription product
Implementation Method 2
the first nucleic acid strand is annealed to the second nucleic acid strand
Data Source
AI summary
The present invention provides a composition and a method for efficiently delivering a nucleic acid agent to the central nervous system and/or the retina and bringing about antisense effects. Provided is a composition for reducing the expression level of a target transcription product in the central nervous system and/or retina of a subject, the composition including a nucleic acid complex that includes a first nucleic acid strand and a second nucleic acid strand, wherein: the first nucleic acid strand comprises a base sequence capable of hybridizing with at least part of the target transcription product and has an antisense effect on the target transcription product; the second nucleic acid strand comprises a base sequence complementary to the first nucleic acid strand and is conjugated to tocopherol, cholesterol, or an analog thereof; and the first nucleic acid strand is annealed to the second nucleic acid strand.