REST-Targeting Oligonucleotide Composition for Selective Gene Suppression
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
There is a need for a therapeutic agent that can target and regulate the abnormal expression of the REST, which is associated with various neurological diseases such as neuroblastoma, glioblastoma, dementia, and fibrositis, among others.
Innovation Solution
An oligonucleotide with a nucleotide sequence complementary to a specific region of the REST gene, capable of regulating its expression, is developed, along with a REST expression suppressing agent and pharmaceutical composition.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If REST expression is suppressed, then neurological diseases such as neuroblastoma, glioblastoma, and dementia can be treated, but the mechanism to achieve selective suppression without affecting normal neural function is not well established
Solution Approach 1:
The patent applies local quality by designing oligonucleotides with specific chemical modifications (such as phosphorothioate backbones, 2'-O-methyl or 2'-O-methoxyethyl modifications) at specific positions to create region-specific binding characteristics. This allows the oligonucleotide to selectively bind to REST mRNA in certain cellular compartments or under specific conditions, thereby suppressing REST expression in disease contexts while preserving normal neural function in healthy tissues.
Solution Approach 2:
The patent utilizes parameter changes by systematically varying multiple parameters of the oligonucleotide including length (15-30 bases), sequence composition, chemical modifications (phosphorothioate, phosphodiester, methylphosphonate), and structural conformation (gapmer, pentamer, hexamer). These parameter variations enable optimization of binding affinity, specificity, and cellular uptake to achieve selective REST suppression without off-target effects.
2Measurement precision
If oligonucleotide sequence is extended to increase binding specificity, then target recognition improves, but synthesis complexity and cost increase
Solution Approach 1:
The patent applies partial action by using oligonucleotides with lengths ranging from 15 to 30 bases, which is sufficient to achieve specific binding to REST mRNA without requiring the full length of the entire gene. This partial sequencing approach provides adequate specificity while keeping synthesis complexity manageable. The patent further optimizes by focusing on critical binding regions rather than sequencing the entire REST mRNA molecule.
Solution Approach 2:
The patent employs composite materials by combining multiple chemical modifications within a single oligonucleotide structure, such as integrating phosphorothioate linkages with 2'-O-methyl or 2'-O-methoxyethyl modifications at specific positions. This composite approach enhances binding affinity and specificity simultaneously, achieving high target recognition without proportionally increasing synthesis complexity, as the modifications are applied to predefined templates.
3Reliability
If chemical modifications are added to improve stability and binding, then therapeutic activity increases, but manufacturing complexity increases
Solution Approach 1:
The patent applies segmentation by dividing the oligonucleotide into distinct functional regions with specific modifications: a 5' end region with phosphorothioate linkages for stability, a central region with 2'-O-methyl or 2'-O-methoxyethyl modifications for binding affinity, and a 3' end region with complementary modifications. This segmented modification strategy allows each region to be optimized independently for its specific function while maintaining overall manufacturability through modular synthesis approaches.
Solution Approach 2:
The patent utilizes universality by designing a platform of oligonucleotide modifications that can be applied across multiple therapeutic contexts. The same basic modification strategies (phosphorothioate, 2'-O-methyl, 2'-O-methoxyethyl) can be used for different oligonucleotide lengths and sequences targeting REST, allowing the manufacturing process to be standardized and scaled. This multi-functional modification toolkit improves binding affinity and stability while avoiding the need to develop entirely new synthesis methods for each application.
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 oligonucleotide effectively suppresses REST expression, providing therapeutic potential for neurological diseases, including malignant tumors, dementia, and central nervous system diseases.
Implementation Method 1
an oligonucleotide or pharmacologically acceptable salt thereof capable of regulating expression of REST, comprising a nucleotide sequence complementary to a continuous sequence with at least 15 bases in a target region included in a base sequence of SEQ ID NO: 1
Data Source
Figure 1
Figure 2(a)~2(b)
Figure 3
AI summary
An oligonucleotide of the present invention includes a nucleotide sequence complementary to a continuous sequence with at least 15 bases in a target region included in a base sequence of SEQ ID NO: 1, and can regulate the expression of REST. The oligonucleotide and pharmacologically acceptable salt thereof of the present invention is applicable as, for example, a material to be included in therapeutic agents for various nervous system diseases (e.g., malignant tumors, dementia, and central nervous system diseases), diabetes, and the like, which are caused by the expression of the REST.