Antisense Oligonucleotide CAG Repeat Editing via ADAR Recruitment
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current treatments for polyglutamine (PolyQ) diseases, such as Huntington's and Spinocerebellar ataxia, lack effective methods to address the toxic aggregation of proteins caused by elongated CAG repeats, leading to protein misfolding and aggregation, with no cure available.
Innovation Solution
Development of antisense oligonucleotides that specifically bind to the CAG repeat region of mRNA encoding PolyQ disease-related proteins, recruiting Adenosine Deaminase Acting on RNA (ADAR) to perform A-to-I exchanges, converting CAG trinucleotides to CGG trinucleotides, thereby reducing the toxic aggregation of PolyQ proteins by introducing arginine residues into the protein tract.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If antisense oligonucleotides bind to CAG repeat region to form double-stranded RNA, then ADAR enzyme is recruited to perform A-to-I exchange, but the complexity of the treatment mechanism increases
Solution Approach 1:
The patent uses ADAR enzyme as an intermediary to mediate the conversion of CAG repeats to CGG repeats. The antisense oligonucleotide recruits endogenous ADAR enzyme to the target site, which then catalyzes the A-to-I exchange. This intermediary approach allows the system to achieve precise editing without requiring direct chemical conversion, thereby improving reliability while managing complexity through biological mediation.
Solution Approach 2:
The patent leverages the cell's own ADAR enzyme to perform the therapeutic function. By recruiting endogenous ADAR to the antisense oligonucleotide-CAG repeat complex, the system utilizes the cell's existing machinery to carry out the editing, reducing the need for external delivery of editing enzymes and simplifying the overall treatment mechanism.
2Object-affected harmful factors
If CAG trinucleotides are converted to CGG trinucleotides, then toxic aggregation of PolyQ proteins is reduced, but the manufacturing precision of mRNA editing is challenging
Solution Approach 1:
The antisense oligonucleotide is designed to bind specifically to the CAG repeat region with high local complementarity, ensuring that ADAR recruitment and editing occur only at the target site. This localized approach allows precise conversion of CAG to CGG at the desired location without affecting other regions of the mRNA, thereby achieving the necessary manufacturing precision for therapeutic efficacy.
Solution Approach 2:
The patent employs multiple mismatches between the antisense oligonucleotide and the target mRNA to create a partially complementary duplex structure. This partial complementarity is sufficient to recruit ADAR and enable editing while preventing complete base pairing that would lead to off-target effects. The excessive mismatches ensure specificity by preventing binding to non-target sequences, thus achieving precise editing despite the imperfect match.
3Stability of the object's composition
If arginine residues are introduced into polyglutamine tract, then protein aggregation is interrupted, but the duration of action of the antisense oligonucleotide must be maintained
Solution Approach 1:
The antisense oligonucleotide is designed to bind to the CAG repeat region before translation occurs, preventing the formation of the pathogenic polyglutamine tract from the outset. By performing the editing action preliminarily at the mRNA level, the system ensures that the translated protein will have interrupted polyQ tracts, providing stable prevention of aggregation. The duration of action is extended by targeting the mRNA template itself, which persists throughout the cell cycle.
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 effectively reduces the expression of PolyQ disease-associated proteins by converting CAG trinucleotides to CGG trinucleotides on the mRNA level, leading to interruptions in the polyglutamine tracts and potentially mitigating the toxic aggregation and symptoms of PolyQ diseases.
Implementation Method 1
specifically binding to a CAG repeat region of an mRNA encoding a polyQ disease-related protein such that a double-stranded RNA is formed
Implementation Method 2
Adenosine Deaminase Acting on RNA (ADAR) inserting an A to I exchange into at least one CAG trinucleotide
Data Source
AI summary
The present invention relates to an antisense oligonucleotide for use in treating and/or preventing a polyglutamine (polyQ) disease, wherein said antisense oligonucleotide is capable of specifically binding to a CAG repeat region of an mRNA encoding a polyQ disease-related protein such that a double stranded RNA is formed which is capable of attracting an Adenosine Deaminase Acting on RNA (ADAR) inserting an A to I exchange into at least one CAG trinucleotide of the CAG repeat region of said mRNA. The present invention further relates to a pharmaceutical composition comprising said antisense molecule.