Bivalent Nucleic Acid Ligands for Expanded CAG Repeat Targeting
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Solution Overview
Problem
Current understanding of Huntington's disease and other polyQ diseases is incomplete, and existing treatments fail to effectively target the toxic-gain of RNA and protein functions associated with expanded CAG-repeats, leading to unaddressed molecular dysfunctions and clinical manifestations.
Innovation Solution
Development of bivalent nucleic acid ligands with a nucleic acid analog backbone and bivalent nucleobases that selectively bind to expanded repeat sequences in nucleic acids, facilitating hybridization and concatenation to form longer oligomers, thereby targeting and interfering with the pathogenic RNA and protein production pathways.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional nucleic acid ligands are used, then they can bind to nucleic acid sequences, but they fail to selectively target expanded repeat sequences and effectively interfere with pathogenic RNA and protein production pathways
Solution Approach 1:
The ligand is divided into multiple modular units, each containing a nucleic acid analog backbone residue and a bivalent nucleobase. These segmented units can independently bind to adjacent CAG repeat sequences on opposite strands, allowing the ligand to selectively target expanded repeats while maintaining the ability to interfere with pathogenic pathways through concatenation of multiple binding units along the repeat expansion.
Solution Approach 2:
The invention combines a nucleic acid analog backbone with bivalent nucleobases that can simultaneously interact with both strands of the RNA duplex formed by expanded CAG repeats. This merging of backbone and bivalent base functionalities creates a unified ligand structure that achieves both selective binding to expanded repeats and effective interference with RAN translation and protein aggregation pathways.
2Reliability
If bivalent nucleobases are incorporated into the ligand structure, then selective binding to expanded repeats is achieved, but the device complexity increases
Solution Approach 1:
The bivalent nucleobase design creates a universal binding unit that can recognize and bind to the conserved structural features of expanded CAG repeats regardless of their specific location or length. Each bivalent nucleobase unit serves multiple functions: recognizing the expanded repeat sequence, forming stable duplex structures, and enabling concatenation with adjacent units, thereby reducing overall ligand complexity while maintaining high binding selectivity.
3Productivity
If the ligand binds to both strands of the RNA duplex, then interference with RAN translation is enhanced, but the manufacturing precision requirements increase
Solution Approach 1:
The bivalent nucleobases are positioned at specific locations within the ligand structure to target particular features of the expanded CAG repeat sequences. This local quality approach allows the ligand to focus its binding capability on the pathogenic repeat expansion region while using the nucleic acid analog backbone to provide structural stability and facilitate concatenation, thereby reducing the precision requirements for overall ligand assembly while maintaining effective dual-strand binding.
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 bivalent nucleic acid ligands effectively bind to expanded repeat sequences, potentially reducing toxic-gain of RNA and protein functions, offering a therapeutic approach to ameliorate symptoms and prolong survival in polyQ diseases.
Implementation Method 1
a sequence of bivalent nucleobases binds to a unit target sequence, or one or more sequential iterations of a unit target sequence of an expanded repeat of a repeat expansion disease on two nucleic acid strands
Implementation Method 2
a first concatenating group attached to the first end of the backbone and a second concatenating group attached to the second end, either binding non-covalently or self-ligating with the first concatenating group, wherein the first concatenating group and the second concatenating group are each independently a two- to five-ring fused polycyclic aromatic moiety that stack with an aryl moiety of an adjacent recognition reagent
Data Source
Figure 1(A)~1(E)
Figure 2A~2F
Figure 3
AI summary
Genetic recognition reagents comprising bivalent nucleobases are provided that bind two strands of nucleic acid, such as an expanded repeat sequence associated with an expanded repeat disease. In one example the expanded repeat disease is a polyQ disease, such as Huntington's disease. Methods of use of the reagents are provided, including a method of binding nucleic acid, such as an expanded repeat sequence associated with an expanded repeat disease, a method of identifying the presence of a nucleic acid comprising an expanded repeat, and a method of treating an expanded repeat disease are provided.