Adenosine Base Editors with Mutations at Positions 82 and 166
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Solution Overview
Problem
Current base editors lack specificity and efficiency in modifying target nucleic acid sequences, limiting their effectiveness in gene editing and therapeutic applications for human genetic diseases.
Innovation Solution
Development of novel adenine base editors (e.g., ABE8) with adenosine deaminase variants, specifically altered at positions 82 and/or 166, which form fusion proteins with a polynucleotide programmable DNA binding domain, enhancing editing efficiency and specificity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If current base editors (e.g., BE4, ABE7.10) are used, then base editing can be performed, but editing efficiency and specificity are insufficient
Solution Approach 1:
The patent applies parameter changes by introducing specific amino acid mutations at positions 82 and 166 in the adenosine deaminase domain of the base editor. These mutations alter the enzymatic parameters of the adenosine deaminase, enhancing its catalytic efficiency and specificity for deaminating adenine at target sites, thereby resolving the contradiction between editing efficiency and specificity
Solution Approach 2:
The patent uses composite materials by fusing the mutated adenosine deaminase domain with a programmable DNA binding domain (such as CRISPR-Cas9). This creates a composite base editor system where the DNA binding domain provides target localization and the mutated adenosine deaminase provides enhanced editing activity, achieving both high efficiency and specificity
2Reliability
If adenosine deaminase variants with alterations at positions 82 and/or 166 are used, then editing specificity and efficiency are improved, but protein sequence complexity increases
Solution Approach 1:
The patent applies local quality by making targeted mutations only at specific positions (82 and/or 166) in the adenosine deaminase sequence rather than redesigning the entire protein. This localized approach maintains the overall simplicity of the protein structure while introducing specific functional improvements at critical residues, thus avoiding excessive complexity
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 novel adenine base editors demonstrate improved efficiency and specificity in editing target sequences, potentially leading to more effective gene editing and therapeutic interventions for genetic diseases.
Implementation Method 1
adenosine deaminase variants for editing a target sequence
Data Source
AI summary
The disclosure provides compositions comprising novel adenosine base editors (e.g., ABE8) that have increased efficiency and methods of using these adenosine deaminase variants for editing a target sequence.