Engineered Recombinant Proteins for Precise Gene Integration
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Solution Overview
Problem
Current gene therapy methods for treating genetic defects lack efficiency, specificity, accuracy, and fidelity in integrating therapeutic genes into the host genome.
Innovation Solution
Development of engineered proteins comprising retroelement-derived polypeptides fused with heterologous polypeptides, such as RNA/DNA processing, repair, binding, or nucleosome binding domains, to enhance integration characteristics.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If traditional gene therapy vectors are used for delivering therapeutic genes, then gene delivery can be achieved, but integration efficiency, specificity, accuracy, and fidelity into the host genome are insufficient
Solution Approach 1:
The patent creates composite proteins by fusing retroelement-derived polypeptides with heterologous polypeptides containing RNA/DNA processing, repair, binding, or nucleosome binding domains. This composite structure combines the genome integration capability of retroelements with the precision and control functions of heterologous domains, thereby simultaneously improving integration efficiency and accuracy
Solution Approach 2:
The invention merges multiple functional domains into a single engineered protein: the retroelement-derived polypeptide provides integration efficiency while heterologous domains contribute RNA/DNA processing, repair, and binding functions. This merging allows the system to achieve both high productivity in integration and high manufacturing precision in terms of integration accuracy and fidelity
2Reliability
If retroelement-derived polypeptides are used alone, then integration function is provided, but integration specificity and fidelity are insufficient
Solution Approach 1:
The engineered protein is segmented into distinct functional modules: the retroelement-derived polypeptide segment handles integration, while separate heterologous domain segments handle RNA/DNA processing, repair, and binding. This segmentation allows each domain to perform its specialized function optimally, improving integration fidelity without creating an uncontrollably complex structure
Solution Approach 2:
The heterologous polypeptide domains provide multiple functions simultaneously: RNA processing, DNA repair, nucleic acid binding, and nucleosome interaction. This multi-functionality within added domains improves integration reliability and fidelity without requiring proportionally increased structural complexity, as each heterologous domain is a self-contained functional unit
Data Source
AI summary
The present disclosure provides compositions and methods for delivering a gene of interest to a subject. Aspects of the application relate to nucleic acids encoding modified retroelement-derived polypeptides and gene delivery constructs that can direct integration of a nucleic acid sequence into a target nucleic acid (e.g., a genome of a subject).