Zip Code Nucleic Acid Constructs for Cell-Specific Integration
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Solution Overview
Problem
There is an unmet need for sensitive, effective, and cell-, tissue-, and/or organ-specific compositions and methods for the detection and treatment of cancer and other chronic diseases, as existing technologies do not adequately address the relationship between transposable elements and disease onset.
Innovation Solution
Nucleic acid constructs comprising specific DNA sequences derived from transposons are developed to target and integrate into specific tissues or cells, utilizing Zip Code Sequences (ZCS) for tropism and genomic integration, which can deliver therapeutic or diagnostic cargo, such as tumor suppressor proteins or fluorophores, via transposon-mediated horizontal gene transfer.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Manufacturing precision
If nucleic acid constructs are designed to target specific tissues using transposon-derived sequences, then cell-specific delivery precision is improved, but the complexity of the nucleic acid construct increases
Solution Approach 1:
The nucleic acid construct is divided into distinct functional segments: a) a first nucleic acid sequence that directs migration to the target tissue, and b) a second nucleic acid sequence that directs integration into the cell genome. This segmentation allows each component to be optimized independently for its specific function while reducing overall construct complexity.
Solution Approach 2:
Transposon-derived sequences serve as intermediary elements that mediate between the external nucleic acid construct and the target cell genome. These sequences facilitate migration and integration without requiring direct modification of the entire construct, simplifying the design process.
2Productivity
If transposon sequences are used for genomic integration, then integration efficiency is improved, but the risk of harmful effects from transposable elements increases
Solution Approach 1:
Only the necessary functional sequences from transposons are extracted and incorporated into the nucleic acid construct (the migration and integration signals), while the potentially harmful portions of the transposon are excluded. This allows utilization of transposon-mediated integration efficiency without the associated risks.
Solution Approach 2:
The nucleic acid construct incorporates transposon-derived sequences only in the specific regions where integration function is needed, rather than using complete transposon elements. This localized approach maintains integration efficiency while minimizing harmful effects from other transposon components.
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 nucleic acid constructs demonstrate high specificity in targeting and integrating into cells of the same origin, allowing for precise delivery of therapeutic cargo, such as tumor suppressor proteins, enhancing treatment efficacy and diagnostic accuracy.
Implementation Method 1
The construct can comprise two or more sequences derived from a transposon, for instance, a 3' sequence and a 5' sequence, for integration into a cell of the target tissue
Data Source
AI summary
The present disclosure provides nucleic acid sequences and nucleic acid delivery constructs comprising “zip code” sequence(s) that home, target, cross a cytoplasm, and/or cross a nuclear membrane of a target cell (e.g., a diseased cell such as a cancer cell) or cell population (e.g., tissue), and integration sequence(s) that allow for integration of at least a portion of such nucleic acid or nucleic acid delivery system into a genome of such target cell. The present disclosure also provides non-naturally occurring nucleic acid constructs and delivery systems comprising such Zip Code and integration sequences as well as one or more cargo molecules that may be coupled covalently or non-covalently to such nucleic acid constructs and systems. Further provided herein are methods of diagnosing and treating diseases such as cancer using the target cell specific nucleic acid constructs and systems described herein.