Targeted Nucleic Acid Nanocarriers for Hit-and-Run Cell Programming
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Solution Overview
Problem
Current genetic therapies, such as those using viral systems and electroporation, are non-selective, costly, and require cell selection and purification processes, with ongoing protein expression decreasing over time.
Innovation Solution
Compositions and methods utilizing targeted nucleic acid nanocarriers for transient expression of nucleic acids in hematopoietic stem cells, allowing selective and permanent therapeutic changes without the need for cell selection or purification, using TALENs, megaTALS, zinc finger nucleases, and CRISPR-Cas systems.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Duration of action of stationary object
If viral systems are used for gene delivery, then long-lasting genetic therapy is achieved, but the method is non-selective, expensive and not widely available
Solution Approach 1:
The patent uses transiently expressed nucleic acids (short-living) delivered by electroporation (simple method) to achieve permanent therapeutic effects. The nucleic acid expression is temporary but sufficient to induce lasting changes, replacing complex viral systems with simpler, cheaper alternatives.
Solution Approach 2:
The patent performs cell selection and purification before gene delivery to ensure target cell specificity. This preliminary action allows subsequent simple electroporation to selectively modify only the desired cell population, avoiding the need for complex selective viral vectors.
2Ease of manufacture
If electroporation is used for gene delivery, then gene delivery into cells is achieved, but cellular membrane disruption compromises cell viability
Solution Approach 1:
The patent optimizes electroporation parameters (voltage, pulse duration, temperature) to achieve sufficient membrane permeabilization for nucleic acid delivery while minimizing cell damage. By carefully controlling these parameters, the method balances delivery efficiency with cell viability preservation.
3Duration of action of stationary object
If viral systems are used for gene delivery, then genetic therapy is achieved, but cell selection and purification processes are required
Solution Approach 1:
The patent performs cell selection and purification before gene delivery to ensure target cell specificity. This preliminary action allows subsequent simple electroporation to selectively modify only the desired cell population, avoiding the need for complex selective viral vectors.
4Duration of action of stationary object
If ongoing cellular expression of therapeutic proteins is maintained, then genetic therapy continues, but expression decreases over time due to cellular events
Solution Approach 1:
The patent uses transient nucleic acid expression to induce permanent therapeutic changes in cells. The temporary expression of nucleic acids (such as CRISPR-Cas systems or transgenes) creates lasting modifications that persist without continued external expression, overcoming the problem of declining protein levels over time.
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
Achieves rapid and efficient genetic modification of selected cell types with lasting therapeutic effects, expediting manufacturing and allowing targeted genetic modification in vivo.
Implementation Method 1
The nanocarrier comprises a coating that shields the encapsulated nucleic acids and reduces or prevents off-target binding
Implementation Method 2
The coating may be a neutral or negative polymer- and/or liposome-based coating
Data Source
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AI summary
Compositions and methods that rapidly and selectively modify hematopoietic stem cells (or cells derived therefrom) to achieve therapeutic objectives by providing for transient expression of nucleic acids are described. The transient expression leads to permanent therapeutic changes in the modified cells, referred to herein as "hit and run" effects.