Targeted Nucleic Acid Nanocarriers for Selective Stem Cell Editing
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Solution Overview
Problem
Current genetic therapies face challenges with non-selective gene delivery methods, such as viral systems and electroporation, which are costly, inefficient, and require cell selection and purification processes, and suffer from decreased therapeutic protein expression over time.
Innovation Solution
Utilizing transient expression of nucleic acids, including TALENs, megaTALS, and CRISPR-Cas systems, to achieve targeted and rapid modification of hematopoietic stem cells, allowing for permanent therapeutic changes without the need for cell selection or purification, using nanocarriers with specific ligands, carriers, and coatings to ensure selective delivery.
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 targeted nanocarriers as intermediary vehicles to deliver nucleic acids to specific cell types. These nanocarriers are coated with ligands that selectively bind to receptors on target cells, serving as a mediator between the therapeutic nucleic acid and the intended cellular destination, thereby achieving both selectivity and sustained expression without requiring complex viral systems
Solution Approach 2:
The invention changes the delivery mechanism from viral vectors to synthetic nanocarriers, altering key parameters such as selectivity (through targeted ligand coating), cost (using synthetic rather than biological systems), and availability (simplifying manufacturing). This parameter transformation maintains long-lasting therapeutic effect while resolving the complexities of viral delivery
2Productivity
If electroporation is used for gene delivery, then genes are delivered into cells, but cellular membranes are disrupted compromising cell viability
Solution Approach 1:
The patent replaces the mechanical electroporation method (which uses electrical pulses to create physical pores in cell membranes) with a chemical/biological approach using targeted nanocarriers. These nanocarriers selectively bind to and are internalized by target cells through receptor-mediated endocytosis, delivering nucleic acids without mechanical membrane disruption, thereby maintaining cell viability while achieving efficient gene delivery
3Productivity
If electroporation or viral methods are used, then gene delivery is achieved, but cell selection and purification processes are required
Solution Approach 1:
The patent applies local quality by coating nanocarriers with specific ligands that recognize and bind only to target cells with particular surface receptors. This localized targeting ensures that gene delivery occurs exclusively in the desired cell types within a heterogeneous population, eliminating the need for prior cell selection and purification while maintaining high delivery efficiency
4Speed
If transient expression of nucleic acids is used, then rapid and selective modification is achieved, but the method must ensure permanent therapeutic changes
Solution Approach 1:
The patent employs preliminary action by delivering nucleic acids that encode self-sustaining therapeutic mechanisms. For example, the nanocarriers deliver CRISPR-Cas9 systems or transcription factors that, once expressed transiently, permanently modify the cell's genome or epigenome, ensuring lasting therapeutic effects from temporary nucleic acid expression
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.