Lipid Nanoparticle Delivery for Lung Cell Gene Editing
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Solution Overview
Problem
Current gene editing technologies, such as CRISPR/Cas, face challenges in delivering targeted editing to specific cells, particularly in the lungs, due to immunogenicity concerns and inefficiencies in viral vectors, and non-viral lipid nanoparticle delivery has limitations mainly to the liver.
Innovation Solution
A method involving a nucleic acid editing system assembled with a lipid composition, comprising a guide nucleic acid, a heterologous polypeptide or polynucleotide encoding an endonuclease, and a donor template nucleic acid, which cleaves and repairs the CFTR gene or transcript to enhance CFTR protein expression or activity in cells, specifically targeting lung cells with mutations like F508del or G542X.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Manufacturing precision
If viral vectors are used for in vivo gene editing, then targeted editing in lung cells can be achieved, but immunogenicity and integration safety concerns arise
Solution Approach 1:
The patent uses lipid nanoparticles as an intermediary delivery vehicle to transport CRISPR/Cas components into lung cells, replacing viral vectors. This mediator enables gene editing delivery without triggering immunogenic responses or integration events, resolving the contradiction between editing effectiveness and safety concerns.
2Object-affected harmful factors
If non-viral lipid nanoparticle delivery is used, then immunogenicity concerns are reduced, but delivery efficiency is limited to liver targets
Solution Approach 1:
The patent modifies the lipid nanoparticle composition with specific lung-targeting ligands or surface modifications that enable selective accumulation in lung tissue. This local quality enhancement allows the delivery system to efficiently target lung cells while maintaining the low immunogenicity advantage of non-viral vectors.
3Manufacturing precision
If CRISPR/Cas gene editing is performed in lung cells, then CFTR mutation correction can be achieved, but off-target insertions and deletions occur
Solution Approach 1:
The patent replaces traditional non-specific CRISPR/Cas delivery mechanisms with a precisely engineered lipid nanoparticle system that enables controlled, targeted delivery of editing components to specific CFTR loci in lung cells. This substitution reduces off-target effects by ensuring precise spatial and temporal delivery of the editing machinery.
Data Source
AI summary
Described herein are compositions, kits, and methods for potent delivery to a cell of a subject. The cell can be of a particular cell type, such as a basal cell, a ciliated cell, or a secretory cell. In some cases, the cell can be a lung cell of a particular cell type. Also described herein are pharmaceutical compositions comprising a therapeutic or prophylactic agent assembled with a lipid composition. The lipid composition can comprise an ionizable cationic lipid, a phospholipid, and a selective organ targeting lipid. Further described herein are high-potency dosage forms of a therapeutic or prophylactic agent formulated with a lipid composition.