LNP-Mediated CRISPR-Cas9 Delivery for Brain-Specific SNP Correction
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Solution Overview
Problem
Current treatments for mental health diseases are inadequate, as they primarily focus on symptom modification rather than addressing underlying genetic causes, and there is a need for a safe and effective method to correct specific single nucleotide polymorphisms (SNPs) associated with severe mental health conditions.
Innovation Solution
A nonviral LNP-mediated CRISPR-Cas9 mRNA-based strategy for in vivo brain-specific genome editing is employed, where mRNA encoding Cas9 endonuclease and guide RNA (gRNA) are delivered directly to the brain or cerebrospinal fluid, minimizing off-target effects by designing gRNA with high specificity and using lipid nanoparticles to enhance delivery efficacy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If gRNA is designed with high specificity to minimize off-target effects, then treatment safety is improved, but the complexity of gRNA design and selection increases
Solution Approach 1:
The patent performs computational in silico analysis before in vivo administration to predict and identify potential off-target effects. By conducting this preliminary screening using computational tools, the gRNA sequences are selected and optimized in advance, ensuring high specificity and minimizing off-target effects before the actual treatment occurs.
Solution Approach 2:
The patent employs iterative design and selection processes where computational predictions are used to guide gRNA selection, and results from in vitro assays provide feedback to further optimize gRNA sequences. This feedback loop continues until gRNAs with sufficient specificity and editing efficiency are identified.
2Productivity
If LNP-mediated delivery is used to achieve brain-specific editing, then delivery efficacy is improved, but the complexity of formulation and administration increases
Solution Approach 1:
The patent optimizes LNP formulation parameters including lipid composition, particle size, charge, and concentration to achieve effective brain delivery. By systematically adjusting these parameters, the formulation achieves enhanced cellular uptake and editing efficiency in the brain while maintaining safety.
Solution Approach 2:
Lipid nanoparticles serve as an intermediary delivery vehicle that facilitates the transport of CRISPR-Cas9 components across the blood-brain barrier and into brain cells. The LNP formulation acts as a mediator that protects the RNA components and enables their specific delivery to the target tissue, improving overall delivery efficacy.
3Reliability
If in vivo gene editing is performed to correct SNPs, then curative treatment potential is improved, but the risk of off-target edits and genomic aberrations increases
Solution Approach 1:
The patent conducts comprehensive in silico analysis to predict potential off-target sites before administering the editing therapy. By performing this preliminary computational screening and selecting gRNAs with minimal predicted off-target effects, the therapy achieves high specificity and reduces the risk of unwanted genomic modifications.
Solution Approach 2:
The patent uses transient expression of Cas9 protein through mRNA delivery, where the protein is expressed only during the editing window and then degrades. This temporary expression reduces the risk of persistent off-target effects compared to permanent genomic integration, allowing the system to be 'disposed' of after serving its editing function.
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
This approach allows for precise correction of target SNPs, potentially treating severe mental health diseases by modifying specific genetic sequences, thereby offering a novel curative option for conditions previously without effective treatment.
Implementation Method 1
mRNA encoding Cas9 endonuclease and guide RNA (gRNA) are delivered directly to the brain or cerebrospinal fluid, minimizing off-target effects by designing gRNA with high specificity and using lipid nanoparticles to enhance delivery efficacy
Implementation Method 2
Genome editing technology utilizes a sequence-specific DNA binding RNA (gRNA) which targets the mutation, and the correction of nucleic acid is performed with help from different forms of endonucleases including meganucleases, zinc-finger nucleases (ZFNs), and transcription activator-like effector nucleases (TALENs), The clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 (CRISPR associated protein 9) as a programmable nuclease
Data Source
AI summary
Mental diseases include a heterogenous array of diseases that affect brain function. Evidence suggests that some of more serious conditions that lead to suicide may have some genetic and epigenetic determinants. Single Nucleotide Polymorphism (SNPs) have been identified that correlate with a variety of mental conditions and diseases. In this patent application we describe a method by which subjects with life threatening mental health disease can be identified using Single Nucleotide Polymorphism (SNP) analysis and such associated SNPs is corrected using in vivo genome editing technologies.