CCM Pathway Gene Editing for Endothelial Barrier Function in CAD
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Solution Overview
Problem
Identifying the convergence of genetic variants that regulate genes in specific biological pathways to understand disease risk has been challenging due to the complexity of vascular diseases like coronary artery disease (CAD), which involve multiple cell types and noncoding risk variants that can affect multiple genes, making it difficult to pinpoint which genes and pathways are involved.
Innovation Solution
An engineered gene editing system using a single guide RNA (sgRNA) and effector proteins, such as CRISPR-Cas systems, is developed to target and modulate genes in the Cerebral Cavernous Malformation (CCM) pathway, specifically targeting genes like TLNRD1, CCM2, and others, to treat vascular diseases by reducing their expression and altering cellular functions.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If gene editing systems are used to target specific genes in the CCM pathway, then therapeutic effectiveness is improved, but device complexity increases
Solution Approach 1:
The gene editing system is segmented into distinct functional components: guide RNA molecules for target recognition, effector proteins (such as Cas9) for DNA cleavage, and delivery vectors for cellular uptake. This segmentation allows each component to be independently optimized and manufactured, reducing overall system complexity while maintaining therapeutic effectiveness.
Solution Approach 2:
Delivery vectors serve as intermediaries between the gene editing components and the target cells. These vectors (viral or non-viral) facilitate the transport of sgRNA and effector proteins into cells without requiring direct injection of the complex editing system, thereby simplifying the therapeutic administration process.
2Reliability
If multiple genes in the CCM pathway are targeted simultaneously, then treatment efficacy is improved, but measurement precision requirements increase
Solution Approach 1:
Multiple gene editing functions are merged into a single therapeutic formulation by co-delivering multiple guide RNA molecules and effector proteins through a unified delivery vector system. This allows simultaneous targeting of multiple CCM pathway genes (such as CCM1, CCM2, CCM3) while maintaining consistent precision controls across all targets.
Solution Approach 2:
The delivery vector system is designed with universal functionality to accommodate multiple different guide RNA sequences and effector protein combinations. This universal platform approach ensures that precision and efficacy can be maintained across diverse gene targets without requiring separate optimization for each gene combination.
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 system effectively modulates gene expression in vascular endothelial cells, potentially treating CAD by altering cellular functions and improving endothelial cell barrier function, as demonstrated in vitro and in vivo models, providing a therapeutic approach for vascular diseases.
Implementation Method 1
a single guide RNA (sgRNA) which comprises a guide sequence capable of hybridizing with a target sequence
Data Source
AI summary
Provided herein are methods and compositions for the diagnosis, prognosis, and treatment of a vascular disease, such as coronary artery disease (CAD), in a subject. In particular, provided are methods and compositions for treating a vascular disease in a subject involving administering a therapy to disrupt the cerebral cavernous malformation (CCM) signaling pathway in endothelial cells (e.g., arterial endothelial cells) in the subject. Also provided are methods of determining the likelihood that a subject will respond to a therapy for a vascular disease such as CAD, based on the identification of one or more loss-of-function variants in a CCM pathway associated gene in the subject.