Base Editing of ANGPTL3 for Durable LDL-C Reduction
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current treatments for atherosclerotic cardiovascular disease (ASCVD) often require chronic management with multiple daily pills or intermittent injections, which insufficiently control cumulative exposure to low-density lipoprotein cholesterol (LDL-C), leading to accelerated cholesterol plaque buildup and increased risk of heart attacks and strokes.
Innovation Solution
Development of compositions capable of safely and effectively editing genes in the liver to durably lower LDL-C and triglycerides, using base editor fusion proteins and guide RNAs that target specific genes such as ANGPTL3 and PCSK9, administered via lipid nanoparticle formulations.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If base editing of ANGPTL3 is performed, then LDL-C and triglycerides are durably lowered, but gene editing complexity and delivery challenges increase
Solution Approach 1:
The gene editing system is segmented into separate functional components: base editor fusion proteins (containing deaminase enzymes), guide RNAs (containing tracr sequences and spacer sequences), and lipid nanoparticle delivery vehicles. This segmentation allows independent optimization of each component and simplifies the overall system by dividing the complex gene editing function into manageable parts that can be produced and administered separately.
Solution Approach 2:
Lipid nanoparticles serve as intermediaries to deliver the base editor fusion proteins and guide RNAs into liver cells. This intermediary delivery mechanism bypasses the complexity of direct genetic modification and provides a controlled, efficient way to introduce the editing components into the target tissue, thereby reducing the overall complexity of the gene editing approach.
2Productivity
If base editor fusion proteins and guide RNAs are administered via lipid nanoparticles, then editing efficiency increases, but manufacturing and formulation complexity increases
Solution Approach 1:
The lipid nanoparticle formulation utilizes specific parameter changes in lipid chemistry and particle characteristics (such as particle size, charge, and lipid composition) to optimize delivery efficiency. By adjusting these physical and chemical parameters, the formulation achieves high editing efficiency while maintaining manufacturability through established lipid nanoparticle production techniques.
Solution Approach 2:
The lipid nanoparticle platform serves multiple functions simultaneously: it protects the fragile guide RNA and base editor proteins, facilitates cellular uptake, enables controlled release of editing components, and can be adjusted for different dosing regimens. This multi-functionality reduces the need for separate delivery systems and simplifies manufacturing by consolidating multiple requirements into a single platform.
3Ease of operation
If single-course dosing is used, then treatment simplicity improves, but sustained editing durability must be maintained
Solution Approach 1:
The base editor fusion proteins and guide RNAs are designed to perform their editing function efficiently during a single administration cycle. The guide RNAs are engineered with optimized spacer sequences that enable precise targeting, and the base editors are designed with high catalytic activity, allowing sufficient editing to occur during the brief window when the components are active before degradation. This preliminary action approach achieves durable editing with minimal dosing.
Solution Approach 2:
The lipid nanoparticle formulation and base editor system are designed to maintain continuous editing activity throughout the treatment period. The guide RNAs and base editors work together in a coordinated manner that ensures uninterrupted editing of the ANGPTL3 gene, and the system is engineered to prevent premature degradation or inactivation, thereby maintaining useful action continuity from administration through the duration of the treatment course.
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
The gene editing compositions achieve significant and durable reductions in LDL-C and triglycerides, as demonstrated in in vitro and in vivo studies, including mouse and non-human primate experiments, with efficacy shown in both single-course and repeat dosing regimens.
Implementation Method 1
a base editor fusion protein comprising a programmable DNA binding domain and a deaminase
Implementation Method 2
a guide RNA comprising a tracr sequence that serves as a binding scaffold for the base editor fusion protein, and a spacer sequence that corresponds to a protospacer on a target gene
Implementation Method 3
administered via lipid nanoparticle formulations
Data Source
AI summary
Provided herein are compositions for gene modification or editing and methods of using same to treat or prevent certain conditions. Specific compositions and methods capable of safely and effectively editing gene targets expressed in the liver to durably lower LDL-C thereby treating a leading cause of cardiovascular disease are disclosed.