Engineered Meganucleases for PCSK9 Gene Cleavage
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Solution Overview
Problem
Current treatments for cardiovascular diseases and hypercholesterolemia, particularly for autosomal dominant familial hypercholesterolemia, are limited in effectively reducing LDL-C levels, especially in homozygous patients, and are associated with adverse effects such as neurocognitive issues and immunogenicity.
Innovation Solution
Engineered meganucleases specifically designed to recognize and cleave a recognition sequence within the PCSK9 gene, disrupting its expression and activity, thereby reducing total and LDL cholesterol levels.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If statins are administered to reduce LDL-C levels, then total cholesterol and LDL-C levels are reduced, but some patient populations (particularly homozygous FH patients) are unable to achieve normal LDL-C levels and experience adverse effects
Solution Approach 1:
The patent extracts and targets the PCSK9 gene product (PCSK9 protein) as the specific cause of elevated LDL-C levels. By using engineered meganucleases to cleave PCSK9 mRNA or genomic DNA, the treatment removes the harmful PCSK9 protein production at its source, thereby reducing LDL-C levels more effectively than statins alone, particularly in homozygous FH patients who cannot achieve normal levels with statin therapy.
Solution Approach 2:
The patent introduces engineered meganucleases as intermediary molecules that mediate between the treatment goal (reducing LDL-C) and the target (PCSK9 gene). These meganucleases serve as the active therapeutic agents that specifically recognize and cleave PCSK9 genetic material, providing a more reliable and effective treatment pathway compared to statins, while avoiding statin-related adverse effects.
2Quantity of substance
If PCSK9 is targeted to reduce LDL receptor degradation, then LDL receptor levels increase and LDL-C levels decrease, but new therapeutic approaches must overcome challenges of gene delivery and specificity
Solution Approach 1:
The patent segments the therapeutic approach into distinct components: engineered meganucleases (comprising recognition domains and catalytic domains) that specifically target PCSK9 genetic material. This segmentation allows for precise molecular recognition and cleavage of PCSK9 mRNA or genomic DNA, increasing LDL receptor levels through reduced PCSK9 activity while managing therapeutic complexity through modular enzyme design.
Solution Approach 2:
The patent applies local quality by designing meganucleases with specific recognition sequences that bind only to particular PCSK9 gene regions. This localized specificity ensures that the therapeutic action occurs precisely at the PCSK9 target site without affecting other genes, thereby increasing LDL receptor levels through targeted PCSK9 reduction while minimizing off-target effects and managing delivery complexity.
3Quantity of substance
If engineered meganucleases are used to cleave PCSK9 gene, then PCSK9 expression is disrupted and LDL-C levels are reduced, but challenges remain in achieving sufficient gene delivery efficiency and in vivo stability
Solution Approach 1:
The patent employs preliminary action by designing and engineering meganucleases with optimized structural features, recognition sequences, and catalytic activities before in vivo administration. The meganucleases are pre-configured with linkers, fusion proteins, or protective modifications to enhance their stability and delivery efficiency ex vivo, thereby improving gene delivery reliability and PCSK9 expression disruption when administered to reduce LDL-C levels.
Solution Approach 2:
The patent utilizes composite materials by creating engineered meganuclease constructs that combine multiple functional elements: DNA-binding recognition domains, catalytic cleavage domains, cell penetration peptides, and stability-enhancing linkers. These composite meganuclease molecules integrate multiple properties to achieve sufficient gene delivery efficiency and in vivo stability while effectively disrupting PCSK9 expression and reducing LDL-C levels.
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 use of engineered meganucleases effectively lowers circulating LDL and total cholesterol levels, providing a promising therapeutic approach for cholesterol-related disorders, including autosomal dominant familial hypercholesterolemia, with potential for reduced adverse effects.
Implementation Method 1
engineered meganucleases having specificity for a recognition sequence within the PCSK9 gene
Implementation Method 2
engineered meganucleases are useful in methods for treating cardiovascular diseases and hypercholesterolemia
Data Source
AI summary
The present invention encompasses engineered meganucleases which recognize and cleave a recognition sequence within the human PCSK9 gene. The present invention also encompasses methods for using such engineered meganucleases in a pharmaceutical composition and in methods for treating or reducing the symptoms of cholesterol-related disorders, such as hypercholesterolemia. Further, the invention encompasses pharmaceutical compositions comprising engineered meganuclease proteins, nucleic acids encoding engineered meganucleases, and the use of such compositions for treating cholesterol-related disorders, such as hypercholesterolemia.