Liver Gene Editing of APOC3 and PCSK9 for Triglyceride Reduction

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Solution Overview

Problem

Current treatments for conditions like familial chylomicronemia syndrome and severe hypertriglyceridemia are inadequate in effectively reducing plasma triglyceride levels, leading to complications such as pancreatitis, cardiovascular disease, and chronic organ damage.

Innovation Solution

The use of guide nucleic acids and CRISPR-associated proteins to modify the expression of APOC3, PCSK9, and ANGPTL3 proteins, leveraging nucleic acid modifying activities like cis cleavage and nucleobase modification to reduce or abolish their expression.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If current treatments are used for familial chylomicronemia syndrome and severe hypertriglyceridemia, then patients can be managed, but plasma triglyceride levels are not effectively reduced, leading to pancreatitis and cardiovascular disease

Engineering Contradiction:

Improveeffectiveness in reducing plasma triglyceride levelsVSAvoidrisk of pancreatitis and cardiovascular disease

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent extracts and targets specific regulatory proteins (APOC3, PCSK9, ANGPTL3) that control triglyceride metabolism. By using guide nucleic acids and CRISPR-associated proteins, the invention selectively modifies or eliminates the expression of these harmful proteins, thereby removing the root cause of elevated triglyceride levels rather than merely managing symptoms with conventional treatments.

Inventive Principle:

Principle #2Taking out (Extraction)

Solution Approach 2:

The patent changes the genetic parameter of protein expression by modifying the DNA sequence through CRISPR-Cas9 mediated cleavage and repair. This results in permanent alteration of the genes encoding APOC3, PCSK9, or ANGPTL3, leading to sustained reduction in plasma triglyceride levels and elimination of long-term health risks.

Inventive Principle:

Principle #35Parameter changes

2Reliability

If guide nucleic acids and CRISPR-associated proteins are used to modify APOC3, PCSK9, and ANGPTL3 expression, then triglyceride levels are significantly lowered, but the complexity of the treatment system increases

Engineering Contradiction:

Improvereduction of triglyceride levelsVSAvoidcomplexity of gene editing system

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent segments the complex gene editing system into distinct functional components: guide nucleic acids for target recognition, CRISPR-associated proteins for DNA cleavage, and cellular repair mechanisms for final modification. This modular approach allows each component to be optimized independently and facilitates delivery through various vectors (viral or non-viral) to achieve the desired triglyceride reduction.

Inventive Principle:

Principle #1Segmentation

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 significantly lowers triglyceride levels, reducing the risk of pancreatitis and cardiovascular disease, and addressing conditions like familial chylomicronemia syndrome and hypertriglyceridemia.

Implementation Method 1

a guide nucleic acid that is capable of hybridizing to a target sequence of a target nucleic acid

Methodology Applied

Scientific EffectComplementarity:

Implementation Method 2

Nucleic acid modifying activities may include, by way of non-limiting example, cis cleavage activity

Methodology Applied

Scientific EffectCis cleavage:

Implementation Method 3

Nucleic acid modifying activities may include, by way of non-limiting example, cis cleavage activity, nickase activity, and nucleobase modifying activity

Methodology Applied

Scientific EffectNucleobase modification:

Data Source

PatentUS20260002151A1Compositions and methods for the modification and regulation of liver gene expression

Publication Date: 2026.01.01 MAMMOTH BIOSCIENCES INC

AI summary

Provided herein are compositions, systems, and methods for modifying a human APOC3 gene, PCSK9 gene, or ANGPTL3 gene. Systems, compositions, and methods may comprise a CRISPR-associated (Cas) protein or uses thereof. Systems, compositions, and methods of the present disclosure may be useful for treatment of APOC3 associated conditions, including familial chylomicronemia syndrome (FCS) and severe hypertriglyceridemia (SHTG).