ANGPTL8 dsRNA Composition for Selective Gene Silencing

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Solution Overview

Problem

Current treatments for conditions associated with elevated triglyceride levels, such as hypertriglyceridemia and pancreatitis, lack effective and safe inhibitors of ANGPTL8 expression.

Innovation Solution

Development of double-stranded ribonucleic acid (dsRNA) molecules that specifically target and inhibit the expression of the ANGPTL8 gene, utilizing complementary sense and antisense strands to form a duplex structure, which can be modified with ligands or linkers for enhanced efficacy.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If double-stranded RNA molecules are used to inhibit ANGPTL8 expression, then triglyceride levels are reduced to normal ranges, but cytotoxicity and immune stimulation may occur

Engineering Contradiction:

Improveclinical efficacyVSAvoidcytotoxicity

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent applies parameter changes by modifying the chemical structure of dsRNA molecules through various nucleotide modifications (2'-O-methyl, 2'-fluoro, locked nucleic acids) and adjusting structural parameters (strand length, overhangs, phosphorothioate modifications) to reduce cytotoxicity while maintaining triglyceride-lowering efficacy

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent uses chemical modifications as intermediaries between the dsRNA molecule and the cellular environment. These modifications (such as 2'-O-methyl and phosphorothioate groups) act as protective intermediaries that reduce immune system recognition and cytotoxic effects while allowing the dsRNA to maintain its gene-silencing function

Inventive Principle:

Principle #24Intermediary (Mediator)

2Reliability

If double-stranded RNA molecules are used to inhibit ANGPTL8 expression, then triglyceride levels are reduced to normal ranges, but immune stimulation may occur

Engineering Contradiction:

Improveclinical efficacyVSAvoidimmune stimulation

Core Design Contradiction:

ReliabilityVSObject-generated harmful factors

Solution Approach 1:

The patent applies parameter changes by modifying the chemical structure of dsRNA molecules through various nucleotide modifications (2'-O-methyl, 2'-fluoro, locked nucleic acids) and adjusting structural parameters (strand length, overhangs, phosphorothioate modifications) to reduce immune stimulation while maintaining triglyceride-lowering efficacy

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent uses chemical modifications as intermediaries that reduce immune system recognition. These modifications (such as 2'-O-methyl and phosphorothioate groups) act as protective layers that prevent the immune system from detecting the dsRNA as foreign, thereby reducing interferon response and inflammation

Inventive Principle:

Principle #24Intermediary (Mediator)

3Measurement precision

If sense and antisense strands are made highly complementary to achieve specific targeting, then gene inhibition precision is improved, but off-target effects and cytotoxicity may increase

Engineering Contradiction:

Improvetargeting precisionVSAvoidoff-target effects

Core Design Contradiction:

Measurement precisionVSObject-affected harmful factors

Solution Approach 1:

The patent applies local quality by making the central region of the dsRNA highly complementary to the target sequence for precise binding, while the terminal regions contain modifications (overhangs, phosphorothioate groups) that reduce off-target effects and improve stability. This localized differentiation optimizes both specificity and safety

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent adjusts the degree of complementarity parameters, using 19-25 nucleotide antisense sequences with 90-100% identity to the target, and incorporates controlled mismatches or modifications at specific positions to enhance target specificity while minimizing off-target binding

Inventive Principle:

Principle #35Parameter changes

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 dsRNA effectively reduces triglyceride levels to normal ranges, providing clinical efficacy in treating lipid metabolism disorders and associated diseases with minimal cytotoxicity and immune stimulation.

Implementation Method 1

Double-stranded RNA molecules (dsRNAs) have been shown to block gene expression in a highly conserved regulatory mechanism known as RNA interference (RNAi)

Methodology Applied

Scientific EffectRNA interference:

Implementation Method 2

Once bound, the target RNA is cleaved by RNA endonuclease Argonaute (AGO) in RISC and then further degraded by RNA exonucleases

Methodology Applied

Scientific EffectRNA cleavage:

Data Source

PatentUS12416004B2RNA compositions and methods for inhibiting ANGPTL8

Publication Date: 2025.09.16 SANOFI SA(FR)

AI summary

The present disclosure relates to dsRNAs targeting ANGPTL8, methods of inhibiting ANGPTL8 gene expression, and methods of treating one or more conditions associated with ANGPTL8 gene expression.