Interfering RNA Sequences for Stable PCSK9 Gene Silencing

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Solution Overview

Problem

Current siRNA medicaments targeting PCSK9 have varying efficacy, safety, and stability, necessitating the development of a more effective and safer medicament to inhibit PCSK9 gene expression and regulate LDL-C metabolism.

Innovation Solution

The use of specific interfering RNA sequences (SEQ ID NOs: 1-40 and 73-96) combined with delivery systems, including viral and non-viral vectors, to target and silence hepatic PCSK9 mRNA, thereby reducing PCSK9 protein levels and enhancing LDL-C metabolism.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If existing siRNA medicaments targeting PCSK9 are used, then PCSK9 gene expression can be inhibited, but the efficacy, safety, and stability vary considerably

Engineering Contradiction:

ImproveefficacyVSAvoidvariability in efficacy, safety, and stability

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The patent applies parameter changes by systematically varying multiple siRNA sequence parameters (targeting different PCSK9 mRNA regions, using different nucleotide compositions) and modification parameters (2'-fluoro, 2'-O-methyl, phosphorothioate backbone modifications) to optimize the medicament's efficacy, safety, and stability profile

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent employs composite materials by combining multiple siRNA sequences with different modifications and incorporating them into various delivery systems (liposomes, polymeric carriers, viral vectors) to create a composite medicament formulation that achieves superior performance characteristics

Inventive Principle:

Principle #40Composite materials

2Stability of the object's composition

If siRNA sequences are modified to improve stability, then pharmacokinetic properties enhance, but interference efficacy may be affected

Engineering Contradiction:

ImprovestabilityVSAvoidinterference efficacy

Core Design Contradiction:

Stability of the object's compositionVSReliability

Solution Approach 1:

The patent systematically modifies siRNA sequence parameters and chemical structures (adding fluorescent tags, incorporating modified nucleotides) to optimize both stability and interference efficacy simultaneously, demonstrating that enhanced stability does not compromise functional activity

Inventive Principle:

Principle #35Parameter changes

3Productivity

If delivery systems are optimized for hepatic targeting, then PCSK9 silencing efficiency improves, but safety concerns may arise

Engineering Contradiction:

Improvesilencing efficiencyVSAvoidsafety

Core Design Contradiction:

ProductivityVSObject-affected harmful factors

Solution Approach 1:

The patent uses intermediary delivery systems (liposomes, polymeric carriers, viral vectors) as mediators to transport siRNA to hepatic cells, achieving efficient PCSK9 silencing while managing safety through controlled delivery mechanisms that reduce off-target effects

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The patent applies local quality by designing delivery systems with hepatic-specific targeting capabilities (using liver-specific receptors or tissue-resident cells) to concentrate siRNA action in the liver where PCSK9 is expressed, thereby improving silencing efficiency while limiting systemic exposure and associated safety risks

Inventive Principle:

Principle #3Local quality

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 interfering RNA efficiently and stably inhibits PCSK9 expression, providing a foundation for treating PCSK9 gene-mediated diseases such as cardiovascular and neoplastic diseases, with improved safety and efficacy.

Implementation Method 1

siRNA (small interfering RNA) is a double-stranded RNA with a length of about 19-23 nucleotides. In vivo, the siRNA duplex unwinds and assembles with other proteins to form an RNA-induced silencing complex (RISC); through base complementary pairing, this complex targets a specific mRNA for degradation, thereby achieving the purpose of inhibiting protein expression.

Methodology Applied

Scientific EffectRNA interference:

Implementation Method 2

the siRNA duplex unwinds and assembles with other proteins to form an RNA-induced silencing complex (RISC); through base complementary pairing, this complex targets a specific mRNA for degradation

Methodology Applied

Scientific EffectRNA-induced silencing complex formation:

Data Source

PatentUS20250313844A1Interfering RNA for inhibiting PCSK9 gene expression and use thereof

Publication Date: 2025.10.09 JENKEM TECH

AI summary

The present invention discloses an interfering RNA for inhibiting PCSK9 gene and use thereof. The interfering RNA comprises a nucleotide sequence set forth in any one or two or more of SEQ ID NOs: 1-40, 73-96. The interfering RNA of the present invention can better target and silence hepatic PCSK9 mRNA, reduce the protein level of PCSK9, enhance LDL-C metabolism, and reduce serum cholesterol, providing a solid technical foundation for the development of siRNA medicaments for the prevention, treatment, and symptom alleviation of PCSK9 gene-mediated diseases.