RNAi Compositions Targeting KLKB1, F12, and KNG1 for HAE Control

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Solution Overview

Problem

Current treatments for hereditary angioedema (HAE) and thrombosis are inadequate, particularly for acute attacks and long-term prophylaxis, due to side effects and administration limitations of existing therapies, necessitating alternative therapies that can be safely and conveniently administered.

Innovation Solution

RNAi agents targeting the Kallikrein B (KLKB1), Factor XII (F12), and Kininogen 1 (KNG1) genes are developed to inhibit their expression, using double-stranded RNAi agents with modified nucleotides and ligands for effective RNA-induced silencing, administered via convenient routes.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If current therapies for hereditary angioedema and thrombosis are used, then treatment effectiveness is achieved, but side effects and administration limitations occur

Engineering Contradiction:

Improvetreatment effectivenessVSAvoidside effects

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent extracts and targets the specific pathological pathways (contact activation system components F12, KLKB1, and KNG1) responsible for HAE and thrombosis, using RNAi agents to selectively inhibit only these disease-causing pathways while preserving normal physiological functions, thereby achieving treatment effectiveness with reduced side effects

Inventive Principle:

Principle #2Taking out (Extraction)

Solution Approach 2:

The patent changes the therapeutic parameter from protein-based replacement therapy to gene expression inhibition using RNAi, fundamentally altering the treatment mechanism to reduce side effects associated with traditional therapies while maintaining effectiveness

Inventive Principle:

Principle #35Parameter changes

2Reliability

If current therapies for hereditary angioedema and thrombosis are used, then treatment effectiveness is achieved, but administration convenience is limited

Engineering Contradiction:

Improvetreatment effectivenessVSAvoidadministration convenience

Core Design Contradiction:

ReliabilityVSEase of operation

Solution Approach 1:

The patent replaces complex mechanical administration systems (intravenous infusions, frequent injections) with RNAi agents that can be administered via simpler routes (subcutaneous injection, oral administration), substituting the mechanical delivery system while maintaining therapeutic effectiveness

Inventive Principle:

Principle #28Mechanics substitution (Replace mechanical system)

3Productivity

If RNAi agents targeting contact activation pathway are developed, then gene expression inhibition is achieved, but treatment safety and convenience need to be ensured

Engineering Contradiction:

Improvegene expression inhibition efficacyVSAvoidtreatment safety

Core Design Contradiction:

ProductivityVSReliability

Solution Approach 1:

The patent applies local quality by designing RNAi agents with specific sequence complementarity to target only F12, KLKB1, and KNG1 mRNA transcripts, ensuring that gene expression inhibition is localized to these specific pathological pathways while leaving other essential physiological processes unaffected, thereby achieving both high efficacy and safety

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 RNAi agents significantly inhibit gene expression, reducing bradykinin levels and coagulation factor XII activity, effectively preventing angioedema attacks and thrombus formation, with potential for safe and convenient administration.

Implementation Method 1

Methodology Applied

Scientific EffectRNA interference:

Data Source

PatentUS20260015613A1Factor xii (hageman factor) (F12), kallikrein b, plasma (fletcher factor) 1 (KLKB1), and kininogen 1 (KNG1) IRNA compositions and methods of use thereof

Publication Date: 2026.01.15 ALNYLAM PHARMACEUTICALS INC

AI summary

The present invention relates to RNAi agents, e.g., double stranded RNAi agents, targeting the Kallikrein B, Plasma (Fletcher Factor) 1 (KLKB1) gene, the Factor XII (Hageman Factor (F12) gene, or the Kininogen 1 (KNG1) gene, and methods of using such RNAi agents to inhibit expression of a KLKB1 gene, an F12 gene, and/or a KNG1 gene, and methods of treating subjects having an hereditary angioedema (HAE) and/or a contact activation pathway-associated disorder.