PROS1 Inhibiting Nucleic Acids for Bleeding Disorder Therapy

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Solution Overview

Problem

Current treatments for bleeding disorders like haemophilia are limited by the development of alloantibodies to clotting factors, necessitating the need for new therapeutic approaches that do not rely on replacement therapy.

Innovation Solution

Development of double-stranded nucleic acids that inhibit PROS1 gene expression, specifically designed to target and reduce Protein S levels, thereby modulating the coagulation pathway to treat bleeding disorders.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If replacement therapy with clotting factors is used to treat bleeding disorders, then coagulation function is improved, but development of alloantibodies occurs leading to treatment failure

Engineering Contradiction:

Improvetreatment effectivenessVSAvoidalloantibody development

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent converts the harmful effect of Protein S (which accelerates thrombin generation and can cause thrombosis) into a beneficial therapeutic effect. By inhibiting Protein S expression using siRNA, the patent reduces excessive coagulation activity and alloantibody formation while maintaining adequate hemostasis, thus treating bleeding disorders without the harmful side effects of replacement therapy

Inventive Principle:

Principle #22Blessing in disguise (Convert harm into benefit)

Solution Approach 2:

Instead of the conventional approach of replacing deficient clotting factors to improve coagulation, the patent inverts the strategy by inhibiting Protein S (an anticoagulant) to enhance coagulation function. This inverse approach treats bleeding disorders by reducing the activity of an anticoagulant protein rather than adding procoagulant factors

Inventive Principle:

Principle #13The other way round (Inversion)

2Ease of manufacture

If nucleic acid silencing triggers are designed using algorithms, then design process is simplified, but potency and off-target effects are not optimized due to ignoring tertiary structure and RNA binding proteins

Engineering Contradiction:

Improvedesign processVSAvoidsilencing efficacy

Core Design Contradiction:

Ease of manufactureVSReliability

Solution Approach 1:

The patent uses experimental methods as an intermediary between algorithmic design and final siRNA selection. High-throughput screening assays serve as mediators to evaluate siRNA potency and specificity, bridging the gap between computational predictions and actual biological activity, thereby optimizing both design efficiency and therapeutic efficacy

Inventive Principle:

Principle #24Intermediary (Mediator)

3Object-affected harmful factors

If Protein S levels are reduced to treat bleeding disorders, then bleeding episodes are decreased, but coagulation regulation may be disrupted

Engineering Contradiction:

Improvebleeding episodesVSAvoidcoagulation regulation

Core Design Contradiction:

Object-affected harmful factorsVSStability of the object's composition

Solution Approach 1:

The patent applies partial inhibition of Protein S expression rather than complete elimination. By using siRNA to reduce Protein S levels to a therapeutic range rather than abolishing its function entirely, the patent effectively treats bleeding episodes while maintaining sufficient Protein S activity for normal coagulation regulation and preventing thrombosis

Inventive Principle:

Principle #16Partial or excessive action

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 nucleic acids effectively inhibit PROS1 expression, reducing bleeding episodes and potentially offering a new therapeutic avenue for haemophilia and other blood coagulation deficiency disorders with fewer off-target effects.

Implementation Method 1

Double-stranded RNAs (dsRNA) able to bind through complementary base pairing to expressed mRNAs have been shown to block gene expression by a mechanism that has been termed 'RNA interference (RNAi)'

Methodology Applied

Scientific EffectRNA interference (RNAi):

Implementation Method 2

Double-stranded RNAs (dsRNA) able to bind through complementary base pairing to expressed mRNAs

Methodology Applied

Scientific EffectComplementary base pairing:

Implementation Method 3

RNAi is mediated by the RNA induced silencing complex (RISC), a sequence specific, multi component nuclease that degrades messenger RNAs having sufficient complementary or homology to the silencing trigger loaded into the RISC complex

Methodology Applied

Scientific EffectmRNA degradation:

Data Source

PatentUS11820971B2Nucleic acids for inhibiting expression of PROS1 in a cell

Publication Date: 2023.11.21 SILENCE THERAPEUTICS GMBH

AI summary

The invention relates to nucleic acid products that interfere with or inhibit PROS1 gene expression. It further relates to therapeutic uses of PROS1 inhibition for the treatment of bleeding disorders.