CFB-Targeting siRNA Duplexes for Complement Modulation

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Solution Overview

Problem

There is a need for therapies to modulate the complement system, particularly targeting complement factor B (CFB), to treat diseases associated with excessive production and dysregulation, such as type 2 diabetes mellitus, cardiovascular diseases, neurological disorders, hematological disorders, eye disorders, autoimmune diseases, and infections.

Innovation Solution

The development of isolated oligonucleotides, specifically small interfering RNAs (siRNAs), designed to target and reduce CFB mRNA expression by forming a double-stranded region with a sense and antisense strand, which are substantially complementary to a region of the CFB mRNA sequence, leading to decreased CFB protein expression.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If complement factor B (CFB) is targeted for therapeutic modulation, then treatment of complement-associated diseases is improved, but the complexity of developing and delivering effective therapies increases

Engineering Contradiction:

Improvetherapeutic efficacyVSAvoidtherapy development complexity

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent replaces complex protein-based complement modulation approaches with nucleic acid-based therapies (siRNA, antisense oligonucleotides) that target CFB mRNA at the transcriptional level, simplifying the therapeutic mechanism while maintaining efficacy

Inventive Principle:

Principle #28Mechanics substitution (Replace mechanical system)

Solution Approach 2:

The patent modifies the CFB protein expression level by changing the mRNA degradation parameter through siRNA-mediated RNA interference, achieving precise control over complement activation without affecting other complement components

Inventive Principle:

Principle #35Parameter changes

2Reliability

If CFB expression is reduced to treat complement-associated diseases, then disease symptoms are improved, but off-target effects and safety concerns increase

Engineering Contradiction:

Improvetherapeutic efficacyVSAvoidoff-target effects

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent employs sequence-specific siRNA design that targets a unique region of CFB mRNA, ensuring localized action only on the intended target without affecting other complement components or non-complement proteins

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent incorporates control mechanisms to monitor CFB expression levels and adjust therapy dosage, preventing excessive reduction that could lead to compensatory effects or off-target damage

Inventive Principle:

Principle #23Feedback

3Productivity

If small interfering RNAs are used to target CFB, then CFB mRNA degradation is improved, but the cost and complexity of oligonucleotide synthesis increases

Engineering Contradiction:

ImprovemRNA degradation efficiencyVSAvoidoligonucleotide synthesis cost

Core Design Contradiction:

ProductivityVSEase of manufacture

Solution Approach 1:

The patent divides the CFB mRNA target into specific 19-25 nucleotide regions, allowing synthesis of multiple short siRNA sequences that can be produced more efficiently and at lower cost than full-length complementary RNAs

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The patent utilizes chemically synthesized oligonucleotides that can be produced relatively cheaply through automated sequencing machines, accepting that the oligonucleotides are single-use therapeutic agents rather than reusable proteins

Inventive Principle:

Principle #27Cheap short-living objects (Disposable)

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 siRNAs effectively decrease CFB mRNA and protein levels, providing therapeutic potential for treating conditions like Paroxysmal Nocturnal Hemoglobinuria, rheumatoid arthritis, ischemia-reperfusion injuries, Multiple Sclerosis, and other complement component-associated diseases.

Implementation Method 1

The present disclosure provides an isolated oligonucleotide comprising a sense strand and an antisense strand, wherein the sense strand comprises a nucleotide sequence that is substantially identical to a region comprising 19-25 nucleotides between the nucleotide positions from 1821 to 1881 from the 5′ end of a human CFB mRNA sequence

Methodology Applied

Scientific EffectRNA interference:

Implementation Method 2

the antisense strand is substantially complementary to the sense strand such that the sense strand and the antisense strand together form a double stranded region

Methodology Applied

Scientific EffectComplementary base pairing:

Data Source

PatentUS20250382616A1Small interfering RNA targeting CFB and uses thereof

Publication Date: 2025.12.18 SANEGENE BIO USA INC

AI summary

This disclosure relates to isolated oligonucleotides comprising duplex regions targeting human CFB mRNA, and delivery systems, and compositions comprising the same, and methods of using the same for inhibiting or downregulating CFB gene expression.