Factor IX R338L Mutation Enhances Coagulation Activity

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Solution Overview

Problem

Current treatments for hemophilia B, including FIX concentrates and gene therapy, face challenges such as low efficiency of FIX expression, immunogenicity, side effects, and increased risk of thrombotic manifestations with elevated FIX levels.

Innovation Solution

Development of a modified FIX polypeptide with a gain-of-function, specifically with amino acid substitutions at position 338, such as leucine, aspartic acid, or glutamine, which enhances its activity levels up to 13 times compared to wild-type FIX, while minimizing side effects.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If FIX levels are elevated to treat severe hemophilia B, then coagulation deficiency is corrected, but risk of thrombotic manifestations increases

Engineering Contradiction:

Improvecoagulation functionVSAvoidthrombotic risk

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent applies parameter changes by modifying the amino acid sequence of FIX at position 338 (R338L mutation) to alter its functional properties. This specific parameter change in the protein structure results in enhanced catalytic activity that achieves therapeutic coagulation correction with potentially lower dosing requirements, thereby reducing thrombotic risk associated with high FIX levels

Inventive Principle:

Principle #35Parameter changes

2Duration of action of stationary object

If gene therapy is used to correct genetic defect, then long-term FIX production is achieved, but immunogenicity and side effects occur

Engineering Contradiction:

ImproveFIX production durationVSAvoidimmunogenicity

Core Design Contradiction:

Duration of action of stationary objectVSObject-generated harmful factors

Solution Approach 1:

The patent applies parameter changes by introducing a specific amino acid substitution (R338L) that not only enhances functional activity but may also reduce immunogenicity. The modified protein structure with leucine at position 338 creates a variant that maintains long-term production capability while potentially lowering immune response compared to wild-type FIX

Inventive Principle:

Principle #35Parameter changes

3Reliability

If current FIX concentrates are administered, then coagulation activity is restored, but treatment efficiency is limited

Engineering Contradiction:

Improvecoagulation activityVSAvoidtreatment efficiency

Core Design Contradiction:

ReliabilityVSProductivity

Solution Approach 1:

The patent applies parameter changes by modifying the catalytic efficiency parameter of FIX through the R338L mutation. This amino acid substitution enhances the enzyme's kcat/Km ratio, resulting in improved treatment efficiency where lower doses achieve the same therapeutic effect, thereby increasing productivity in terms of treatment effectiveness per unit dose

Inventive Principle:

Principle #35Parameter changes

Data Source

PatentUSRE50288E1Factor IX polypeptide mutant, its uses and a method for its production

Publication Date: 2025.02.04 UNIQURE BIOPHARMA BV

AI summary

Disclosed are a modified FIX (factor IX) polypeptide comprising a leucine, cysteine, aspartic acid, glutamic acid, histidine, lysine, asparagine, glutamine or tyrosine in position 338; pharmaceutical preparations containing said modified FIX polypeptide; a nucleotide sequence coding for the modified FIX polypeptide; and a method for producing the modified FIX polypeptide.