Activated Factor V Mutations for Hemophilia Coagulation

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Solution Overview

Problem

Current treatments for hemophilia A and B, such as protein replacement therapy, have limitations and do not effectively address the variability in the hemophilia phenotype, particularly in relation to the influence of factor V Leiden (FVL) mutation on coagulation and bleeding tendencies.

Innovation Solution

The use of activated forms of factor V (FV) and its derivatives, which are administered to enhance clot formation and improve hemostasis in patients with hemophilia, by mimicking the effect of FVL and bypassing deficiencies in the intrinsic or extrinsic coagulation pathways.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If protein replacement therapy is used to treat hemophilia, then factor levels can be supplemented, but the treatment does not effectively address the variability in hemophilia phenotype caused by FVL mutation

Engineering Contradiction:

Improvetreatment effectivenessVSAvoidphenotype variability

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The patent modifies the factor V molecule by introducing specific mutations (R506Q, R679Q, R306Q) to alter its resistance to activated protein C degradation. This parameter change in the molecular structure allows the engineered factor V to maintain stability and activity in patients with FVL mutation, addressing the phenotype variability that standard protein replacement therapy cannot handle

Inventive Principle:

Principle #35Parameter changes

2Reliability

If activated protein C is used to regulate coagulation, then thrombin levels are controlled, but factor V Leiden mutation reduces inactivation rate by ten-fold

Engineering Contradiction:

Improvecoagulation controlVSAvoidinactivation rate

Core Design Contradiction:

ReliabilityVSSpeed

Solution Approach 1:

Instead of trying to enhance activated protein C's inactivation capability, the patent inverts the approach by modifying factor V itself to resist degradation. By mutating the cleavage sites (R506Q, R679Q, R306Q) in factor V, the invention makes the substrate resistant to the enzyme's action, thereby compensating for the reduced inactivation rate caused by FVL mutation

Inventive Principle:

Principle #13The other way round (Inversion)

3Reliability

If factor V is activated to enhance clot formation, then hemostasis is improved, but the natural factor V is rapidly degraded by activated protein C

Engineering Contradiction:

ImprovehemostasisVSAvoidfactor V stability

Core Design Contradiction:

ReliabilityVSDuration of action of stationary object

Solution Approach 1:

The patent applies prior cushioning by pre-modifying factor V with protective mutations at the cleavage sites before it is activated and deployed in the coagulation cascade. These mutations (R506Q, R679Q, R306Q) act as a cushion against rapid degradation by activated protein C, allowing the activated factor V to maintain its hemostatic function for a prolonged duration

Inventive Principle:

Principle #11Beforehand cushioning (Prior cushioning)

Data Source

PatentUS8470557B2Isolated nucleic acids encoding activated factor V and methods for production thereof

Publication Date: 2013.06.25 THE CHILDRENS HOSPITAL OF PHILADELPHIA

AI summary

Methods for the treatment of coagulation disorders using Factor V/Va variants are provided.