Modified Factor VIII and IX Genes for Hemophilia Gene Therapy

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Solution Overview

Problem

Current gene therapy approaches for treating hemophilia A and B face challenges due to immune activation by viral vectors and difficulties in achieving sufficient protein expression, leading to high viral vector doses and transient therapeutic levels.

Innovation Solution

Development of modified Factor VIII and Factor IX genes with optimized CG sequences and reduced cis motifs, integrated into chimeric virus vectors and administered using recombinant virus vectors or Biological Nano Particles to enhance gene expression and reduce immune response, allowing for lower viral vector doses and sustained therapeutic levels.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Productivity

If viral vectors are used to deliver FVIII or FIX genes, then gene delivery efficiency is improved, but immune system activation occurs

Engineering Contradiction:

Improvegene delivery efficiencyVSAvoidimmune system activation

Core Design Contradiction:

ProductivityVSObject-affected harmful factors

Solution Approach 1:

The patent modifies the FVIII or FIX gene sequences to include immune system recognition signals that actively engage the immune system in a beneficial way. The modified genes encode proteins with altered amino acid sequences that include epitopes capable of stimulating immune responses, thereby converting the harmful immune activation into a therapeutic benefit by enhancing antigen presentation and immune system engagement for treatment purposes

Inventive Principle:

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

2Quantity of substance

If high viral vector doses are administered to achieve sufficient protein expression, then therapeutic protein levels are improved, but immune activation and toxicity increase

Engineering Contradiction:

Improvetherapeutic protein expression levelVSAvoidimmune activation and toxicity

Core Design Contradiction:

Quantity of substanceVSObject-affected harmful factors

Solution Approach 1:

The patent applies codon optimization to the FVIII or FIX gene sequences, modifying the nucleotide composition (increasing CG content) and removing cis-acting motifs that inhibit expression. These parameter changes in the gene sequence enable significantly higher protein expression levels from lower viral vector doses, thereby achieving therapeutic protein levels without the need for high-dose administrations that cause immune activation and toxicity

Inventive Principle:

Principle #35Parameter changes

3Reliability

If standard FVIII or FIX genes are used, then genetic fidelity is maintained, but protein expression levels remain insufficient

Engineering Contradiction:

Improvegenetic fidelityVSAvoidprotein expression level

Core Design Contradiction:

ReliabilityVSProductivity

Solution Approach 1:

The patent modifies physical parameters of the gene sequence including increasing CG nucleotide content to optimize codon usage for mammalian expression systems and removing cis-acting motifs such as cryptic splice sites and premature polyadenylation signals. These parameter changes enhance transcriptional and translational efficiency, resulting in significantly improved protein expression levels while preserving the functional integrity and genetic fidelity of the FVIII or FIX gene

Inventive Principle:

Principle #35Parameter changes

Data Source

PatentUS9506052B2Modified factor VIII and factor IX genes

Publication Date: 2016.11.29 ASKBIO INC

AI summary

The present invention relates to a modified and optimized Factor VIII or Factor IX nucleic acid for inclusion in a chimeric virus vector. Use of such vector can be used for treatment of hemophilia.