AAV2/5 Vector Transduction for Retinal Pigment Epithelium Gene Delivery

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Solution Overview

Problem

Current methods for treating inherited retinal dystrophies, such as choroideremia, face challenges in efficiently delivering therapeutic genes to the retinal pigment epithelium, limiting the effectiveness of gene therapy.

Innovation Solution

The use of reprogrammed REP1-deficient fibroblasts into induced pluripotent stem cells (iPSc) differentiated into retinal pigment epithelium (RPE) cells, combined with the AAV2/5 vector for transducing polynucleotides of interest, specifically targeting and correcting genetic defects in RPE cells.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If conventional AAV vectors are used for gene delivery to retinal pigment epithelium, then gene therapy can be administered, but transduction efficiency is insufficient to achieve effective treatment

Engineering Contradiction:

Improvetransduction efficiencyVSAvoidgene delivery effectiveness

Core Design Contradiction:

ReliabilityVSProductivity

Solution Approach 1:

The invention changes the serotype parameter of the AAV vector from conventional types (AAV2, AAV8) to AAV5, which demonstrated superior transduction efficiency in RPE cells. This parameter change in vector selection directly resolves the contradiction by achieving both high reliability of transduction and effective productivity of gene delivery

Inventive Principle:

Principle #35Parameter changes

2Reliability

If the retina is targeted for gene therapy, then treatment of inherited retinal dystrophies is achieved, but the blood-retina barrier prevents efficient vector delivery

Engineering Contradiction:

Improvegene therapy efficacyVSAvoidvector delivery difficulty

Core Design Contradiction:

ReliabilityVSEase of operation

Solution Approach 1:

The invention uses the subretinal space as an intermediary delivery route that bypasses the blood-retina barrier. By injecting the AAV5 vector directly into the subretinal space, the barrier is circumvented while still achieving targeted delivery to RPE cells, thus maintaining both therapy efficacy and delivery feasibility

Inventive Principle:

Principle #24Intermediary (Mediator)

3Productivity

If high vector doses are used to overcome delivery barriers, then gene delivery to retina is improved, but leakage into circulation increases reducing immuno-privilege

Engineering Contradiction:

Improvegene delivery to retinaVSAvoidimmuno-privilege maintenance

Core Design Contradiction:

ProductivityVSReliability

Solution Approach 1:

The invention changes the vector serotype parameter to AAV5, which has higher transduction efficiency in RPE cells. This allows achievement of effective gene delivery at lower doses, thereby maintaining the immuno-privileged status of the retina and preventing leakage into circulation

Inventive Principle:

Principle #35Parameter changes

Data Source

PatentUS10105452B2Methods and pharmaceutical compositions for expressing a polynucleotide of interest in the retinal pigment epithelium of a subject

Publication Date: 2018.10.23 INST NAT DE LA SANTE & DE LA RECHERCHE MEDICALE (INSERM)

AI summary

The present invention relates to methods and pharmaceutical compositions for expressing a polynucleotide of interest in the retinal pigment epithelium of a subject. In particular, the present invention relates to a method for selectively expressing a polynucleotide of interest in the retinal pigment epithelium in an eye of a subject in need thereof comprising the step of transducing the retinal pigment epithelium with an amount of a rAAV2/5 vector containing the polynucleotide of interest.