rAAV Gene Therapy for Sustained Ocular TNF-alpha Inhibition

Solution Overview

Problem

Current treatments for non-infectious uveitis require frequent injections of anti-TNFα therapies, leading to a significant treatment burden for patients and potential systemic toxicity, while existing immunomodulatory therapies may not provide sustained or consistent levels of biologic inhibitors at the site of action.

Innovation Solution

The use of recombinant adeno-associated virus (rAAV) gene therapy to deliver a fully human post-translationally modified anti-TNFα Fc fusion protein, such as etanercept or EYS606, directly to the eye or liver, creating a depot for sustained expression and reducing the need for frequent injections by providing a consistent level of biologic inhibitor.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If repeated injections of anti-TNFα therapies are administered, then treatment efficacy is maintained, but treatment burden and patient discomfort increase

Engineering Contradiction:

Improvetreatment efficacyVSAvoidtreatment burden

Core Design Contradiction:

ReliabilityVSEase of operation

Solution Approach 1:

The patent applies self-service by enabling the patient's own body to produce and secrete the anti-TNFα Fc fusion protein through transduced ocular tissues. The gene therapy delivers the therapeutic transgene to ocular cells, which then autonomously express and secrete the biologic inhibitor, eliminating the need for external injection administration and reducing treatment burden while maintaining efficacy.

Inventive Principle:

Principle #25Self-service

Solution Approach 2:

The patent implements continuity of useful action by establishing long-term sustained expression of the anti-TNFα Fc fusion protein through integrated gene therapy. The transgene is expressed continuously by ocular tissues over extended periods, providing persistent therapeutic activity without requiring repeated dosing intervals, thus maintaining treatment efficacy while reducing administration frequency.

Inventive Principle:

Principle #20Continuity of useful action

2Reliability

If conventional immunomodulatory therapies are used, then inflammation is controlled, but sustained or consistent levels of biologic inhibitor at the site of action are not achieved

Engineering Contradiction:

Improveinflammation controlVSAvoidconsistency of biologic inhibitor levels

Core Design Contradiction:

ReliabilityVSStability of the object's composition

Solution Approach 1:

The patent applies self-service by enabling the patient's own body to produce and secrete the anti-TNFα Fc fusion protein through transduced ocular tissues. The gene therapy delivers the therapeutic transgene to ocular cells, which then autonomously express and secrete the biologic inhibitor, eliminating the need for external injection administration and reducing treatment burden while maintaining efficacy.

Inventive Principle:

Principle #25Self-service

Solution Approach 2:

The patent implements parameter changes by transitioning from exogenous administration of biologic inhibitors to endogenous production through gene therapy. This fundamental parameter change from external supply to internal synthesis enables consistent and sustained therapeutic levels at the site of action, improving both reliability of inflammation control and stability of inhibitor levels.

Inventive Principle:

Principle #35Parameter changes

3Reliability

If frequent ocular administration is performed, then therapeutic levels are maintained, but risk of systemi toxicity increases

Engineering Contradiction:

Improvetherapeutic level maintenanceVSAvoidsystemic toxicity risk

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent applies local quality by directing the gene therapy specifically to ocular tissues, where the transgene is expressed and the anti-TNFα Fc fusion protein is produced locally. This localized expression maintains therapeutic levels at the site of action (eye) while minimizing systemic exposure and reducing the risk of systemic toxicity associated with frequent ocular administrations.

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent implements continuity of useful action by establishing long-term sustained expression of the anti-TNFα Fc fusion protein through integrated gene therapy. The transgene is expressed continuously by ocular tissues over extended periods, providing persistent therapeutic activity without requiring repeated dosing intervals, thus maintaining treatment efficacy while reducing administration frequency.

Inventive Principle:

Principle #20Continuity of useful action

Data Source

PatentUS20240384292A1Vectorized TNF-alpha antagonists for ocular indications

Publication Date: 2024.11.21 REGENXBIO INC

AI summary

Provided are methods and compositions for the delivery of fully human post-translationally modified therapeutic TNF receptor Fc fusions. The fully human post-translationally modified therapeutic TNF receptor Fc fusions may be delivered by gene therapy methods, e.g., as a recombinant adeno-associated virus (rAAV) vector to the appropriate tissue. Also provided are methods of treating ocular indications such as non-infectious uveitis with the fully human post-translationally modified therapeutic TNF receptor Fc fusions.