Genetically Modified Extracellular Vesicles for Corneal Transparency

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Solution Overview

Problem

Current treatments for ocular surface blinding disorders (OSBD) are inadequate, particularly for conditions like limbal stem cell deficiency (LSCD), as they fail to restore the limbal stem cell niche and often result in corneal scarring, fibrosis, and vision loss, with existing therapies like allogenic corneal grafts and autologous epithelial cell transplants having limitations such as rejection risks and incomplete vision restoration.

Innovation Solution

The use of extracellular vesicles (EVs) produced by genetically modified mesenchymal stromal cells expressing recombinant Paired Box 6 (rPAX6) and type VII Collagen (rCOL7A1) to promote corneal epithelial regeneration, restore epithelial-stromal interactions, and prevent fibrosis, offering a flexible and safe alternative for tissue regeneration and immune modulation.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Illumination intensity

If allogenic corneal graft is used to restore vision by replacing opaque stroma, then corneal transparency is restored, but the limbal stem cell niche cannot be restored and rejection risk remains

Engineering Contradiction:

Improvecorneal transparencyVSAvoidrejection risk

Core Design Contradiction:

Illumination intensityVSReliability

Solution Approach 1:

The patent uses extracellular vesicles (EVs) as an intermediary carrier to deliver recombinant PAX6 and COL7A1 proteins/mRNAs to the corneal tissue. These EVs act as a mediator that promotes limbal stem cell regeneration and basement membrane restoration without direct cell transplantation, thereby avoiding rejection risks while restoring corneal transparency and the stem cell niche

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The patent replaces the mechanical surgical intervention of corneal grafting with a biochemical approach using genetically modified EVs. Instead of physically transplanting cells or tissue, the therapy uses EVs to deliver therapeutic molecules that stimulate endogenous regeneration, substituting a surgical mechanical system with a molecular biochemical system

Inventive Principle:

Principle #28Mechanics substitution (Replace mechanical system)

2Reliability

If autologous epithelial cell transplantation (COMET) is performed to treat OSBD, then epithelial coverage is achieved, but significant and long-lasting vision improvement is rarely achieved and corneal stromal neovascularization may be induced

Engineering Contradiction:

Improveepithelial coverageVSAvoidvision restoration effectiveness

Core Design Contradiction:

ReliabilityVSEase of manufacture

Solution Approach 1:

The patent changes the therapeutic parameters by using genetically modified EVs that overexpress specific molecules (recombinant PAX6 and COL7A1) rather than simply transplanting epithelial cells. This parameter change in the therapeutic approach enables not only epithelial coverage but also promotes basement membrane restoration and stem cell niche regeneration, leading to sustained vision improvement without neovascularization

Inventive Principle:

Principle #35Parameter changes

3Reliability

If MSC therapy is used to treat corneal scarring, then tissue regeneration is promoted, but repeated injections or surgeries are needed and cell survival and migration cannot be controlled

Engineering Contradiction:

Improvetissue regenerationVSAvoidtreatment frequency

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent extracts the therapeutic components (PAX6 and COL7A1 proteins/mRNAs) from the complex living MSC system and encapsulates them in EVs. This extraction simplifies the treatment by delivering only the essential therapeutic molecules needed for tissue regeneration, eliminating the need for repeated administrations and providing controlled, sustained action without the complexity of live cell therapy

Inventive Principle:

Principle #2Taking out (Extraction)

4Object-affected harmful factors

If chronic EBM disruption occurs leading to abnormal epithelial-stromal interactions, then massive induction of matrix proteolytic enzymes occurs causing corneal lysis and irregular scarring, but rapid epithelial healing is needed to prevent these outcomes

Engineering Contradiction:

Improvecorneal lysis and scarringVSAvoidepithelial healing speed

Core Design Contradiction:

Object-affected harmful factorsVSSpeed

Solution Approach 1:

The patent applies preliminary action by using EVs to deliver recombinant PAX6 and COL7A1 that pre-establish the basement membrane structure and promote early epithelial-stromal interactions. This preliminary restoration of the basement membrane prevents the subsequent massive induction of matrix proteolytic enzymes and corneal lysis, enabling rapid healing before harmful processes can occur

Inventive Principle:

Principle #10Preliminary action

Data Source

PatentUS20250017865A1Extracellular vesicles or composition thereof for use as a medicament, such as for the treatment of ocular surface disorders

Publication Date: 2025.01.16 FONDATION A DE ROTHSCHILD

AI summary

The invention provides extracellular vesicles (EVs) or composition thereof for use as a medicament, in particular for use in the treatment or the prevention of an ocular surface blinding disorder (OSBD), wherein said EVs are produced by a genetically modified cell comprising one or more recombinant nucleic acid sequence(s) expressing recombinant Paired Box 6 (rPAX6) and/or recombinant type VII Collagen (rCOL7A1).