MBP-Specific Regulatory T Cells With Stable FOXP3 Epigenome

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Solution Overview

Problem

There are no approved therapies for non-relapsing progressive multiple sclerosis, and existing methods for generating regulatory T cells for treating autoimmune diseases, such as those with engineered FOXP3 expression, lack stability and efficacy due to functional instability and epigenomic differences from natural Tregs.

Innovation Solution

A stable population of CD4+ T regulatory cells (T regs) with a hypomethylated T cell-specific demethylated region (TSDR) at the FOXP3 locus and engineered to express a myelin basic protein (MBP)-specific T cell receptor (TCR) are produced, ensuring high purity and stability, using a method that includes isolating CD4+CD25+CD127−/lo cells and transducing them with a lentiviral vector encoding the TCR.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Ease of manufacture

If engineered FOXP3 expression is used to generate regulatory T cells, then regulatory T cell production is achieved, but functional stability and epigenomic fidelity deteriorate

Engineering Contradiction:

Improveregulatory T cell productionVSAvoidfunctional stability

Core Design Contradiction:

Ease of manufactureVSReliability

Solution Approach 1:

Instead of engineering FOXP3 expression in conventional T cells (which produces unstable cells), the invention inverts the approach by isolating natural regulatory T cells that already express FOXP3 and engineering them with antigen-specific TCRs. This preserves the stable epigenomic foundation of natural Tregs while adding the desired antigen specificity through TCR transduction.

Inventive Principle:

Principle #13The other way round (Inversion)

Solution Approach 2:

The invention separates the regulatory T cell generation process into distinct segments: (1) isolation of natural Tregs with stable FOXP3 expression, and (2) engineering of antigen-specificity through TCR transduction. This segmentation allows preservation of the stable regulatory phenotype while adding therapeutic antigen specificity.

Inventive Principle:

Principle #1Segmentation

2Adaptability or versatility

If conventional T cell engineering methods are used, then antigen-specific T cells are produced, but regulatory function and epigenomic fidelity deteriorate

Engineering Contradiction:

Improveantigen specificityVSAvoidepigenomic stability

Core Design Contradiction:

Adaptability or versatilityVSStability of the object's composition

Solution Approach 1:

The invention reverses the conventional engineering approach by starting with cells that already have the desired regulatory epigenome and adding antigen specificity, rather than starting with conventional T cells and attempting to induce regulatory function. This ensures epigenomic stability is maintained while achieving antigen specificity.

Inventive Principle:

Principle #13The other way round (Inversion)

Solution Approach 2:

The invention applies local quality modification by introducing only the TCR component (antigen recognition function) into otherwise native regulatory T cells. This localized engineering approach preserves the global epigenomic stability and regulatory phenotype of the host cells while providing the specific antigen-binding capability needed for therapeutic effect.

Inventive Principle:

Principle #3Local quality

3Quantity of substance

If regulatory T cells are expanded for therapeutic use, then cell quantity increases, but functional stability may deteriorate

Engineering Contradiction:

ImproveT reg cell numberVSAvoidfunctional stability

Core Design Contradiction:

Quantity of substanceVSReliability

Solution Approach 1:

The invention performs preliminary selection and characterization of Tregs before expansion, ensuring that only cells with stable FOXP3 expression and appropriate phenotype are subjected to expansion protocols. This preliminary action establishes a stable foundation that maintains functional integrity during subsequent proliferation.

Inventive Principle:

Principle #10Preliminary action

Solution Approach 2:

The invention employs feedback monitoring of FOXP3 expression and Treg phenotype markers during and after expansion to ensure functional stability is maintained. Cells that lose their regulatory phenotype during expansion can be identified and removed, ensuring only stable, functional Tregs are used for therapy.

Inventive Principle:

Principle #23Feedback

Applied Scientific Principles

This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.

Function Achieved in This Case

The engineered T regs specifically target myelin-degraded tissues, suppress local inflammation, and maintain therapeutic efficacy for extended periods without causing systemic immune suppression, providing a stable treatment for progressive multiple sclerosis.

Implementation Method 1

transducing them with a lentiviral vector encoding the TCR

Methodology Applied

Scientific EffectLentiviral transduction:

Implementation Method 2

at least 80% of the cells are stable CD4+ T regs comprising a hypomethylated T cell specific demethylated region (TSDR) at the FOXP3 locus

Methodology Applied

Scientific EffectDNA hypomethylation:

Data Source

PatentUS20260034215A1Cell therapies for multiple sclerosis

Publication Date: 2026.02.05 ABATA THERAPEUTICS INC

AI summary

The present disclosure is directed to isolated cell populations comprising stable regulatory T cells and methods of producing the same.