Treg Cell Persistence via miRNA Antagomir Knockdown

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Solution Overview

Problem

Adoptive cellular therapy using regulatory T (Treg) cells faces challenges in translating effectiveness from animal models to humans due to the high numbers of pure cells required and the short-term persistence of Treg cells, which affects their therapeutic potential in treating autoimmunity, organ rejection, and graft-versus-host disease.

Innovation Solution

The use of specific miRNA/mRNA pairs, such as miRNA-146b, miRNA-4484, and miRNA-155, is described to increase the survival, stability, and function of Treg cells by knocking down or inhibiting these microRNAs using antagomirs, thereby enhancing their suppressive function and persistence.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If high numbers of very pure Treg cells are used for adoptive cellular therapy, then suppressive function is improved, but cell persistence is reduced

Engineering Contradiction:

Improvesuppressive functionVSAvoidcell persistence

Core Design Contradiction:

ReliabilityVSDuration of action of moving object

Solution Approach 1:

The patent changes the molecular parameter of miRNA expression levels in Treg cells. By knocking down specific miRNAs (miR-146b, miR-4484, miR-155) using antagomirs, the patent modifies the genetic regulatory parameters of Treg cells to simultaneously improve their suppressive function and persistence, resolving the contradiction between these two parameters.

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent introduces antagomirs as intermediary molecules that mediate the knockdown of specific miRNAs in Treg cells. These antagomirs serve as the connecting mechanism between the desired outcome (improved suppressive function and persistence) and the molecular target (miRNA expression), enabling controlled modification of Treg cell properties.

Inventive Principle:

Principle #24Intermediary (Mediator)

2Stability of the object's composition

If miRNA knockdown is performed to increase Treg survival, then cell stability is improved, but therapeutic complexity increases

Engineering Contradiction:

Improvecell stabilityVSAvoidtherapeutic complexity

Core Design Contradiction:

Stability of the object's compositionVSDevice complexity

Solution Approach 1:

The patent employs antagomirs as transient, disposable therapeutic agents that temporarily knock down miRNAs in Treg cells. These short-acting molecules provide the necessary stability improvement without requiring permanent genetic modification, thereby limiting the increase in therapeutic complexity while achieving the desired cell stability enhancement.

Inventive Principle:

Principle #27Cheap short-living objects (Disposable)

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 approach demonstrated increased survival and suppressive function of Treg cells in vitro and in a xenogeneic model of GVHD, leading to improved therapeutic potential and prolonged persistence, suggesting a method to enhance the efficacy of Treg cell therapy.

Implementation Method 1

Representative nucleic acid molecules include RNA interference molecules

Methodology Applied

Scientific EffectRNA interference:

Data Source

PatentUS11390848B2Materials and methods for modifying the activity of T cells

Publication Date: 2022.07.19 REGENTS OF THE UNIVERSITY OF MINNESOTA

AI summary

This disclosure provides miRNA/mRNA pairs that can be used to increase the efficacy of T cells or to down-modulate T cell efficacy and restore equilibrium.