DNMT3A Gene Modification in T Cells for Cancer Therapy

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Solution Overview

Problem

Current cancer treatments, such as chemotherapy, are not effective for all cancer types, and immune cells like T cells often become exhausted during chronic infections, limiting their ability to target cancerous cells effectively due to de novo DNA methylation programming.

Innovation Solution

Genetic modification of the DNMT3A gene in immune cells, specifically using zinc-finger nucleases, CRISPR/Cas systems, or TALEN nucleases to disrupt DNA methylation, combined with the expression of chimeric antigen receptors (CARs) and immune checkpoint blockade therapies, to enhance antigen-specific T cell functions and longevity.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If T cells are genetically modified to bind cancer surface proteins, then the ability to target cancerous cells is improved, but the cells become exhausted during chronic infections limiting their effectiveness

Engineering Contradiction:

Improvecancer targeting effectivenessVSAvoidT cell longevity

Core Design Contradiction:

ReliabilityVSDuration of action of moving object

Solution Approach 1:

The patent extracts and removes the DNMT3A gene from T cells to eliminate the source of harmful DNA methylation that causes T cell exhaustion. By taking out this specific gene responsible for epigenetic silencing, the invention prevents the gradual loss of T cell functionality while maintaining their cancer-targeting capabilities over extended periods

Inventive Principle:

Principle #2Taking out (Extraction)

Solution Approach 2:

The patent converts the harmful effect of DNA methylation (which causes T cell exhaustion) into a benefit by specifically targeting and removing the DNMT3A gene. This selective removal eliminates the exhaustion mechanism while preserving other essential T cell functions, thereby extending their operational lifespan and effectiveness in cancer therapy

Inventive Principle:

Principle #22Blessing in disguise (Convert harm into benefit)

2Duration of action of stationary object

If DNMT3A gene is deleted to prevent DNA methylation, then T cell exhaustion is reduced and longevity is improved, but the complexity of genetic modification increases

Engineering Contradiction:

ImproveT cell longevityVSAvoidgenetic modification complexity

Core Design Contradiction:

Duration of action of stationary objectVSDevice complexity

Solution Approach 1:

The patent introduces CRISPR-Cas9 nuclease as an intermediary tool to achieve precise DNMT3A gene deletion. This molecular machinery acts as a mediator that guides site-specific DNA cutting and repair, enabling clean gene removal without requiring complex multiple gene editing operations, thus managing the complexity of the genetic modification process

Inventive Principle:

Principle #24Intermediary (Mediator)

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 modified immune cells maintain functionality and longevity, effectively targeting cancer cells or chronic infections by preventing exhaustion, thereby enhancing immune responses and improving treatment outcomes.

Implementation Method 1

the use of zinc-finger nucleases, CRISPR/Cas systems, or TALEN nucleases in order to institute sequence specific or non-specific double strand breaks

Methodology Applied

Scientific EffectDNA double-strand break:

Implementation Method 2

it is believed that nonhomologous end joining (NHEJ) or homology-directed repair (HDR) mechanisms in the cells results in nucleotide alterations, insertions, or deletions that disrupt gene expression

Methodology Applied

Scientific EffectNonhomologous end joining:

Implementation Method 3

it is believed that nonhomologous end joining (NHEJ) or homology-directed repair (HDR) mechanisms in the cells results in nucleotide alterations, insertions, or deletions that disrupt gene expression

Methodology Applied

Scientific EffectHomology-directed repair:

Implementation Method 4

DNA methylation typically occurs at cytosine in cytosine guanosine dinucleotides (CpG) within the DNA of mammals and is broadly used during cellular differentiation to repress transcription

Methodology Applied

Scientific EffectDNA methylation:

Implementation Method 5

Mammalian DNA methylation is predominantly catalyzed by DNA methyltransferases (Dnmt)

Methodology Applied

Scientific EffectDNA methyltransferase catalysis:

Data Source

PatentUS12161671B2Immune cells with DNMT3A gene modifications and methods related thereto

Publication Date: 2024.12.10 EMORY UNIVERSITY

AI summary

This disclosure relates to the genetic modification of DNMT3A gene in immune cells. In certain embodiments, the modified immune cells may be used in adoptive T cells therapies to enhance immune responses against cancer or chronic infections. In certain embodiments, the disclosure relates to deleting, changing, or inserting nucleotides within the DNMT3A gene in immune cells, e.g., human CD8 T cells, such that the DNMT3A gene product does not function for methylation. In certain embodiments, modification of the DNMT3A gene provides an improvement in antigen-specific T cells functions and/or an enhancement of the longevity of the cells.