Universal Donor Stem Cells with MHC Gene Editing

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Solution Overview

Problem

Existing cell replacement therapies face significant challenges due to immune rejection, limiting the effectiveness of human pluripotent stem cell-based treatments, despite strategies like HLA-matching and immunosuppressive drugs.

Innovation Solution

Genome editing tools such as TALEN and CRISPR are used to reduce or knock out MHC-I and MHC-II genes in human pluripotent stem cells, combined with the insertion of tolerogenic factors into a safe harbor locus to create hypoimmunogenic stem cells.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Adaptability or versatility

If human pluripotent stem cells are used for cell replacement therapy, then the potential to treat most degenerative illnesses is improved, but immune rejection by the subject's immune system worsens

Engineering Contradiction:

Improvetreatment potentialVSAvoidimmune rejection

Core Design Contradiction:

Adaptability or versatilityVSObject-affected harmful factors

Solution Approach 1:

The patent extracts and removes the harmful MHC-I and MHC-II genes from the stem cell genome using CRISPR/Cas9 genome editing technology. By specifically targeting and deleting these immunogenic molecules, the therapy eliminates the primary cause of immune rejection while preserving the therapeutic potential of pluripotent stem cells

Inventive Principle:

Principle #2Taking out (Extraction)

Solution Approach 2:

The patent introduces tolerogenic factors (such as HLA-G, PD-L1, or CTLA-4Ig) as intermediary molecules that mediate immune tolerance. These factors act as biological mediators that suppress immune activation and promote acceptance of the transplanted cells by the host immune system

Inventive Principle:

Principle #24Intermediary (Mediator)

2Reliability

If HLA-matching or immunosuppressive drugs are used to overcome immune rejection, then immune acceptance is improved, but treatment complexity and cost worsen

Engineering Contradiction:

Improveimmune acceptanceVSAvoidtreatment complexity

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent performs preliminary genome editing to create hypoimmunogenic stem cells before transplantation. By pre-modifying the cells to express tolerogenic factors and lack MHC molecules, the need for post-transplantation immunosuppression is eliminated, simplifying the overall treatment protocol

Inventive Principle:

Principle #10Preliminary action

Solution Approach 2:

The patent creates universal donor stem cell lines that can be used for multiple transplantations without requiring individual HLA matching. These standardized hypoimmunogenic cell lines serve as reusable therapeutic products that eliminate the need for complex immunosuppressive regimens in each patient

Inventive Principle:

Principle #27Cheap short-living objects (Disposable)

Data Source

PatentUS12421493B2Universal donor stem cells and related methods

Publication Date: 2025.09.23 PRESIDENT & FELLOWS OF HARVARD COLLEGE

AI summary

Disclosed herein are universal donor stem cells and related methods of their use and production. The universal donor stem cells disclosed herein are useful for overcoming the immune rejection in cell-based transplantation therapies. In certain embodiments, the universal donor stem cells disclosed herein do not express one or more MHC-I and MHC-II human leukocyte antigens. Similarly, in certain embodiments, the universal donor stem cells disclosed herein do not express one or more human leukocyte antigens (e.g., HLA-A, HLA-B and/or HLA-C) corresponding to MHC-I and MHC-II human leukocyte antigens, thereby rendering such cells hypoimmunogenic.