B2M-Deficient Cells for Universal Donor Compatibility

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Solution Overview

Problem

The clinical use of human pluripotent stem cells is limited by rejection due to differences in the major histocompatibility complex (MHC), requiring costly and time-consuming processes for individualized HLA-matched cell lines, which impedes the development of stem cell-based therapies.

Innovation Solution

Genetically engineered primate cells, preferably human cells, with disruptions in the beta-2 microglobulin (B2M) gene to prevent HLA class I protein expression, combined with recombinant immunomodulatory genes such as single chain fusion HLA class I proteins, are developed to reduce immunogenicity and facilitate universal donor compatibility.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If HLA-matched cell lines are developed for each patient, then immune rejection is reduced, but the process becomes costly and time-consuming

Engineering Contradiction:

Improveimmune compatibilityVSAvoidcell culture time

Core Design Contradiction:

ReliabilityVSLoss of time

Solution Approach 1:

The invention extracts and removes the beta-2 microglobulin component from the HLA class I molecule through genetic disruption. By eliminating this essential component, the cell loses the ability to express functional HLA class I molecules, thereby preventing immune recognition and rejection without requiring individualized matching procedures

Inventive Principle:

Principle #2Taking out (Extraction)

Solution Approach 2:

The invention changes the immunological parameters of the cell by disrupting the B2M gene, fundamentally altering the cell's HLA expression profile. This parameter change transforms the cell from being immunologically recognized (and thus rejectable) to being immunologically invisible to CD8+ T cells, achieving universal donor status

Inventive Principle:

Principle #35Parameter changes

2Reliability

If HLA-matched cell lines are developed for each patient, then immune rejection is reduced, but the cost increases significantly

Engineering Contradiction:

Improveimmune compatibilityVSAvoidmanufacturing cost

Core Design Contradiction:

ReliabilityVSEase of manufacture

Solution Approach 1:

The invention creates a universal cell product that can be used for any patient regardless of HLA type. By disrupting B2M in the parent cell line, all descendant cells inherit this trait, allowing a single cell product to serve multiple patients without requiring individualized HLA matching, thereby reducing manufacturing costs

Inventive Principle:

Principle #6Universality (Multi-functionality)

3Reliability

If individualized stem cell preparations are developed, then transplantation success is improved, but the process becomes technically difficult and expensive

Engineering Contradiction:

Improvetransplantation successVSAvoidcell line characterization complexity

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The invention performs the immunological matching action in advance during cell line development by disrupting the B2M gene. This preliminary genetic modification ensures that all future cell products from this line will be universally compatible, eliminating the need for complex individualized characterization and matching procedures for each patient

Inventive Principle:

Principle #10Preliminary action

Data Source

PatentUS20240207378A1Beta-2 microglobulin-deficient cells

Publication Date: 2024.06.27 UNIVERSITY OF WASHINGTON THROUGH ITS CENTER FOR COMMERCIALIZATION

AI summary

The invention provides isolated primate cells preferably human cells that comprise a genetically engineered disruption in a beta-2 microglobulin (B2M) gene, which results in deficiency in MHC class I expression and function. Also provided are the method of using the cells for transplantation and treating a disease condition.