HLA-Modified Cell Populations for Scalable Allogeneic Therapy
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Solution Overview
Problem
Current cellular therapies face challenges such as immune rejection, graft versus host disease (GVHD), consistency issues, scalability, and high costs due to HLA mismatching, making allogeneic and autologous cell transplants impractical and autologous cell banks inadequate for widespread use.
Innovation Solution
Development of HLA-modified cell populations, specifically HLA-Aneg, HLA-DPB1neg, and HLA-DQA1neg, which are homozygous for HLA-C*07:01, HLA-B*03:01, and HLA-B*08:01, or heterozygous for HLA-DPA1, and derived from iPSCs, to create immune-compatible cell banks covering global, ethnic, and disease-specific populations, using CRISPR-Cas9 gene editing to modify HLA genes.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If allogeneic cell transplants are used, then scalability and cost-effectiveness are improved, but immune rejection and graft versus host disease occur due to HLA mismatching
Solution Approach 1:
The patent applies parameter changes by modifying the HLA genotype parameters of the cells through CRISPR-Cas9 gene editing. Specifically, the cells are edited to have homozygous HLA-C*07:01, HLA-B*03:01, and HLA-B*08:01 alleles, which changes the HLA profile to reduce immunogenicity while maintaining scalability for allogeneic use.
Solution Approach 2:
The patent extracts and removes specific HLA alleles (HLA-A, HLA-DP, HLA-DQ) through CRISPR-Cas9-mediated gene editing. By deleting or inactivating these HLA genes, the cells lose the ability to present certain antigens, thereby reducing immune recognition and rejection while enabling broader allogeneic compatibility.
2Reliability
If HLA-modified cell banks are created, then immune compatibility is improved, but manufacturing complexity increases due to gene editing requirements
Solution Approach 1:
The patent applies preliminary action by performing HLA gene editing on cells before they are used for therapy. The CRISPR-Cas9 system is used to pre-modify the HLA genotype of the cells in advance, so that when the cells are administered to patients, they already have the desired HLA profile for reduced immunogenicity, eliminating the need for complex post-transplant modifications.
Solution Approach 2:
The patent creates cell banks with standardized HLA profiles that can be replicated and scaled. By establishing master cell lines with specific HLA modifications (homozygous HLA-C*07:01, HLA-B*03:01, HLA-B*08:01), the same genetically modified cells can be produced multiple times through cell division and expansion, simplifying manufacturing while maintaining consistent immune compatibility.
3Stability of the object's composition
If autologous cell banks are used, then consistency is improved, but scalability and affordability are reduced
Solution Approach 1:
The patent creates universal cell banks with standardized HLA modifications that can serve multiple patients across different populations. The cells are edited to have common HLA alleles (such as HLA-C*07:01, HLA-B*03:01, HLA-B*08:01) that are representative of various ethnic groups, making the same cell bank applicable to multiple recipients while maintaining consistency in the cell composition.
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 HLA-modified cells provide immune compatibility, reducing GVHD and graft rejection, ensuring scalability and cost-effectiveness, and enabling allogeneic cell therapies that are consistent across diverse populations.
Implementation Method 1
using CRISPR-Cas9 gene editing to modify HLA genes
Data Source
AI summary
In the various aspects and embodiments, the present disclosure provides cell populations or cell “banks” thereof to provide immune compatible, allogeneic cell therapies. In the various aspects and embodiments, the cell populations and progeny thereof maintain sufficient HLA Class I and HLA Class II functionalities, while facilitating patient matching to prevent or reduce graft versus host disease (GVHD) or graft rejection. The disclosure further provides methods for creating the populations by gene editing, and methods for cell therapy involving cells or tissues derived from the cell populations (including but not limited to hematopoietic stem cells, or “HSCs”, progenitors, or progenies thereof).