CD34 Gene Modification for CAR-T Safety
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Solution Overview
Problem
Immunotherapies like CAR-T therapy can cause 'on-target, off-disease' effects, where healthy cells expressing the targeted antigen are depleted, leading to severe side effects or rendering the therapy ineffective due to shared antigen expression on both malignant and healthy cells.
Innovation Solution
Genetically engineered hematopoietic cells with modified CD34 genes, such as INDEL mutations or exon skipping, are developed to reduce or eliminate CD34 expression, making them resistant to immunotherapeutic agents targeting CD34, thereby replacing or replenishing healthy cell populations.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If immunotherapeutic agents targeting CD34 are administered to deplete malignant cells, then the therapeutic effect against cancer is improved, but healthy hematopoietic stem cells expressing CD34 are also depleted causing severe side effects
Solution Approach 1:
The patent applies local quality by creating heterogeneous cell populations with different CD34 expression levels. Healthy HSCs are engineered to have reduced or variant CD34 expression, while malignant cells retain normal CD34 expression. This allows the immunotherapeutic agent to selectively target malignant cells while sparing the genetically modified healthy cells, resolving the contradiction between therapeutic efficacy and healthy cell preservation
Solution Approach 2:
The patent changes the CD34 expression parameter in healthy HSCs through genetic engineering. By reducing CD34 expression levels or creating variant forms that are not recognized by the immunotherapeutic agent, the healthy cells become distinguishable from malignant cells based on their CD34 parameter, enabling selective targeting of malignant cells without harming healthy cells
2Object-affected harmful factors
If genetically engineered cells with reduced CD34 expression are administered to evade immunotherapeutic killing, then healthy cell population preservation is improved, but the complexity of cell engineering and administration increases
Solution Approach 1:
The patent applies self-service by using the patient's own hematopoietic stem cells as the source for genetic engineering. The autologous HSCs are harvested, genetically modified ex vivo to reduce CD34 expression, and then reinfused into the patient. This self-service approach avoids the complexities of finding and matching donor cells, reducing immunogenicity issues, and simplifying the overall treatment protocol while still achieving the goal of preserving healthy cells
Data Source
AI summary
Provided herein are gRNA comprising a targeting domain that targets CD34, which may be used, for example, to make modifications in cells. Also provided herein are methods of genetically engineered cell having a modification (e.g., insertion or deletion) in the CD34 gene and methods involving administering such genetically engineered cells to a subject, such as a subject having a hematopoietic malignancy.