CD123-Modified Hematopoietic Stem Cells for Anti-CD123 Therapy
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Solution Overview
Problem
Anti-CD123 cancer therapies often deplete not only cancerous CD123+ cells but also noncancerous CD123+ cells, leading to hematopoietic system depletion, necessitating the use of rescue cells modified with CD123 gene modifications to repopulate the system.
Innovation Solution
Development of genetically engineered cells with modifications in the CD123 gene using guide RNAs (gRNAs) to create cells resistant to anti-CD123 therapy, allowing for targeted treatment while minimizing harm to noncancerous cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If anti-CD123 cancer therapy is administered to deplete CD123+ cancer cells, then cancer cell depletion is improved, but noncancerous CD123+ cells are also depleted causing hematopoietic system depletion
Solution Approach 1:
The patent applies local quality by creating hematopoietic stem cells with heterogeneous CD123 expression levels, where some cells maintain high CD123 expression for cancer cell targeting while others have reduced CD123 expression to escape therapy-induced depletion. This spatial and functional differentiation within the cell population allows simultaneous achievement of cancer cell depletion and hematopoietic system preservation
Solution Approach 2:
The patent employs parameter changes by modulating the CD123 expression level in hematopoietic stem cells through genetic modification. By altering the CD123 expression parameter to subtherapeutic or low levels, the engineered cells become resistant to anti-CD123 therapy while maintaining their hematopoietic function, thereby resolving the contradiction between cancer cell depletion and hematopoietic system preservation
2Reliability
If rescue cells with CD123 gene modification are administered to repopulate the hematopoietic system, then hematopoietic system recovery is improved, but the complexity of treatment increases
Solution Approach 1:
The patent applies preliminary action by pre-modifying hematopoietic stem cells with reduced CD123 expression before administration to cancer patients. These pre-engineered rescue cells are prepared in advance with genetic modifications that confer resistance to anti-CD123 therapy, enabling them to survive and repopulate the hematopoietic system during and after cancer cell depletion without requiring complex post-therapy interventions
Solution Approach 2:
The patent uses an intermediary approach by introducing genetically modified hematopoietic stem cells as a mediator between the anti-CD123 therapy and the hematopoietic system recovery. These intermediate cells serve as a bridge that protects the hematopoietic system from therapy-induced depletion while facilitating system recovery, simplifying the overall treatment architecture
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 cells effectively reduce CD123 expression in hematopoietic cells, mitigating the 'on-target, off-tumor' effect and enabling safer administration of anti-CD123 therapies by repopulating the hematopoietic system.
Implementation Method 1
A gRNA comprising a targeting domain which binds a target domain of Table 1
Data Source
AI summary
This disclosure provides, e.g., novel cells having a modification (e.g., insertion or deletion) in the endogenous CD 123 gene. The disclosure also provides compositions, e.g., gRNAs, that can be used to make such a modification.