CLL1-Modified Hematopoietic Cells for Anti-CLL1 Therapy Rescue
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Solution Overview
Problem
Anti-CLL1 cancer therapies often deplete both cancerous and noncancerous CLL1+ cells, leading to hematopoietic system depletion, necessitating the use of rescue cells modified to resist the therapy and repopulate the system.
Innovation Solution
Genetically engineered cells with modifications in the CLL1 gene, using guide RNAs (gRNAs) to direct cleavage or editing, are administered to patients receiving anti-CLL1 therapy, reducing CLL1 expression and minimizing therapy-induced depletion.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If anti-CLL1 cancer therapy is administered to deplete CLL1+ cancer cells, then cancer cell depletion is improved, but noncancerous CLL1+ cells are also depleted causing hematopoietic system depletion
Solution Approach 1:
The patent applies local quality by creating heterogeneous cell populations with different CLL1 expression levels. Normal hematopoietic stem cells are engineered to express low levels of CLL1 (below detection by anti-CLL1 antibodies), while cancer cells maintain high CLL1 expression. This spatial and functional differentiation allows the therapy to selectively target cancer cells while protecting engineered normal cells, resolving the contradiction between cancer cell depletion and hematopoietic system preservation.
Solution Approach 2:
The patent implements parameter changes by modifying the CLL1 expression level parameter in normal hematopoietic cells. Through CRISPR/Cas9-mediated gene editing, the CLL1 expression in normal cells is reduced to a threshold below which anti-CLL1 therapy does not bind effectively. This parameter modification creates a therapeutic window where cancer cells (high CLL1) are eliminated while engineered normal cells (low CLL1) are protected, simultaneously achieving cancer cell depletion and preventing hematopoietic system depletion.
2Reliability
If rescue cells are administered to repopulate the hematopoietic system, then hematopoietic system recovery is improved, but the cells must be genetically modified to resist anti-CLL1 therapy
Solution Approach 1:
The patent applies preliminary action by pre-engineering normal hematopoietic stem cells with reduced CLL1 expression before administering them as rescue cells. The CRISPR/Cas9 system is used ex vivo to modify the cells, ensuring they are resistant to anti-CLL1 therapy before transplantation. This preliminary genetic modification allows the rescue cells to survive and repopulate the hematopoietic system during and after cancer therapy, achieving reliable hematopoietic recovery while managing the complexity through controlled ex vivo editing.
Solution Approach 2:
The patent implements self-service by enabling the engineered hematopoietic stem cells to self-renew and self-differentiate into various blood cell lineages. The modified cells maintain their competitive advantage against anti-CLL1 therapy and can autonomously repopulate the entire hematopoietic system without requiring continuous external intervention. This self-service capability ensures sustained hematopoietic recovery and long-term protection against therapy-related depletion.
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 CLL1 expression, protecting noncancerous cells and allowing them to repopulate the hematopoietic system during or after anti-CLL1 therapy, thereby mitigating the 'on-target, off-tumor' effect.
Implementation Method 1
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Data Source
AI summary
This disclosure provides, e.g., novel cells having a modification (e.g., insertion or deletion) in the endogenous CLL1 gene. The disclosure also provides compositions, e.g., gRNAs, that can be used to make such a modification.