CLL1 Gene Editing for Hematopoietic 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, created using guide RNAs (gRNAs) that target and edit the CLL1 gene, are administered to patients to reduce CLL1 expression, thereby protecting noncancerous cells from 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 achieved, but noncancerous CLL1+ hematopoietic cells are also depleted causing hematopoietic system depletion
Solution Approach 1:
The invention divides the CLL1 gene into two separate target sequences (SEQ ID NO: 1 and SEQ ID NO: 2) that are both necessary for functional CLL1 expression. The anti-CLL1 therapy targets one sequence while the rescue cells are engineered to have a modification in the other sequence, allowing selective protection of rescue cells while maintaining cancer cell vulnerability.
Solution Approach 2:
The invention applies local quality by making specific modifications at particular locations in the CLL1 gene (either SEQ ID NO: 1 or SEQ ID NO: 2) in rescue cells, while leaving the other sequence intact. This localized modification approach allows the rescue cells to retain resistance to anti-CLL1 therapy while maintaining normal hematopoietic function.
2Reliability
If rescue cells modified in the CLL1 gene are administered to repopulate the hematopoietic system, then hematopoietic repopulation is achieved, but the complexity of cell engineering increases
Solution Approach 1:
The invention extracts only the essential modification needed for therapy resistance - a specific modification in either SEQ ID NO: 1 or SEQ ID NO: 2 of the CLL1 gene. This minimal extraction approach reduces engineering complexity compared to complete gene replacement or multiple gene modifications, while still achieving the desired rescue cell functionality.
Solution Approach 2:
The invention changes specific parameters of the CLL1 gene sequence (introducing modifications at defined positions in SEQ ID NO: 1 or SEQ ID NO: 2) rather than altering the entire gene structure. This parameter-based modification approach simplifies the engineering process while maintaining the ability to confer therapy resistance and enable hematopoietic repopulation.
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, minimizing the depletion of noncancerous hematopoietic cells during anti-CLL1 therapy, allowing for the repopulation of the hematopoietic system and reducing the cytotoxic effects of the treatment.
Implementation Method 1
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 CLL1 gene. The disclosure also provides compositions, e.g., gRNAs, that can be used to make such a modification.