Genetically Modified Microglia for CSF1R Antagonist Resistance
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Solution Overview
Problem
Current therapies for neurological diseases involving microglia impairments or alterations are ineffective, and existing CSF1R antagonists used to treat cancer paradoxically kill human microglia, limiting the engraftment of transplanted therapeutic microglia in the central nervous system.
Innovation Solution
Development of human microglia with modified CSF1R proteins exhibiting differential resistance to CSF1R antagonists, allowing them to survive and proliferate in the presence of these inhibitors, thereby facilitating their engraftment and treatment of neurological diseases.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If CSF1R antagonists are used to treat neurological diseases, then microglia can be modified to achieve resistance, but the antagonists will kill endogenous microglia
Solution Approach 1:
The patent modifies the CSF1R receptor protein parameters (amino acid sequence, phosphorylation sites, ligand binding domains) to create resistance mutations. These parameter changes allow therapeutic microglia to survive CSF1R antagonist treatment while endogenous microglia are eliminated, achieving selective pressure for engraftment.
Solution Approach 2:
The patent converts the harmful effect of CSF1R antagonist-induced microglia death into a beneficial selective pressure mechanism. By making therapeutic microglia resistant through genetic modification, the cell death of endogenous microglia becomes a useful tool for clearing the way for therapeutic cell engraftment and establishment.
2Productivity
If therapeutic microglia are transplanted into the CNS, then they can occupy the microglial niche, but they will be killed by CSF1R inhibition
Solution Approach 1:
The patent applies preliminary action by generating CSF1R-resistant microglia in vitro before transplantation. The microglia are pre-modified with resistance mutations (e.g., in the CSF1R ligand binding domain or phosphorylation sites) so that they are already equipped to survive the post-transplantation CSF1R antagonist treatment, ensuring their establishment in the host CNS.
3Quantity of substance
If CSF1R antagonists are administered at high doses to kill endogenous microglia, then therapeutic engraftment is facilitated, but therapeutic microglia may also be affected
Solution Approach 1:
The patent introduces parameter changes in the CSF1R receptor structure, specifically modifying amino acid residues in the ligand binding domain or phosphorylation sites. These changes alter the pharmacological parameters of the receptor, creating a dose-response divergence where endogenous microglia remain sensitive to CSF1R antagonists at therapeutic doses, while modified microglia exhibit resistance.
Data Source
AI summary
Microglia/monocytes exist within a ‘niche’ which limits the total number of microglia/monocytes/macrophages that reside within a mammalian central nervous system (CNS). Therefore, methods are needed that can help therapeutically modify microglia, monocytes, and macrophages or the cells that give rise to them to compete with endogenous microglia and partially or completely occupy the CNS niche. The present disclosure features therapeutic microglia, monocytes, or macrophages that have a selective advantage in comparison to endogenous brain resident microglia in their response to CSF1R inhibitors. Specifically, therapeutic cells developed in the present disclosure do not die at a given dose of CSF1R inhibitor that is sufficient to kill endogenous microglia. The therapeutic cells described herein can be used to treat neurological diseases.