Pathology-Responsive Recombinant Microglia for BBB Delivery
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Solution Overview
Problem
The blood-brain barrier presents a significant hurdle to the delivery of therapeutic agents for treating central nervous system disorders, particularly for neurodegenerative diseases like Alzheimer's, Parkinson's, and ALS, as most macromolecules cannot penetrate the brain endothelium, and existing cellular delivery vehicles like human neural stem cells have safety concerns or require dangerous preconditioning.
Innovation Solution
Development of human microglia cells modified to express therapeutic molecules under amyloid beta-responsive promoters, allowing them to target and alter amyloid beta-related pathologies by reducing Aβ aggregates and enhancing phagocytosis, using a novel isolation and genetic engineering approach.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If macromolecules are used as therapeutic agents, then therapeutic efficacy is improved, but ability to cross the blood-brain barrier deteriorates
Solution Approach 1:
The patent uses engineered microglia cells as intermediary carriers to deliver therapeutic macromolecules across the blood-brain barrier. These cells naturally traverse the BBB and deliver their therapeutic payload directly to brain tissue, solving the contradiction between macromolecule efficacy and BBB penetration capability
Solution Approach 2:
The patent replaces the mechanical approach of directly administering macromolecules (which cannot cross the BBB) with a biological system (engineered microglia cells) that naturally possesses the ability to cross the BBB and deliver therapeutic cargo
2Adaptability or versatility
If human neural stem cells are used as cellular delivery vehicles, then therapeutic delivery capability is improved, but safety deteriorates due to tumorigenic potential
Solution Approach 1:
The patent uses microglia cells instead of neural stem cells as cellular vehicles. Microglia are short-lived immune cells that perform their therapeutic function and then naturally die off, eliminating the long-term tumorigenic risk associated with stem cells while maintaining therapeutic delivery capability
Solution Approach 2:
The patent changes the cell type parameter from neural stem cells to microglia, fundamentally altering the safety profile while preserving the therapeutic delivery function. This parameter change eliminates tumorigenic potential while maintaining the ability to deliver therapeutic agents to the brain
3Adaptability or versatility
If bone marrow stem cells are used as cellular delivery vehicles, then therapeutic delivery capability is improved, but safety deteriorates due to dangerous preconditioning requirements
Solution Approach 1:
The patent uses microglia cells that can be generated without dangerous preconditioning steps. These cells are produced through a safer differentiation process and serve as disposable therapeutic vehicles that deliver their payload and then die naturally, eliminating the need for risky bone marrow transplantation procedures
Data Source
AI summary
Modified cells that express and present or secrete at least one therapeutic molecule that can treat or ameliorate a disease of interest such as but not limited to Alzheimer's disease. In the modified cells, expression of the therapeutic molecule is induced when the modified cells are proximate to or in contact with pathology related to the disease of interest. The present disclosure also relates to compositions and kits comprising the disclosed cells. The present disclosure also relates to methods of using the disclosed cells for treating disease.