Viral Vectors with Myeloid-Specific Promoters for Microglia Targeting
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Solution Overview
Problem
Current gene therapy approaches for neurodegenerative diseases and brain tumors face challenges in effectively targeting and expressing therapeutic proteins in brain microglia, leading to neuronal toxicity and safety concerns, particularly with AAV vectors that overexpress PGRN in neurons rather than microglia, and lack safe strategies for transgene expression in myeloid cells and hematopoietic stem cells.
Innovation Solution
Development of viral vectors with cell-specific promoters that drive expression in myeloid cells and microglia while being silent in hematopoietic stem and progenitor cells, utilizing promoters like miR223, ITGAM, AIF1, P2RY12, TMEM119, OLFML3, and their fusion constructs to ensure precise and safe transgene expression.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If AAV vectors are used to deliver therapeutic genes to the brain, then gene delivery efficiency is improved, but the therapeutic protein is overexpressed in neurons instead of microglia, leading to neuronal toxicity
Solution Approach 1:
The patent applies local quality by using cell-specific promoters (miR223, ITGAM, AIF1, P2RY12, TMEM119, OLFML3) that are selectively active only in microglia and myeloid cells, while being silent in neurons and hematopoietic stem cells. This ensures the therapeutic protein is expressed only in the intended target cells (microglia) and not in neurons, thereby achieving high gene delivery efficiency to microglia while avoiding neuronal toxicity.
2Adaptability or versatility
If viral vectors express therapeutic proteins in hematopoietic stem cells, then gene therapy coverage is improved, but the risk of oncogenic transformation and immune reactions increases
Solution Approach 1:
The patent uses promoters that are specifically active in differentiated microglia and myeloid cells but silent in hematopoietic stem and progenitor cells. This localized expression control allows the therapeutic protein to be expressed in the target cells (microglia) while avoiding expression in hematopoietic stem cells, thereby maintaining gene therapy coverage in microglia while eliminating the risks of oncogenic transformation and immune reactions associated with stem cell transduction.
3Quantity of substance
If non-specific promoters are used to drive transgene expression, then expression level is improved, but cell-type specificity is lost, leading to off-target effects
Solution Approach 1:
The patent employs multiple cell-specific promoters (miR223 for myeloid cells, ITGAM for macrophages/microglia, AIF1 for microglia, P2RY12 for microglia, TMEM119 for microglia, OLFML3 for microglia) that provide both high expression levels in the target cell type and precise cell-type specificity. Each promoter is engineered to be highly active in microglia while being silent in other cell types including neurons and hematopoietic stem cells, thereby achieving both high transgene expression and strict cell-type specificity to avoid off-target effects.
Data Source
AI summary
The present invention provides novel viral vectors for use in human therapy, particularly for use in in the treatment of a disease or disorder which has its origin in the brain or is brain based, particularly a PGRN-associated neurodegenerative disease or disorder including frontotemporal degenerative disease or disorder such as Alzheimer's disease, amyotrophic lateral sclerosis, and Parkinson's disease. The invention also provides viral vectors for use in the treatment of brain tumors, particularly brain tumors selected from the group consisting of glioblastoma, glioma, ganglioneuroblastoma, astrocytoma, oligodendroglioma, PNET (primitive neuroectodermal), medulloblastoma, CNS lymphoma, and neuroblastoma, or any other CNS tumor and further in the treatment of brain metastasis, originating from any forms of breast, lung, colon, testicular, renal carcinomas and melanoma, or any other solid tumor, and any hematologic tumor, comprising all forms of leukemia and lymphomas. Further, the viral vectors may be used in the treatment of autoimmune diseases, inflammatory diseases and/or allergic diseases.