ArticleCell reports methods2026
Immune response to adeno-associated viral vectors in a human iPSC-derived microglia chimeric mouse model.
Article in Cell reports methods, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Adeno-associated virus (AAV)-based gene therapy for severe neurological diseases is challenged by immune responses, which are difficult to study accurately in genetically divergent rodent models or in in vitro human induced pluripotent stem cell (iPSC)-derived microglia (iMGL) that acquire activated phenotypes lacking complex brain environment cues. To address this, we generated human microglia chimeric mice. We developed a high-yield iMGL differentiation protocol incorporating a cryopreservation stopping point at the induced hematopoietic precursor cell (iHPC) stage, which increased flexibility and enabled a high level of chimerism. Engrafted iMGL transcriptionally and phenotypically resembled primary human microglia and were functionally active, displaying phagocytosis and immune response to inflammatory stimuli. Assessment of AAV serotypes revealed that murine microglia induced a larger immune response compared to human iMGL, cautioning against overinterpreting inflammatory responses in rodent models. This model provides a critical tool to define the human immune response to AAVs early in vector discovery.
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