2. Academic Validation
  3. Harnessing human iPSC-microglia for CNS-wide delivery of disease-modifying proteins

Harnessing human iPSC-microglia for CNS-wide delivery of disease-modifying proteins

  • Cell Stem Cell. 2025 Jun 5;32(6):914-934.e8. doi: 10.1016/j.stem.2025.03.009.
Jean Paul Chadarevian 1,  Hayk Davtyan 2,  Alina L Chadarevian 1,  Jasmine Nguyen 3,  Joia K Capocchi 3,  Lauren Le 3,  Adrian Escobar 4,  Talar Chadarevian 4,  Kimiya Mansour 4,  Ekaterina Deynega 3,  Michael Mgerian 4,  Christina Tu 2,  Sepideh Kiani Shabestari 1,  William Carlen-Jones 3,  Ghazaleh Eskandari-Sedighi 3,  Jonathan Hasselmann 2,  Robert C Spitale 5,  Mathew Blurton-Jones 6
Affiliations

Affiliations

  • 1 Department of Neurobiology & Behavior, University of California, Irvine, Irvine, CA 92697, USA; Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, CA 92697, USA; Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, CA 92697, USA.
  • 2 Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, CA 92697, USA; Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, CA 92697, USA.
  • 3 Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, CA 92697, USA.
  • 4 Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, CA 92697, USA.
  • 5 Department of Pharmaceutical Sciences, University of California, Irvine, Irvine, CA 92697, USA. Electronic address: rspitale@uci.edu.
  • 6 Department of Neurobiology & Behavior, University of California, Irvine, Irvine, CA 92697, USA; Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, CA 92697, USA; Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, CA 92697, USA. Electronic address: mblurton@uci.edu.
PMID: 40233761 DOI: 10.1016/j.stem.2025.03.009
Abstract

Widespread delivery of therapeutic proteins to the brain remains challenging. To determine whether human induced pluripotent stem cell (iPSC)-microglia (iMG) could enable brain-wide and pathology-responsive delivery of therapeutic cargo, we utilized CRISPR gene editing to engineer iMG to express the Aβ-degrading enzyme Neprilysin under control of the plaque-responsive promoter, CD9. To further determine whether increased engraftment enhances efficacy, we utilized a CSF1R-inhibitor resistance approach. Interestingly, both localized and brain-wide engraftment in Alzheimer's disease (AD) mice reduced multiple biochemical measures of pathology. However, within the plaque-dense subiculum, reductions in plaque load, dystrophic neurites, and astrogliosis and preservation of neuronal density were only achieved following widespread microglial engraftment. Lastly, we examined chimeric models of breast Cancer brain metastases and demyelination, demonstrating that iMG adopt diverse transcriptional responses to differing neuropathologies, which could be harnessed to enable widespread and pathology-responsive delivery of therapeutics to the CNS.

Keywords

Alzheimer’s disease; CRISPR; iMG; iPSC; immune cell therapy; microglia; microglia replacement; neprilysin; neurodegeneration; payload delivery.

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