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Chadarevian et al. publish in Cell Stem Cell

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

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.

Highlights
  • iPSC-microglia enable pathology-responsive delivery of therapeutic proteins
  • Both regional and CNS-wide microglial secretion of neprilysin reduces Aβ pathology
  • Neprilysin delivery also lowers inflammation, dystrophic neurites, and plasma NfL
  • iPSC-microglia can be harnessed to provide a promising new cell therapy platform
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Blurton-Jones lab presents at ADPD 2025 in Vienna, Austria

Dr. Mathew Blurton-Jones and Jean Paul Chadarevian were invited to share their research at this year’s ADPD 2025 (April 1-5) International Conference on Alzheimer’s and Parkinson’s Diseases.

Dr. Mathew Blurton-Jones was invited to moderate the session on cell replacement therapy & diagnostics, where he presented key findings highlighting the differences between CNS-wide engrafted human monocytes and iPSC-microglia.  Dr. Jean Paul Chadarevian was also selected to present his research harnessing human iPSC-microglia for CNS-wide delivery of therapeutic peptides.

Congratulations to all the attendees and participants of ADPD 2025!

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Blurton-Jones lab attends Emerging Scientists Symposium at UCI

The UCI MIND trainee-led organization ReMIND held its annual Emerging Scientists Symposium at the UCI Student Center. This yearly event gives UCI MIND graduate students, medical students, and post-doctoral scholars opportunities to get out of the laboratory to present their work through posters and oral presentations, to network with and learn from each other, and to generally stay excited about research and the progress we are making toward understanding and discovering solutions for Alzheimer’s disease and related disorders (ADRD) research. Congratulations to Zahara Keulen, Dr. Ghazaleh Eskandari-Sedighi, and Dr. Jean Paul Chadarevian on your selection and presentations!

Read more about this important event: https://mind.uci.edu/remind_train/

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Chadarevian et al. publish in Neuron

Therapeutic potential of human microglia transplantation in a chimeric model of CSF1R-related leukoencephalopathy

Microglia replacement strategies are increasingly being considered for the treatment of primary microgliopathies like adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP). However, available mouse models fail to recapitulate the diverse neuropathologies and reduced microglia numbers observed in patients. In this study, we generated a xenotolerant mouse model lacking the fms-intronic regulatory element (FIRE) enhancer within Csf1r, which develops nearly all the hallmark pathologies associated with ALSP. Remarkably, transplantation of human induced pluripotent stem cell (iPSC)-derived microglial (iMG) progenitors restores a homeostatic microglial signature and prevents the development of axonal spheroids, white matter abnormalities, reactive astrocytosis, and brain calcifications. Furthermore, transplantation of CRISPR-corrected ALSP-patient-derived iMG reverses pre-existing spheroids, astrogliosis, and calcification pathologies. Together with the accompanying study by Munro and colleagues, our results demonstrate the utility of FIRE mice to model ALSP and provide compelling evidence that iMG transplantation could offer a promising new therapeutic strategy for ALSP and perhaps other microglia-associated neurological disorders.

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MBJ Lab attends Keystone Symposia

Dr. Jean Paul Chadarevian and Joia K. Capocchi attend 2024 Keystone Symposia on Neurodegeneration in Santa Fe, NM where Jean Paul presented, “Therapeutic potential of human microglia transplantation in a chimeric model of CSF1R-related leukoencephalopathy“.