2025-04-21 カリフォルニア大学アーバイン校 (UCI)
<関連情報>
- https://news.uci.edu/2025/04/21/engineered-microglia-show-promise-for-treating-alzheimers-other-brain-diseases/
- https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(25)00099-2
ヒトiPS細胞ミクログリアを用いた疾患修飾タンパク質の中枢神経系への送達 Harnessing human iPSC-microglia for CNS-wide delivery of disease-modifying proteins
Jean Paul Chadarevian ∙ Hayk Davtyan ∙ Alina L. Chadarevian ∙ … ∙ Jonathan Hasselmann, ∙ Robert C. Spitale ∙ Mathew Blurton-Jones
Cell Stem Cell Published:April 14, 2025
DOI:https://doi.org/10.1016/j.stem.2025.03.009
Graphical abstract
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
Summary
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.
