Telmisartan is neuroprotective in a hiPSC-derived spinal microtissue model for C9orf72 ALS via inhibition of neuroinflammation
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor neuron (MN) loss. The most common genetic cause, a hexanucleotide repeat expansion in C9orf72 (C9-ALS), disrupts microglial function, contributing to neuroinflammation, a key disease driver. To investigate this, we developed a three-dimensional spinal microtissue (SM) model incorporating human induced pluripotent stem cell (hiPSC)-derived MNs, astrocytes, and microglia. Screening 190 Food and Drug Administration (FDA)-approved compounds, we identified sartans-angiotensin II receptor I blockers (ARBs)-as potent inhibitors of neuroinflammation. Telmisartan, a highly brain-penetrant ARB, significantly reduced the levels of pro-inflammatory cytokines interleukin (IL)-6 and IL-8 and rescued MN loss in C9-ALS SMs. Our findings suggest that C9-ALS microglia drive MN toxicity and that telmisartan can effectively mitigate inflammation and preserve MN viability. This work lays the groundwork for modeling disease-related neuroinflammation and points to telmisartan as a therapeutic candidate worth further exploration for treating C9-ALS.
Authors
- Aaron Zhong (ORCID: https://orcid.org/0000-0002-2468-0923)
- Elisa Giacomelli (ORCID: https://orcid.org/0000-0001-9233-235X)
- Johannes Jungverdorben (ORCID: https://orcid.org/0000-0002-7227-1139)
- David G. Míguez (ORCID: https://orcid.org/0000-0001-8065-1142)
- Elizabeth L. Calder
- Mara Monetti (ORCID: https://orcid.org/0009-0006-9778-9010)
- Ting Zhou (ORCID: https://orcid.org/0000-0003-1423-1507)
- Berkiye Sonustun (ORCID: https://orcid.org/0000-0002-1403-6931)
- Mario Ledesma-Terrón (ORCID: https://orcid.org/0000-0003-4045-3939)
- Lorenz Studer (ORCID: https://orcid.org/0000-0003-0741-7987)
- Zhuoning Li (ORCID: https://orcid.org/0009-0005-9064-8170)
- Björn F. Vahsen (ORCID: https://orcid.org/0000-0002-5159-5070)
- Leslie Weber (ORCID: https://orcid.org/0000-0003-1187-7812)
- Nan Xu (ORCID: https://orcid.org/0000-0003-4642-2877)
- Laura Tuffery
Institutions
- Memorial Sloan Kettering Cancer Center (US)
- Cornell University (US)
- John Radcliffe Hospital (GB)
- Kettering University (US)
- Centro de Biología Molecular Severo Ochoa (ES)
Publication Details
- Journal
- Stem Cell Reports
- Published
- 2025-06-19
- DOI
- https://doi.org/10.1016/j.stemcr.2025.102535
- Citations
- 7
- Primary Topic
- Amyotrophic Lateral Sclerosis Research
- Type
- article
- Field-Weighted Citation Impact
- 9.72
Funders
- U.S. Department of Defense
- Charles H. Revson Foundation
- Motor Neurone Disease Association
- Boehringer Ingelheim Fonds
- National Institutes of Health
- National Institute of Mental Health
- National Institute of Neurological Disorders and Stroke