Telmisartan is neuroprotective in a hiPSC-derived spinal microtissue model for C9orf72 ALS via inhibition of neuroinflammation

Journal article

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: Sonustun, B; Vahsen, BF; Ledesma-Terrón, M; Li, Z; Tuffery, L

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Cell Press
• Journal: Stem Cell Reports
• Volume: 20
• Issue: 7
• Article number: 102535
• Publication date: 2025-06-19
• Acceptance date: 2025-05-20
• DOI: 10.1016/j.stemcr.2025.102535
• EISSN: 2213-6711
• Language: English
• Keywords: neuroinflammation; amyotrophic lateral sclerosis; C9orf72; motor neurons; astrocytes; microglia; triculture; 3D microtissue; drug screen; sartans