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

ABSTRACT: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by motor neurons (MN) loss. Mutations in C9orf72 are the leading genetic cause of ALS and involve hexanucleotide repeat expansions (HRE) in the noncoding region of the gene. Neuroinflammation is a key feature and candidate therapeutic target in ALS, particularly in individuals with C9orf72 mutations (C9-ALS), as the gene affects microglial cell function and neuroinflammation. Here, we established a novel protocol to model the ALS neuroinflammatory axis by combining C9-ALS human iPSC-derived spinal MNs, astrocytes, and microglia. The resulting three-dimensional (3D) Spinal Microtissue (SM) represents a scalable multicellular platform for disease modeling and drug discovery. We next performed a screen of 190 FDA-approved compounds in C9-ALS SMs and in microglia-only tissues. Sartans, a class of Angiotensin II Receptor I Blockers (ARB), were identified as top hits in reducing C9-ALS-related neuroinflammation, including IL-6 and IL-8 levels in the culture supernatant. We validated these findings in SMs from two additional C9-ALS hiPSC lines and in isogenic control cultures using telmisartan, a particularly potent and brain penetrant sartan. Further, telmisartan rescued C9-ALS related MN death in both coculture and tricultures conditions and restored MN cell proportions within C9-ALS SMs. Our study suggests that C9-ALS microglia are toxic to MNs, and that telmisartan can attenuate microglia-related neuroinflammation and MN death presenting a potential treatment for C9-ALS.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Zhuoning Li  

LAB HEAD: Lorenz Studer

PROVIDER: PXD057067 | Pride | 2025-07-28

REPOSITORIES: Pride