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

Berkiye Sonustun; Björn F Vahsen; Mario Ledesma-Terrón; Zhuoning Li; Laura Tuffery; Nan Xu; Elizabeth L Calder; Johannes Jungverdorben; Leslie Weber; Aaron Zhong; David G Miguez; Mara Monetti; Ting Zhou; Elisa Giacomelli; Lorenz Studer

doi:10.1016/j.stemcr.2025.102535

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

Stem Cell Reports. 2025 Jun 16:102535. doi: 10.1016/j.stemcr.2025.102535. Online ahead of print.

Authors

Affiliations

¹ Developmental Biology Program & Center for Stem Cell Biology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Weill Cornell Graduate School of Medical Sciences, Cornell University, New York, NY 10065, USA.
² Oxford Motor Neuron Disease Centre, Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK; Kavli Institute for Nanoscience Discovery, University of Oxford, Dorothy Crowfoot Hodgkin Building, OX1 3QU Oxford, UK.
³ Centro de Biologia Molecular Severo Ochoa, Departamento de Fisica de la Materia Condensada, Instituto Nicolas Cabrera, and Condensed Matter Physics Center (IFIMAC), Universidad Autonoma de Madrid, 28049 Madrid, Spain.
⁴ Proteomics Innovation Laboratory and Proteomics Core, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
⁵ Developmental Biology Program & Center for Stem Cell Biology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Louis V. Gerstner Jr. Graduate School of Biomedical Sciences, New York, NY 10065, USA.
⁶ Developmental Biology Program & Center for Stem Cell Biology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
⁷ The SKI Stem Cell Research Facility, The Center for Stem Cell Biology and Developmental Biology Program, Sloan Kettering Institute, 1275 York Avenue, New York, NY 10065, USA.
⁸ Developmental Biology Program & Center for Stem Cell Biology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; The SKI Stem Cell Research Facility, The Center for Stem Cell Biology and Developmental Biology Program, Sloan Kettering Institute, 1275 York Avenue, New York, NY 10065, USA.
⁹ Developmental Biology Program & Center for Stem Cell Biology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Sean M. Healey and the AMG Center for ALS and the Neurological Clinical Research Institute, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. Electronic address: studerl@mskcc.org.
¹⁰ Developmental Biology Program & Center for Stem Cell Biology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Weill Cornell Graduate School of Medical Sciences, Cornell University, New York, NY 10065, USA. Electronic address: studerl@mskcc.org.

PMID: 40541176
DOI: 10.1016/j.stemcr.2025.102535

Abstract

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.

Keywords: 3D microtissue; C9orf72; amyotrophic lateral sclerosis; astrocytes; drug screen; microglia; motor neurons; neuroinflammation; sartans; triculture.