A promising treatment for ALS

Amyotrophic lateral sclerosis (ALS) is a deadly neurodegenerative disease with limited treatment options, making the development of new, effective therapeutics critically important.  

Research has shown that the immune system plays a substantial role in ALS, with multiple immune cell types implicated in its progression. One such type of immune cell is the natural killer (NK) cell.  NK cells accumulate in the brain and spinal cord during ALS, increasing neuroinflammation and killing healthy motor neurons.

Our research has already shown that depleting NK cells in ALS mouse models extends survival.  Building on this finding, tofacitinib - an FDA-approved drug that reduces NK cell cytotoxicity (their ability to damage or kill other cells) and lowers circulating NK cell levels – emerges as a promising candidate for repurposing as a potential ALS therapy.

Researchers led by Benjamin Murdock, Ph.D., Robert A. Epstein and Joan M. Chernoff-Epstein Emerging Scholar, tested tofacitinib in an ALS mouse model to assess its effects on ALS.  They also aimed to determine the most effective dose and regimen.

In Frontiers in Immunology, they published findings that low-dose (but not high-dose) treatment of tofacitinib significantly increased survival and delayed weight loss, a hallmark of ALS, in mouse models.  RNA-seq—a technology that provides a snapshot of gene activity at a specific time—revealed that low-dose tofacitinib treatment reversed the dysregulation (due to ALS) of multiple immune and metabolic pathways.

“These findings are really exciting,” explained Dr. Murdock.  “They further point to tofacitinib as a promising treatment for ALS and bring us one step closer to a clinical trial.”

Other authors: Lillia A. Baird, Samuel J. Teener, Ian F. Webber-Davis, Andrew D. Carter, Dae-Gyu Jang, Ph.D., Joshua P. Famie, Caroline E. Piecuch, Kai Guo, Ph.D., Eva L. Feldman, M.D., Ph.D., and Benjamin Murdock, Ph.D., from the University of Michigan.  Fang Huang from North Dakota University.

Funding for this research includes the Department of Defense, ALS Association, National Institutes of Health, Peter R. Clark Fund for ALS Research, Coleman Therapeutic Discovery Fund, Michael R. Johns Assistance Fund for UofM ALS Clinic, Stanford Morris ALS Research Fund, and Robert A. Epstein and Joan M. Chernoff-Epstein Emerging Scholar Fund.

Paper cited: Baird LA, Teener SJ, Webber-Davis IF, Carter AD, Huang F, Jang DG, Famie JP, Piecuch CE, Guo K, Feldman EL, Murdock BJ. Tofacitinib extends survival in a mouse model of ALS through NK cell-independent mechanisms. Front Immunol. 2025 Nov 5;16:1662197. doi: 10.3389/fimmu.2025.1662197. PMID: 41268542; PMCID: PMC12626996.