Cell-free miRNAs are pharmacodynamic biomarkers for enhanced DICER activity by enoxacin in human patients with ALS

Iddo Magen; Hannah Marlene Kaneb; Maria Masnata; Nisha Pulimood; Anna Emde; Angela Genge; Eran Hornstein

doi:10.1016/j.ymthe.2026.03.002

Cell-free miRNAs are pharmacodynamic biomarkers for enhanced DICER activity by enoxacin in human patients with ALS

Mol Ther. 2026 Mar 6:S1525-0016(26)00187-5. doi: 10.1016/j.ymthe.2026.03.002. Online ahead of print.

Authors

Iddo Magen¹, Hannah Marlene Kaneb², Maria Masnata², Nisha Pulimood², Anna Emde¹, Angela Genge³, Eran Hornstein⁴

Affiliations

¹ Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel; Department of Molecular Neuroscience, Weizmann Institute of Science, Rehovot, Israel.
² Montreal Neurological Institute-Hospital, McGill University, Montreal, QC, Canada.
³ Montreal Neurological Institute-Hospital, McGill University, Montreal, QC, Canada. Electronic address: angela.genge@mcgill.ca.
⁴ Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel; Department of Molecular Neuroscience, Weizmann Institute of Science, Rehovot, Israel. Electronic address: eran.hornstein@weizmann.ac.il.

PMID: 41792996
DOI: 10.1016/j.ymthe.2026.03.002

Abstract

The activity of the RNase III enzyme DICER is downregulated in both sporadic and genetic forms of amyotrophic lateral sclerosis (ALS). Accordingly, hundreds of microRNAs (miRNAs) are broadly downregulated, leading to de-repression of their mRNA targets. Enoxacin is a fluoroquinolone that enhances DICER activity and miRNA biogenesis. Here, we tested for the first time the molecular effect of enoxacin on miRNA biogenesis in ALS patients and demonstrated that enoxacin's engagement with DICER can be pharmacodynamically monitored via miRNA levels in human subjects. In an investigator-initiated, first-in-human study (REALS1), we explored miRNAs as pharmacodynamic biomarkers of DICER activation. Patients with sporadic ALS received oral enoxacin twice daily for 30 days in a double-blind, randomized clinical trial. The study demonstrated comparable enoxacin levels in plasma and cerebrospinal fluid (CSF). Furthermore, an increase in cell-free miRNA levels in both plasma and CSF at all time points following enoxacin treatment (400 or 800 mg/day), was measured relative to baseline. Additionally, no serious adverse events were reported. In conclusion, pharmacological enhancement of DICER activity by enoxacin increases miRNA biogenesis in patients with ALS. These results support further investigation of enoxacin efficacy in larger clinical trials.

Keywords: DICER; amyotrophic lateral sclerosis; enoxacin; miRNAs; pharmacodynamic marker; target engagement.