Abstract
Amyotrophic lateral sclerosis (ALS) is a relentless neurodegenerative disease of the human motor neuron system, where variability in progression rate limits clinical trial efficacy. Therefore, better prognostication will facilitate therapeutic progress. In this study, we investigated the potential of plasma cell-free microRNAs (miRNAs) as ALS prognostication biomarkers in 252 patients with detailed clinical phenotyping. First, we identified, in a longitudinal cohort, miRNAs whose plasma levels remain stable over the course of disease. Next, we showed that high levels of miR-181, a miRNA enriched in neurons, predicts a greater than two-fold risk of death in independent discovery and replication cohorts (126 and 122 patients, respectively). miR-181 performance is similar to neurofilament light chain (NfL), and when combined together, miR-181 + NfL establish a novel RNA–protein biomarker pair with superior prognostication capacity. Therefore, plasma miR-181 alone and a novel miRNA–protein biomarker approach, based on miR-181 + NfL, boost precision of patient stratification. miR-181-based ALS biomarkers encourage additional validation and might enhance the power of clinical trials.
| Original language | English |
|---|---|
| Journal | Nature Neuroscience |
| Volume | 24 |
| Issue number | 11 |
| Pages (from-to) | 1534-1541 |
| Number of pages | 8 |
| ISSN | 1097-6256 |
| DOIs | |
| Publication status | Published - 11.2021 |
Funding
We thank V. Lombardi (University College London) for technical assistance and I. Ben-Dov (Hadassah Hebrew University Medical Center) for advice on statistics. We acknowledge patients for their contributions and all ALS biomarker study coworkers and their contributions to the biobanking project, which made this study possible (REC 09/ H0703/27). We also thank the North Thames Local Research Network for its support and life science editors for editorial assistance. E.H. is the Mondry Family Professorial Chair and Head of the Nella and Leon Benoziyo Center for Neurological Diseases. Imaging was performed at the de Picciotto Cancer Cell Observatory, in memory of Wolfgang and Ruth Lesser. Funding: this research was supported by the following grants: Motor Neurone Disease Association (MNDA no. 839-791), Redhill Foundation – Sam and Jean Rothberg Charitable Trust and J. and E. Moravitz. Research at the Hornstein lab is supported by the CReATe Consortium and ALSA (program: ‘Prognostic value of miRNAs in biofluids from ALS patients’); the RADALA Foundation; AFM Telethon (20576); Weizmann - Brazil Center for Research on Neurodegeneration at the Weizmann Institute of Science; the Minerva Foundation, with funding from the Federal German Ministry for Education and Research; the ISF Legacy Heritage Fund 828/17; the Israel Science Foundation 135/16 and ISF IPMP 3497/21; Target ALS 118945; the Thierry Latran Foundation for ALS Research; the European Research Council, under the European Union’s Seventh Framework Programme (FP7/2007–2013)/ERC grant agreement no. 617351; ERA-Net for Research Programmes on Rare Diseases (eRARE FP7), via the Israel Ministry of Health; Dr. Sydney Brenner and friends; A. Alfred Taubman through IsrALS; Yeda-Sela; Yeda-CEO; the Israel Ministry of Trade and Industry; the Y. Leon Benoziyo Institute for Molecular Medicine; the Kekst Family Institute for Medical Genetics; the David and Fela Shapell Family Center for Genetic Disorders Research; the Crown Human Genome Center; the Nathan, Shirley, Philip and Charlene Vener New Scientist Fund; the Julius and Ray Charlestein Foundation; the Fraida Foundation; the Wolfson Family Charitable Trust; the Adelis Foundation; Merck (United Kingdom); M. Halphen; and the estates of F. Sherr, L. Asseof and L. Fulop. P.F. is supported by a Medical Research Council Senior Clinical Fellowship and the Lady Edith Wolfson Fellowship scheme (MR/M008606/1 and MR/S006508/1). J.G. was supported in the JPND framework ONWebDUALS, and L.G. is the Graeme Watts Senior Research Fellow supported by the Brain Research Trust. N.S.Y. was supported by the Israeli Council for Higher Education via the Weizmann Data Science Research Center, by a research grant from the Estate of Tully and Michele Plesser and by Maccabim Foundation. I.M. was supported by Teva Pharmaceutical Industries as part of the Israeli National Network of Excellence in Neuroscience (fellowship no. 117941).
Research Areas and Centers
- Academic Focus: Center for Brain, Behavior and Metabolism (CBBM)
- Centers: Center for Neuromuscular Diseases
