Background and Rationale: Among the key players in the pathogenesis of Amyotrophic Lateral Sclerosis (ALS), microglia and T regulatory lymphocytes (Treg) are candidate cells for modifying the course of the disease. The gut microbiota (GM) acts by shaping immune tolerance and regulating the Treg number and suppressive function, besides circulating neuropeptides, and other immune cells that play in concert through the gut-brain axis. Previous mouse models have shown an altered enteric flora in early stage ALS, pointing to a possible GM role in ALS pathogenesis. Fecal Microbial Transplantation (FMT) is a well-known therapeutic intervention used to re-establish the proper microenvironment and to modulate enteric and systemic immunity. Methods: We are going to perform a multicenter randomized double-blind clinical trial employing FMT as a therapeutic intervention for ALS patients (NCT0376632). Forty-two ALS patients, at an early stage, will be enrolled with a 2:1 allocation ratio (28 FMT-treated patients vs. 14 controls). Study duration will be 12 months per patient. Three endoscopic procedures for intestinal biopsies in FMT and control groups are predicted at baseline, month 6 and month 12; at baseline and at month 6 fresh feces from healthy donors will be infused at patients in the intervention arm. The primary outcome is a significant change in Treg number between FMT-treated patients and control arm from baseline to month 6. Secondary outcomes include specific biological aims, involving in-depth analysis of immune cells and inflammatory status changes, central and peripheral biomarkers of ALS, besides comprehensive analysis of the gut, saliva and fecal microbiota. Other secondary aims include validated clinical outcomes of ALS (survival, forced vital capacity, and modifications in ALSFRS-R), besides safety and quality of life. Expected Results: We await FMT to increase Treg number and suppressive functionality, switching the immune system surrounding motorneurons to an anti-inflammatory, neuroprotective status. Extensive analysis on immune cell populations, cytokines levels, and microbiota (gut, fecal and saliva) will shed light on early processes possibly leading the degenerative ALS course. Conclusions: This is the first trial with FMT as a potential intervention to modify immunological response to ALS and disease progression at an early stage.
Keywords: T cells; adaptive immunity; amyotrophic lateral sclerosis; fecal microbiota transplantation; microbiota; randomized controlled clinical trial; treg lymphocytes.
Copyright © 2019 Mandrioli, Amedei, Cammarota, Niccolai, Zucchi, D'Amico, Ricci, Quaranta, Spanu and Masucci.
Rapamycin Treatment for Amyotrophic Lateral Sclerosis: Protocol for a Phase II Randomized, Double-Blind, Placebo-Controlled, Multicenter, Clinical Trial (RAP-ALS Trial)J Mandrioli et al. Medicine (Baltimore) 97 (24), e11119. PMID 29901635. - Clinical TrialThe study protocol was approved by the Ethics Committee of Azienda Ospedaliero Universitaria of Modena and by the Ethics Committees of participating centers (Eudract n. 2 …
Ropinirole Hydrochloride Remedy for Amyotrophic Lateral Sclerosis - Protocol for a Randomized, Double-Blind, Placebo-Controlled, Single-Center, and Open-Label Continuation Phase I/IIa Clinical Trial (ROPALS Trial)S Morimoto et al. Regen Ther 11, 143-166. PMID 31384636.Patient recruitment began in December 2018 and the last patient is expected to complete the trial protocol in November 2020.
Phase 2 Randomized Placebo Controlled Double Blind Study to Assess the Efficacy and Safety of Tecfidera in Patients With Amyotrophic Lateral Sclerosis (TEALS Study): Study Protocol Clinical Trial (SPIRIT Compliant)S Vucic et al. Medicine (Baltimore) 99 (6), e18904. PMID 32028398. - Clinical TrialThis Phase 2 multi-center, randomized, placebo controlled, double blind clinical trial will provide evidence of efficacy and safety of Tecfidera in sporadic ALS.
Creatine for Amyotrophic Lateral Sclerosis/Motor Neuron DiseaseDM Pastula et al. Cochrane Database Syst Rev (6), CD005225. PMID 20556761. - ReviewIn patients already diagnosed with clinically probable or definite amyotrophic lateral sclerosis (ALS), creatine at doses ranging from 5 to 10 g per day did not have a st …
Neuroinflammatory Mechanisms in Amyotrophic Lateral Sclerosis PathogenesisJR Thonhoff et al. Curr Opin Neurol 31 (5), 635-639. PMID 30048339. - ReviewA delicate balance between anti-inflammatory and proinflammatory factors modulates the rates of disease progression and survival times in ALS. Tipping the balance toward …