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Updated: Jul 19, 2025
A Semi-Quantitative Drug Affinity Responsive Target Stability DARTS assay for studying Rapamycin/mTOR interaction
Published on: August 27, 2019
Randomized, double-blind, placebo-controlled trial of rapamycin in amyotrophic lateral sclerosis
Jessica Mandrioli1,2, Roberto D'Amico3,4, Elisabetta Zucchi5,6
1Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy. jessica.mandrioli@unimore.it.
Abstract:
In preclinical studies rapamycin was found to target neuroinflammation, by expanding regulatory T cells, and affecting autophagy, two pillars of amyotrophic lateral sclerosis (ALS) pathogenesis. Herein we report a multicenter, randomized, double-blind trial, in 63 ALS patients who were randomly assigned in a 1:1:1 ratio to receive rapamycin 2 mg/m2/day,1 mg/m2/day or placebo (EUDRACT 2016-002399-28; NCT03359538). The primary outcome, the number of patients exhibiting an increase >30% in regulatory T cells from baseline to treatment end, was not attained. Secondary outcomes were changes from baseline of T, B, NK cell subpopulations, inflammasome mRNA expression and activation status, S6-ribosomal protein phosphorylation, neurofilaments; clinical outcome measures of disease progression; survival; safety and quality of life. Of the secondary outcomes, rapamycin decreased mRNA relative expression of the pro-inflammatory cytokine IL-18, reduced plasmatic IL-18 protein, and increased the percentage of classical monocytes and memory switched B cells, although no corrections were applied for multiple tests. In conclusion, we show that rapamycin treatment is well tolerated and provides reassuring safety findings in ALS patients, but further trials are necessary to understand the biological and clinical effects of this drug in ALS.
Insights
Rapamycin, investigated for amyotrophic lateral sclerosis (ALS), showed good tolerability in patients. While not increasing regulatory T cells as hypothesized, it reduced inflammation markers and altered immune cell populations, warranting further ALS research.
Area of Science:
- Neuroscience
- Immunology
- Pharmacology
Background:
- Preclinical studies suggest rapamycin targets neuroinflammation and autophagy, key factors in amyotrophic lateral sclerosis (ALS).
- Regulatory T cells and autophagy are critical pathways implicated in ALS pathogenesis.
Purpose of the Study:
- To evaluate the efficacy and safety of rapamycin in ALS patients.
- To assess rapamycin's impact on regulatory T cells, immune cell subpopulations, and inflammatory markers in ALS.
Main Methods:
- A multicenter, randomized, double-blind, placebo-controlled trial involving 63 ALS patients.
- Patients were assigned to receive rapamycin (2 mg/m²/day or 1 mg/m²/day) or placebo.
- Outcomes included changes in regulatory T cells, immune cell populations, inflammasome expression, neurofilaments, clinical progression, survival, and quality of life.
Main Results:
- The primary outcome of increasing regulatory T cells by >30% was not met.
- Rapamycin treatment demonstrated good tolerability and a reassuring safety profile in ALS patients.
- Secondary analyses indicated rapamycin reduced IL-18 mRNA and protein levels, and increased classical monocytes and memory switched B cells.
Conclusions:
- Rapamycin is well-tolerated in ALS patients, suggesting a favorable safety profile.
- The drug modulated specific immune and inflammatory markers, though the primary immunomodulatory goal was not achieved.
- Further clinical trials are needed to elucidate the biological and clinical significance of rapamycin in ALS treatment.
