Randomized, double-blind, placebo-controlled trial of rapamycin in amyotrophic lateral sclerosis

Jessica Mandrioli (), Roberto D’Amico, Elisabetta Zucchi, Sara De Biasi, Federico Banchelli, Ilaria Martinelli, Cecilia Simonini, Domenico Lo Tartaro, Roberto Vicini, Nicola Fini, Giulia Gianferrari, Marcello Pinti, Christian Lunetta, Francesca Gerardi, Claudia Tarlarini, Letizia Mazzini, Fabiola De Marchi, Ada Scognamiglio, Gianni Sorarù, Andrea Fortuna, Giuseppe Lauria, Eleonora Dalla Bella, Claudia Caponnetto, Giuseppe Meo, Adriano Chio, Andrea Calvo and Andrea Cossarizza
Additional contact information
Jessica Mandrioli: University of Modena and Reggio Emilia
Roberto D’Amico: Azienda Ospedaliero-Universitaria
Elisabetta Zucchi: Azienda Ospedaliero-Universitaria di Modena
Sara De Biasi: University of Modena and Reggio Emilia
Federico Banchelli: Azienda Ospedaliero-Universitaria
Ilaria Martinelli: Azienda Ospedaliero-Universitaria di Modena
Cecilia Simonini: Azienda Ospedaliero-Universitaria di Modena
Domenico Lo Tartaro: University of Modena and Reggio Emilia
Roberto Vicini: Azienda Ospedaliero-Universitaria
Nicola Fini: Azienda Ospedaliero-Universitaria di Modena
Giulia Gianferrari: University of Modena and Reggio Emilia
Marcello Pinti: University of Modena and Reggio Emilia
Christian Lunetta: Serena Onlus Foundation
Francesca Gerardi: Serena Onlus Foundation
Claudia Tarlarini: Serena Onlus Foundation
Letizia Mazzini: Maggiore della Carità University Hospital
Fabiola De Marchi: Maggiore della Carità University Hospital
Ada Scognamiglio: Maggiore della Carità University Hospital
Gianni Sorarù: University of Padua
Andrea Fortuna: University of Padua
Giuseppe Lauria: IRCCS ‘Carlo Besta’ Neurological Institute
Eleonora Dalla Bella: IRCCS ‘Carlo Besta’ Neurological Institute
Claudia Caponnetto: Rehabilitatioņ Ophthalmology, Genetics, Mother and Child Disease, Ospedale Policlinico San Martino
Giuseppe Meo: Rehabilitatioņ Ophthalmology, Genetics, Mother and Child Disease, Ospedale Policlinico San Martino
Adriano Chio: University of Turin and Azienda Ospedaliero Universitaria Città della Salute e della Scienza
Andrea Calvo: University of Turin and Azienda Ospedaliero Universitaria Città della Salute e della Scienza
Andrea Cossarizza: University of Modena and Reggio Emilia

Nature Communications, 2023, vol. 14, issue 1, 1-14

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-40734-8

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