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.

Randomized, double-blind, placebo-controlled trial of rapamycin in amyotrophic lateral sclerosis / Mandrioli, J.; D'Amico, R.; Zucchi, E.; De Biasi, S.; Banchelli, F.; Martinelli, I.; Simonini, C.; Lo Tartaro, D.; Vicini, R.; Fini, N.; Gianferrari, G.; Pinti, M.; Lunetta, C.; Gerardi, F.; Tarlarini, C.; Mazzini, L.; De Marchi, F.; Scognamiglio, A.; Soraru, G.; Fortuna, A.; Lauria, G.; Bella, E. D.; Caponnetto, C.; Meo, G.; Chio, A.; Calvo, A.; Cossarizza, A.. - In: NATURE COMMUNICATIONS. - ISSN 2041-1723. - 14:1(2023), pp. 4970-4970. [10.1038/s41467-023-40734-8]

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

Mandrioli J.;D'Amico R.;Zucchi E.;De Biasi S.;Banchelli F.;Martinelli I.;Lo Tartaro D.;Vicini R.;Gianferrari G.;Pinti M.;Cossarizza A.
2023

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.
2023
14
1
4970
4970
Randomized, double-blind, placebo-controlled trial of rapamycin in amyotrophic lateral sclerosis / Mandrioli, J.; D'Amico, R.; Zucchi, E.; De Biasi, S.; Banchelli, F.; Martinelli, I.; Simonini, C.; Lo Tartaro, D.; Vicini, R.; Fini, N.; Gianferrari, G.; Pinti, M.; Lunetta, C.; Gerardi, F.; Tarlarini, C.; Mazzini, L.; De Marchi, F.; Scognamiglio, A.; Soraru, G.; Fortuna, A.; Lauria, G.; Bella, E. D.; Caponnetto, C.; Meo, G.; Chio, A.; Calvo, A.; Cossarizza, A.. - In: NATURE COMMUNICATIONS. - ISSN 2041-1723. - 14:1(2023), pp. 4970-4970. [10.1038/s41467-023-40734-8]
Mandrioli, J.; D'Amico, R.; Zucchi, E.; De Biasi, S.; Banchelli, F.; Martinelli, I.; Simonini, C.; Lo Tartaro, D.; Vicini, R.; Fini, N.; Gianferrari, G.; Pinti, M.; Lunetta, C.; Gerardi, F.; Tarlarini, C.; Mazzini, L.; De Marchi, F.; Scognamiglio, A.; Soraru, G.; Fortuna, A.; Lauria, G.; Bella, E. D.; Caponnetto, C.; Meo, G.; Chio, A.; Calvo, A.; Cossarizza, A.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11380/1320113
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