Rapamycin treatment for amyotrophic lateral sclerosis: Protocol for a phase II randomized, double-blind, placebo-controlled, multicenter, clinical trial (RAP-ALS trial)
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INTRODUCTION: Misfolded aggregated proteins and neuroinflammation significantly contribute to amyotrophic lateral sclerosis (ALS) pathogenesis, hence representing therapeutic targets to modify disease expression. Rapamycin inhibits mechanistic target of Rapamycin (mTOR) pathway and enhances autophagy with demonstrated beneficial effects in neurodegeneration in cell line and animal models, improving phenotype in SQSTM1 zebrafish, in Drosophila model of ALS-TDP, and in the TDP43 mouse model, in which it reduced neuronal loss and TDP43 inclusions. Rapamycin also expands regulatory T lymphocytes (Treg) and increased Treg levels are associated with slow progression in ALS patients.Therefore, we planned a randomized clinical trial testing Rapamycin treatment in ALS patients. METHODS: RAP-ALS is a phase II randomized, double-blind, placebo-controlled, multicenter (8 ALS centers in Italy), clinical trial. The primary aim is to assess whether Rapamycin administration increases Tregs number in treated patients compared with control arm. Secondary aims include the assessment of safety and tolerability of Rapamycin in patients with ALS; the minimum dosage to have Rapamycin in cerebrospinal fluid; changes in immunological (activation and homing of T, B, NK cell subpopulations) and inflammatory markers, and on mTOR downstream pathway (S6RP phosphorylation); clinical activity (ALS Functional Rating Scale-Revised, survival, forced vital capacity); and quality of life (ALSAQ40 scale). DISCUSSION: Rapamycin potentially targets mechanisms at play in ALS (i.e., autophagy and neuroinflammation), with promising preclinical studies. It is an already approved drug, with known pharmacokinetics, already available and therefore with significant possibility of rapid translation to daily clinics. Findings will provide reliable data for further potential trials. ETHICS AND DISSEMINATION: The study protocol was approved by the Ethics Committee of Azienda Ospedaliero Universitaria of Modena and by the Ethics Committees of participating centers (Eudract n. 2016-002399-28) based on the Helsinki declaration.
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A phase II trial of rapamycin (sirolimus) for ALS patients began in 2018.
“Autophagy induction using MTOR inhibitors is currently being tested in ALS – a phase II trial of rapamycin (sirolimus) for ALS patients began in 2018 [498].”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [498]
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- Authors
- Mandrioli, J., D’Amico, R., Zucchi, E., Gessani, A., Fini, N., Fasano, A., Caponnetto, C., Chiò, A., Dalla Bella, E., Lunetta, C., Mazzini, L., Marinou, K., Sorarù, G., de Biasi, S., Lo Tartaro, D., Pinti, M., & Cossarizza, A.
- Affiliations
- University of Modena and Reggio Emilia (IT)
- Ospedale Policlinico San Martino (IT)
- Azienda Ospedaliera Citta' della Salute e della Scienza di Torino (IT)
- Azienda Ospedaliero Universitaria Maggiore della Carita (IT)
- Corresponding author
- Mandrioli, Jessica
- ORCID
- Venue
- Medicine
- Published
- 2018-06
- Volume
- 97
- Issue
- 24
- Pages
- e11119
- ISSN
- 0025-7974 (ISSN-L)
- PMC
- PMC6024184
- OpenAlex
- W2807994366
- Cited by
- 128
- References
- 31
- Citations by year
- 2026: 6 · 2025: 7 · 2024: 9 · 2023: 11 · 2022: 24 · 2021: 27 · 2020: 26 · 2019: 18
- FWCI
- 12.20
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Medicine (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, cc-by)
- IRIS UNIMORE (University of Modena and Reggio Emilia) (submittedVersion, cc-by)
- Institutional Research Information System University of Turin (University of Turin) (submittedVersion, other-oa)
- Padua Research Archive (University of Padova) (submittedVersion, cc-by)
- Funders
- Università Degli Studi di Modena e Reggio Emila
- Università degli Studi di Padova
- Università degli Studi di Torino
- Topics
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
- Keywords
- amyotrophic lateral sclerosis, rapamycin, mTOR signaling, autophagy, neuroinflammation, regulatory T cells, TDP-43, S6 phosphorylation, cerebrospinal fluid drug concentration, immunological markers, neurodegeneration, drug repurposing, ALS Functional Rating Scale, survival, forced vital capacity, quality of life
- MeSH terms
- Amyotrophic Lateral Sclerosis, Double-Blind Method, Humans, Immunosuppressive Agents, Italy, Quality of Life, Research Design, Biomarkers, Survival Rate, Treatment Outcome, Sirolimus, TOR Serine-Threonine Kinases
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