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A Protocol for Comprehensive Assessment of Bulbar Dysfunction in Amyotrophic Lateral Sclerosis ALS
Published on: February 21, 2011
Rapamycin treatment for amyotrophic lateral sclerosis: Protocol for a phase II randomized, double-blind,
Jessica Mandrioli1, Roberto D'Amico, Elisabetta Zucchi
1Department of Neuroscience, St. Agostino-Estense Hospital, Azienda Ospedaliero Universitaria di Modena, University of Modena and Reggio Emilia, Modena Unit of Statistics, Department of Diagnostic, Clinical and Public Health Medicine, University of Modena and Reggio Emilia, Azienda Ospedaliero Universitaria di Modena, Modena Department of Neurosciences, Rehabilitation Ophthalmology, Genetics, Mother and Child Disease, Ospedale Policlinico San Martino, Genova "Rita Levi Montalcini"-Department of Neurosciences, ALS Centre, University of Turin and Azienda Ospedaliero Universitaria Città della Salute e della Scienza, Turin 3rd Neurology Unit and ALS Centre, IRCCS "Carlo Besta" Neurological Institute, Milan NEuroMuscular Omnicenter, Serena Onlus Foundation, Milan ALS Centre, Neurologic Clinic, Maggiore della Carità University Hospital, Novara ALS Center, "Salvatore Maugeri" Clinical-Scientific Institutes, Milan Department of Neurosciences, University of Padua, Padua, Department of Life Sciences, University of Modena and Reggio Emilia, Modena Department of Medical and Surgical Sciences for Children and Adults, University of Modena and Reggio Emilia School of Medicine, Modena, Italy.
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.
Insights
This clinical trial investigates Rapamycin for amyotrophic lateral sclerosis (ALS), focusing on its potential to increase regulatory T lymphocytes (Tregs) and combat neuroinflammation. Results will inform future ALS treatment strategies.
Area of Science:
- Neuroscience
- Immunology
- Pharmacology
Background:
- Amyotrophic lateral sclerosis (ALS) pathogenesis involves misfolded proteins and neuroinflammation.
- Rapamycin, an mTOR inhibitor, enhances autophagy and shows neuroprotective effects in preclinical models.
- Rapamycin expands regulatory T lymphocytes (Tregs), which are linked to slower ALS progression.
Purpose of the Study:
- To evaluate Rapamycin's efficacy in increasing Treg numbers in ALS patients.
- To assess the safety and tolerability of Rapamycin in ALS.
- To explore Rapamycin's effects on immunological markers, the mTOR pathway, and clinical outcomes.
Main Methods:
- RAP-ALS is a phase II, randomized, double-blind, placebo-controlled, multicenter trial.
- The primary endpoint is the change in Treg count.
- Secondary endpoints include safety, cerebrospinal fluid drug levels, immune cell profiles, inflammatory markers, and clinical assessments.
Main Results:
- This section is not available in the provided abstract.
Conclusions:
- Rapamycin targets key ALS mechanisms like autophagy and neuroinflammation.
- As an approved drug with known pharmacokinetics, Rapamycin offers potential for rapid clinical translation.
- The study aims to provide data for future clinical trials in ALS treatment.
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