Proteostasis and ALS

protocol for a phase II, randomised, double-blind, placebo-controlled, multicentre clinical trial for colchicine in ALS (Co-ALS)

Jessica Mandrioli, Valeria Crippa, Cristina Cereda, Valentina Bonetto, Elisabetta Zucchi, Annalisa Gessani, Mauro Ceroni, Adriano Chio, Roberto D'Amico, Maria Rosaria Monsurrò, Nilo Riva, Mario Sabatelli, Vincenzo Silani, Isabella Laura Simone, Gianni Sorarù, Alessandro Provenzani, Vito Giuseppe D'Agostino, Serena Carra, Angelo Poletti

Research output: Contribution to journalArticle

Abstract

INTRODUCTION: Disruptions of proteasome and autophagy systems are central events in amyotrophic lateral sclerosis (ALS) and support the urgent need to find therapeutic compounds targeting these processes. The heat shock protein B8 (HSPB8) recognises and promotes the autophagy-mediated removal of misfolded mutant SOD1 and TDP-43 fragments from ALS motor neurons (MNs), as well as aggregating species of dipeptides produced in C9ORF72-related diseases. In ALS-SOD1 mice and in human ALS autopsy specimens, HSPB8 is highly expressed in spinal cord MNs that survive at the end stage of disease. Moreover, the HSPB8-BAG3-HSP70 complex maintains granulostasis, which avoids conversion of dynamic stress granules (SGs) into aggregation-prone assemblies. We will perform a randomised clinical trial (RCT) with colchicine, which enhances the expression of HSPB8 and of several autophagy players, blocking TDP-43 accumulation and exerting crucial activities for MNs function.

METHODS AND ANALYSIS: Colchicine in amyotrophic lateral sclerosis (Co-ALS) is a double-blind, placebo-controlled, multicentre, phase II RCT. ALS patients will be enrolled in three groups (placebo, colchicine 0.01 mg/day and colchicine 0.005 mg/day) of 18 subjects treated with riluzole; treatment will last 30 weeks, and follow-up will last 24 weeks. The primary aim is to assess whether colchicine decreases disease progression as measured by ALS Functional Rating Scale - Revised (ALSFRS-R) at baseline and at treatment end. Secondary aims include assessment of (1) safety and tolerability of Colchicine in patiets with ALS; (2) changes in cellular activity (autophagy, protein aggregation, and SG and exosome secretion) and in biomarkers of disease progression (neurofilaments); (3) survival and respiratory function and (4) quality of life. Preclinical studies with a full assessment of autophagy and neuroinflammation biomarkers in fibroblasts, peripheral blood mononuclear cells and lymphoblasts will be conducted in parallel with clinic assessment to optimise time and resources.

ETHICS AND DISSEMINATION: The study protocol was approved by the Ethics Committee of Area Vasta Emilia Nord and by Agenzia Italiana del Farmaco (EUDRACT N.2017-004459-21) based on the Declaration of Helsinki. This research protocol was written without patient involvement. Patients' association will be involved in disseminating the study design and results. Results will be presented during scientific symposia or published in scientific journals.

TRIAL REGISTRATION NUMBER: EUDRACT 2017-004459-21; NCT03693781; Pre-results.

Original languageEnglish
Pages (from-to)e028486
JournalBMJ Open
Volume9
Issue number5
DOIs
Publication statusPublished - May 30 2019

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Controlled Clinical Trials
Amyotrophic Lateral Sclerosis
Colchicine
Multicenter Studies
Placebos
Autophagy
Heat-Shock Proteins
Motor Neurons
Disease Progression
Randomized Controlled Trials
Biomarkers
Helsinki Declaration
Riluzole
Exosomes
Patient Participation
Ethics Committees
Phase II Clinical Trials
Intermediate Filaments
Dipeptides
Proteasome Endopeptidase Complex

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Proteostasis and ALS : protocol for a phase II, randomised, double-blind, placebo-controlled, multicentre clinical trial for colchicine in ALS (Co-ALS). / Mandrioli, Jessica; Crippa, Valeria; Cereda, Cristina; Bonetto, Valentina; Zucchi, Elisabetta; Gessani, Annalisa; Ceroni, Mauro; Chio, Adriano; D'Amico, Roberto; Monsurrò, Maria Rosaria; Riva, Nilo; Sabatelli, Mario; Silani, Vincenzo; Simone, Isabella Laura; Sorarù, Gianni; Provenzani, Alessandro; D'Agostino, Vito Giuseppe; Carra, Serena; Poletti, Angelo.

In: BMJ Open, Vol. 9, No. 5, 30.05.2019, p. e028486.

Research output: Contribution to journalArticle

Mandrioli, J, Crippa, V, Cereda, C, Bonetto, V, Zucchi, E, Gessani, A, Ceroni, M, Chio, A, D'Amico, R, Monsurrò, MR, Riva, N, Sabatelli, M, Silani, V, Simone, IL, Sorarù, G, Provenzani, A, D'Agostino, VG, Carra, S & Poletti, A 2019, 'Proteostasis and ALS: protocol for a phase II, randomised, double-blind, placebo-controlled, multicentre clinical trial for colchicine in ALS (Co-ALS)', BMJ Open, vol. 9, no. 5, pp. e028486. https://doi.org/10.1136/bmjopen-2018-028486
Mandrioli, Jessica ; Crippa, Valeria ; Cereda, Cristina ; Bonetto, Valentina ; Zucchi, Elisabetta ; Gessani, Annalisa ; Ceroni, Mauro ; Chio, Adriano ; D'Amico, Roberto ; Monsurrò, Maria Rosaria ; Riva, Nilo ; Sabatelli, Mario ; Silani, Vincenzo ; Simone, Isabella Laura ; Sorarù, Gianni ; Provenzani, Alessandro ; D'Agostino, Vito Giuseppe ; Carra, Serena ; Poletti, Angelo. / Proteostasis and ALS : protocol for a phase II, randomised, double-blind, placebo-controlled, multicentre clinical trial for colchicine in ALS (Co-ALS). In: BMJ Open. 2019 ; Vol. 9, No. 5. pp. e028486.
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TY - JOUR

T1 - Proteostasis and ALS

T2 - protocol for a phase II, randomised, double-blind, placebo-controlled, multicentre clinical trial for colchicine in ALS (Co-ALS)

AU - Mandrioli, Jessica

AU - Crippa, Valeria

AU - Cereda, Cristina

AU - Bonetto, Valentina

AU - Zucchi, Elisabetta

AU - Gessani, Annalisa

AU - Ceroni, Mauro

AU - Chio, Adriano

AU - D'Amico, Roberto

AU - Monsurrò, Maria Rosaria

AU - Riva, Nilo

AU - Sabatelli, Mario

AU - Silani, Vincenzo

AU - Simone, Isabella Laura

AU - Sorarù, Gianni

AU - Provenzani, Alessandro

AU - D'Agostino, Vito Giuseppe

AU - Carra, Serena

AU - Poletti, Angelo

N1 - © Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

PY - 2019/5/30

Y1 - 2019/5/30

N2 - INTRODUCTION: Disruptions of proteasome and autophagy systems are central events in amyotrophic lateral sclerosis (ALS) and support the urgent need to find therapeutic compounds targeting these processes. The heat shock protein B8 (HSPB8) recognises and promotes the autophagy-mediated removal of misfolded mutant SOD1 and TDP-43 fragments from ALS motor neurons (MNs), as well as aggregating species of dipeptides produced in C9ORF72-related diseases. In ALS-SOD1 mice and in human ALS autopsy specimens, HSPB8 is highly expressed in spinal cord MNs that survive at the end stage of disease. Moreover, the HSPB8-BAG3-HSP70 complex maintains granulostasis, which avoids conversion of dynamic stress granules (SGs) into aggregation-prone assemblies. We will perform a randomised clinical trial (RCT) with colchicine, which enhances the expression of HSPB8 and of several autophagy players, blocking TDP-43 accumulation and exerting crucial activities for MNs function.METHODS AND ANALYSIS: Colchicine in amyotrophic lateral sclerosis (Co-ALS) is a double-blind, placebo-controlled, multicentre, phase II RCT. ALS patients will be enrolled in three groups (placebo, colchicine 0.01 mg/day and colchicine 0.005 mg/day) of 18 subjects treated with riluzole; treatment will last 30 weeks, and follow-up will last 24 weeks. The primary aim is to assess whether colchicine decreases disease progression as measured by ALS Functional Rating Scale - Revised (ALSFRS-R) at baseline and at treatment end. Secondary aims include assessment of (1) safety and tolerability of Colchicine in patiets with ALS; (2) changes in cellular activity (autophagy, protein aggregation, and SG and exosome secretion) and in biomarkers of disease progression (neurofilaments); (3) survival and respiratory function and (4) quality of life. Preclinical studies with a full assessment of autophagy and neuroinflammation biomarkers in fibroblasts, peripheral blood mononuclear cells and lymphoblasts will be conducted in parallel with clinic assessment to optimise time and resources.ETHICS AND DISSEMINATION: The study protocol was approved by the Ethics Committee of Area Vasta Emilia Nord and by Agenzia Italiana del Farmaco (EUDRACT N.2017-004459-21) based on the Declaration of Helsinki. This research protocol was written without patient involvement. Patients' association will be involved in disseminating the study design and results. Results will be presented during scientific symposia or published in scientific journals.TRIAL REGISTRATION NUMBER: EUDRACT 2017-004459-21; NCT03693781; Pre-results.

AB - INTRODUCTION: Disruptions of proteasome and autophagy systems are central events in amyotrophic lateral sclerosis (ALS) and support the urgent need to find therapeutic compounds targeting these processes. The heat shock protein B8 (HSPB8) recognises and promotes the autophagy-mediated removal of misfolded mutant SOD1 and TDP-43 fragments from ALS motor neurons (MNs), as well as aggregating species of dipeptides produced in C9ORF72-related diseases. In ALS-SOD1 mice and in human ALS autopsy specimens, HSPB8 is highly expressed in spinal cord MNs that survive at the end stage of disease. Moreover, the HSPB8-BAG3-HSP70 complex maintains granulostasis, which avoids conversion of dynamic stress granules (SGs) into aggregation-prone assemblies. We will perform a randomised clinical trial (RCT) with colchicine, which enhances the expression of HSPB8 and of several autophagy players, blocking TDP-43 accumulation and exerting crucial activities for MNs function.METHODS AND ANALYSIS: Colchicine in amyotrophic lateral sclerosis (Co-ALS) is a double-blind, placebo-controlled, multicentre, phase II RCT. ALS patients will be enrolled in three groups (placebo, colchicine 0.01 mg/day and colchicine 0.005 mg/day) of 18 subjects treated with riluzole; treatment will last 30 weeks, and follow-up will last 24 weeks. The primary aim is to assess whether colchicine decreases disease progression as measured by ALS Functional Rating Scale - Revised (ALSFRS-R) at baseline and at treatment end. Secondary aims include assessment of (1) safety and tolerability of Colchicine in patiets with ALS; (2) changes in cellular activity (autophagy, protein aggregation, and SG and exosome secretion) and in biomarkers of disease progression (neurofilaments); (3) survival and respiratory function and (4) quality of life. Preclinical studies with a full assessment of autophagy and neuroinflammation biomarkers in fibroblasts, peripheral blood mononuclear cells and lymphoblasts will be conducted in parallel with clinic assessment to optimise time and resources.ETHICS AND DISSEMINATION: The study protocol was approved by the Ethics Committee of Area Vasta Emilia Nord and by Agenzia Italiana del Farmaco (EUDRACT N.2017-004459-21) based on the Declaration of Helsinki. This research protocol was written without patient involvement. Patients' association will be involved in disseminating the study design and results. Results will be presented during scientific symposia or published in scientific journals.TRIAL REGISTRATION NUMBER: EUDRACT 2017-004459-21; NCT03693781; Pre-results.

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DO - 10.1136/bmjopen-2018-028486

M3 - Article

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SP - e028486

JO - BMJ Open

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