Protein misfolding, amyotrophic lateral sclerosis and guanabenz: protocol for a phase II RCT with futility design (ProMISe trial)

IntroductionRecent studies suggest that endoplasmic reticulum stress may play a critical role in the pathogenesis of amyotrophic lateral sclerosis (ALS) through an altered regulation of the proteostasis, the cellular pathway-balancing protein synthesis and degradation. A key mechanism is thought to be the dephosphorylation of eIF2α, a factor involved in the initiation of protein translation. Guanabenz is an alpha-2-adrenergic receptor agonist safely used in past to treat mild hypertension and is now an orphan drug. A pharmacological action recently discovered is its ability to modulate the synthesis of proteins by the activation of translational factors preventing misfolded protein accumulation and endoplasmic reticulum overload. Guanabenz proved to rescue motoneurons from misfolding protein stress both in in vitro and in vivo ALS models, making it a potential disease-modifying drug in patients. It is conceivable investigating whether its neuroprotective effects based on the inhibition of eIF2α dephosphorylation can change the progression of ALS.Methods and analysesProtocolised Management In Sepsis is a multicentre, randomised, double-blind, placebo-controlled phase II clinical trial with futility design. We will investigate clinical outcomes, safety, tolerability and biomarkers of neurodegeneration in patients with ALS treated with guanabenz or riluzole alone for 6 months. The primary aim is to test if guanabenz can reduce the proportion of patients progressed to a higher stage of disease at 6 months compared with their baseline stage as measured by the ALS Milano-Torino Staging (ALS-MITOS) system and to the placebo group. Secondary aims are safety, tolerability and change in at least one biomarker of neurodegeneration in the guanabenz arm compared with the placebo group. Findings will provide reliable data on the likelihood that guanabenz can slow the course of ALS in a phase III trial.Ethics and disseminationThe study protocol was approved by the Ethics Committee of IRCCS ‘Carlo Besta Foundation’ of Milan (Eudract no. 2014-005367-32 Pre-results) based on the Helsinki declaration.

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Oral levosimendan in amyotrophic lateral sclerosis: a phase II multicentre, randomised, double-blind, placebo-controlled trial

Journal of Neurology Neurosurgery & Psychiatry ◽

10.1136/jnnp-2018-320288 ◽

2019 ◽

Vol 90 (10) ◽

pp. 1165-1170 ◽

Cited By ~ 7

Author(s):

Ammar Al-Chalabi ◽

Pamela Shaw ◽

P Nigel Leigh ◽

Leonard van den Berg ◽

Orla Hardiman ◽

...

Keyword(s):

Heart Rate ◽

Amyotrophic Lateral Sclerosis ◽

Phase Ii ◽

Primary Endpoint ◽

Phase Iii ◽

Open Label ◽

Double Blind ◽

Double Blind Placebo ◽

Lateral Sclerosis

ObjectiveTo evaluate the efficacy and safety of oral levosimendan in patients with amyotrophic lateral sclerosis (ALS). This phase II, randomised, double-blind, placebo-controlled, crossover, three-period study with 6 months open-label follow-up enrolled adults with ALS and sitting slow vital capacity (SVC) 60%–90 % of predicted from 11 sites in four countries.MethodsPatients received levosimendan 1 mg daily, 1 mg two times a day or placebo during three 14-day crossover periods and levosimendan 1–2 mg daily during open-label follow-up. Primary endpoint was sitting SVC; secondary endpoints included supine SVC, ALS Functional Rating Scale-Revised (ALSFRS-R), tolerability and safety.ResultsOf 66 patients randomised, 59 contributed to the double-blind results and 50 entered open-label follow-up. Sitting SVC was not significantly different between the treatments. In post hoc analysis using period-wise baselines, supine SVC favoured levosimendan over placebo, estimated mean differences from baseline being −3.62% on placebo, +0.77% on levosimendan 1 mg daily (p=0.018) and +2.38% on 1 mg two times a day (p=0.001). Headache occurred in 16.7% of patients during levosimendan 1 mg daily (p=0.030), 28.6% during 1 mg two times a day (p=0.002) and 3.3% during placebo. The respective frequencies for increased heart rate were 5.1% (p=0.337), 18.5% (p=0.018) and 1.7%. No significant differences between the treatments were seen for other adverse events.ConclusionsLevosimendan did not achieve the primary endpoint of improving sitting SVC in ALS. Headache and increased heart rate were increased on levosimendan, although it was otherwise well tolerated. A phase III study to evaluate the longer term effects of oral levosimendan in ALS is ongoing.

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The decapentaplegic core promoter region plays an integral role in the spatial control of transcription.

Molecular and Cellular Biology ◽

10.1128/mcb.15.7.3960 ◽

1995 ◽

Vol 15 (7) ◽

pp. 3960-3968 ◽

Cited By ~ 21

Author(s):

D H Schwyter ◽

J D Huang ◽

T Dubnicoff ◽

A J Courey

Keyword(s):

Expression Pattern ◽

Phase Ii ◽

Promoter Region ◽

Core Promoter ◽

Critical Role ◽

Regulatory Elements ◽

Drosophila Embryo ◽

Phase Iii ◽

Core Promoter Region ◽

Flanking Region

The Drosophila melanogaster decapentaplegic (dpp) gene encodes a transforming growth factor beta-related cell signaling molecule that plays a critical role in dorsal/ventral pattern formation. The dpp expression pattern in the Drosophila embryo is dynamic, consisting of three phases. Phase I, in which dpp is expressed in a broad dorsal domain, depends on elements in the dpp second intron that interact with the Dorsal transcription factor to repress transcription ventrally. In contrast, phases II and III, in which dpp is expressed first in broad longitudinal stripes (phase II) and subsequently in narrow longitudinal stripes (phase III), depend on multiple independent elements in the dpp 5'-flanking region. Several aspects of the normal dpp expression pattern appear to depend on the unique properties of the dpp core promoter. For example, this core promoter (extending from -22 to +6) is able to direct a phase II expression pattern in the absence of additional upstream or downstream regulatory elements. In addition, a ventral-specific enhancer in the dpp 5'-flanking region that binds the Dorsal factor activates the heterologous hsp70 core promoter but not the dpp core promoter. Thus, the dpp core promoter region may contribute to spatially regulated transcription both by interacting directly with spatially restricted activators and by modifying the activity of proteins bound to enhancer elements.

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A perspective on therapies for amyotrophic lateral sclerosis: can disease progression be curbed?

Translational Neurodegeneration ◽

10.1186/s40035-021-00250-5 ◽

2021 ◽

Vol 10 (1) ◽

Author(s):

Xiaojiao Xu ◽

Dingding Shen ◽

Yining Gao ◽

Qinming Zhou ◽

You Ni ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Disease Progression ◽

Motor Neurons ◽

Critical Role ◽

Cell Therapies ◽

Gene Therapies ◽

Open Questions ◽

Novel Therapeutic Strategies ◽

Lateral Sclerosis

AbstractAmyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease involving both upper and lower motor neurons, leading to paralysis and eventually death. Symptomatic treatments such as inhibition of salivation, alleviation of muscle cramps, and relief of spasticity and pain still play an important role in enhancing the quality of life. To date, riluzole and edaravone are the only two drugs approved by the Food and Drug Administration for the treatment of ALS in a few countries. While there is adequate consensus on the modest efficacy of riluzole, there are still open questions concerning the efficacy of edaravone in slowing the disease progression. Therefore, identification of novel therapeutic strategies is urgently needed. Impaired autophagic process plays a critical role in ALS pathogenesis. In this review, we focus on therapies modulating autophagy in the context of ALS. Furthermore, stem cell therapies, gene therapies, and newly-developed biomaterials have great potentials in alleviating neurodegeneration, which might halt the disease progression. In this review, we will summarize the current and prospective therapies for ALS.

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Poly(GR) impairs protein translation and stress granule dynamics in C9orf72-associated frontotemporal dementia and amyotrophic lateral sclerosis

Nature Medicine ◽

10.1038/s41591-018-0071-1 ◽

2018 ◽

Vol 24 (8) ◽

pp. 1136-1142 ◽

Cited By ~ 95

Author(s):

Yong-Jie Zhang ◽

Tania F. Gendron ◽

Mark T. W. Ebbert ◽

Aliesha D. O’Raw ◽

Mei Yue ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Frontotemporal Dementia ◽

Protein Translation ◽

Stress Granule ◽

Lateral Sclerosis

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Correction to: the Cysteine (Cys) Residues Cys-6 and Cys-111 in Mutant Superoxide Dismutase 1 (SOD1) A4V Are Required for Induction of Endoplasmic Reticulum Stress in Amyotrophic Lateral Sclerosis

Journal of Molecular Neuroscience ◽

10.1007/s12031-020-01617-5 ◽

2020 ◽

Vol 70 (9) ◽

pp. 1369-1369

Author(s):

Emma R. Perri ◽

Sonam Parakh ◽

Marta Vidal ◽

Prachi Mehta ◽

Yi Ma ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Amyotrophic Lateral Sclerosis ◽

Superoxide Dismutase ◽

Endoplasmic Reticulum Stress ◽

Superoxide Dismutase 1 ◽

Lateral Sclerosis

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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)

BMJ Open ◽

10.1136/bmjopen-2018-028486 ◽

2019 ◽

Vol 9 (5) ◽

pp. e028486 ◽

Cited By ~ 11

Author(s):

Jessica Mandrioli ◽

Valeria Crippa ◽

Cristina Cereda ◽

Valentina Bonetto ◽

Elisabetta Zucchi ◽

...

Keyword(s):

Clinical Trial ◽

Amyotrophic Lateral Sclerosis ◽

Disease Progression ◽

Phase Ii ◽

Mononuclear Cells ◽

Rating Scale ◽

Double Blind ◽

Peripheral Blood Mononuclear ◽

Double Blind Placebo ◽

Lateral Sclerosis

IntroductionDisruptions 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 analysisColchicine 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 disseminationThe 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 numberEUDRACT 2017-004459-21;NCT03693781; Pre-results.

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