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Protein misfolding, amyotrophic lateral sclerosis and guanabenz: protocol for a phase II RCT with futility design
Eleonora Dalla Bella1, Irene Tramacere2, Giovanni Antonini3
13rd Neurology Unit and ALS Centre, IRCCS 'Carlo Besta' Neurological Institute, Milan, Italy.
Introduction:
Recent 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 Analyses:
Protocolised 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 Dissemination:
The 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.
Insights
Guanabenz may slow amyotrophic lateral sclerosis (ALS) progression by reducing protein misfolding and endoplasmic reticulum stress. This study investigates its efficacy and safety in ALS patients compared to riluzole and placebo.
Area of Science:
- Neuroscience
- Pharmacology
- Genetics
Background:
- Amyotrophic lateral sclerosis (ALS) pathogenesis involves endoplasmic reticulum stress and impaired proteostasis.
- eIF2α dephosphorylation is a key mechanism contributing to motoneuron degeneration in ALS.
- Guanabenz, an alpha-2-adrenergic agonist, modulates protein synthesis and prevents misfolded protein accumulation.
Purpose of the Study:
- To evaluate the efficacy of guanabenz in slowing ALS progression.
- To assess the safety and tolerability of guanabenz in ALS patients.
- To investigate guanabenz's effect on neurodegeneration biomarkers.
Main Methods:
- A multicentre, randomized, double-blind, placebo-controlled phase II clinical trial.
- Patients with ALS treated with guanabenz or riluzole for 6 months.
- Primary endpoint: reduction in disease progression using the ALS Milano-Torino Staging (ALS-MITOS) system.
Main Results:
- Guanabenz demonstrated neuroprotective effects in preclinical ALS models.
- The study aims to provide data for a potential phase III trial.
- Results on clinical outcomes, safety, and biomarkers are pending.
Conclusions:
- Guanabenz shows promise as a disease-modifying drug for ALS.
- Further research is warranted to confirm its therapeutic potential.
- Inhibition of eIF2α dephosphorylation may be a viable therapeutic strategy for ALS.
