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H2020

MIROCALS Report Summary

Project ID: 633413
Funded under: H2020-EU.3.1.

Periodic Reporting for period 1 - MIROCALS (Efficacy and safety of low-dose IL-2 (ld-IL-2) as a Treg enhancer for anti-neuroinflammatory therapy in newly diagnosed Amyotrophic Lateral Sclerosis (ALS) patients)

Reporting period: 2015-09-01 to 2017-02-28

Summary of the context and overall objectives of the project

Amyotrophic Lateral Sclerosis (ALS) is a fatal degenerative disorder of the brain and spinal cord affecting some 40,000 individuals in Europe, causing 11,000 deaths each year. Our pioneering work on riluzole showed that it is possible to modify ALS progression but all subsequent trials of potential neuroprotective agents have failed. Nerve cell death in ALS is associated with inflammation, which contributes to cell damage, and is a logical target for therapy. Although therapeutic attempts to modify this have failed so far, the discovery of regulatory T cells (Tregs) as key players in controlling inflammatory processes opens new possibilities since defective Treg function is important in ALS. In fact, Treg numbers and function predict rates of disease progression and survival. Low-dose interleukin-2 (ld IL-2) safely and specifically increases and activates Tregs in conditions such as type 1 diabetes, HBc-vasculitis and chronic graft-versus-host disease, so ld IL-2 has the potential to significantly improve survival and deliver a therapeutic breakthrough in ALS. Our ambition is to develop a new therapy for ALS and through this novel trial design break the impasse in drug development of other disease-modifying agents in ALS. The impact will be to enhance quality of life and care for people with ALS, and provide a robust model for Industry to encourage investment in ALS and other neurodegenerative diseases.

The program is structured into 7 work packages (WP): WP1 dedicated to the strategic and administrative management of the project; WP2 developing all Good Clinical Practice (GCP) Essential Documents, get approval from regulatory bodies and Institutional Review Boards, and organize the preparation of treatment units, clinical data collection, sample collection, banking and assays, all in compliance with the GCPs and GCLPs; WP3 to conduct the clinical trial; WP4 to establish the effect of low dose IL-2 on key effectors and regulators of the neuro-inflammatory process and their relationship with response to treatment and disease activity; WP5 to try to establish proof of concepts that will shorten and simplify future trials by investigating a number of candidate biomarkers in different body fluids; WP6 to see what genes are expressed in the blood in response to treatment with riluzole and a low dose of interleukin-2 (ld-IL2) over a period of time and to screen the patients for rare variants in the DNA sequence in genes associated with ALS or T-lymphocyte regulation (the process the IL2 treatment is targeting); WP7 to ensure the dissemination and communication through international visibility as well as the optimal exploitation of the results of MIROCALS.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

In the first period of the project the following work has been done:
In WP1, management tools and templates for the scientific and financial monitoring of the project have been set up. Two physical meetings with all partners have been organised. Partners have been briefed at those meetings on the general H2020 rules and reporting procedures.
In WP2, dossier files for Regulatory and IRBs review were developed and successfully submitted to France and UK Regulatories and IRBs. 13 Centres were selected, 11 were trained and 8 are contracted. 3 Study Committees were constituted and installed (TMT, TSC, and DSMB). All tools necessary for running the trial were developed and/or assembled and/or purchased, and distributed to Clinical Centres. The Central lab was selected and contracted; Validation studies for cytometry were successfully performed and SOPs were drafted. The CMO for treatment preparation was selected; the treatment management specifications document was developed and agreed with the CMO as well as costs. A contract with the CMO should be signed shortly ending the trial start-up phase.
In WP4, FACS and qPCR analysis have been to set up as well as Luminex and ELISA analysis and microRNA purification from peripheral blood.
In WP5, preliminary development of analysis method on a class of proteins that are involved in maintaining the structural integrity of neuronal cells has been performed.
In WP6, preliminary activities were conducted to see what genes are expressed in the blood in response to treatment with riluzole and a low dose of interleukin-2 (ld-IL2) over a period of time and to screen the patients for rare variants in the DNA sequence in genes associated with ALS or T-lymphocyte regulation (the process the IL2 treatment is targeting).
In WP7 during Period 1 were (i) established the MIROCALS logo and website; (ii) established an area within the MNDA website for MIROCALS and drafting an information sheet which for ethical reasons cannot be disseminated until we have a precise date for opening Centres (to avoid raising expectations and then disappointing patient volunteers); (iii) disseminated information about MIROCALS throughout National (UK, French) professional networks and internationally via MNDA through the International ALS/MND Alliance and the Annual Symposia and (iv) drafted information for patients ready to be released directly when the site initiation visits have occurred (as soon as possible after signature of the sub-contracting agent’s contract).

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

Living with ALS is a constant burden, due to muscle weakness and respiratory impairment. Finding a cure early in the course of the disease, before severe disability occurs, would mean dramatically improving quality of life for the patients and families, and reducing the burden on society. There is no doubt that interfering with ALS at the onset would be of global importance. This disease has a major impact on patients since it interferes with all aspects of life and is often disrupting for the affected subject but also for the whole family and social structure around the patient. We bring the hope of intervention in this disease. We firmly believe that by building on a strong model of ALS pathogenesis, we are proposing a sound approach towards effective interventions in ALS. MIROCALS proposed clinical trial, designed to demonstrate efficacy, should prove the potential of low dose IL-2 as a treatment aimed at stopping neuronal damage. Its success will be a major breakthrough for the treatment of ALS. In addition, we have designed the trial in order to identify biomarkers that could assess early responses to treatment. The validation of these biomarkers would be a major achievement in ALS trial methodology, notably for investigation of novel therapies.
During the first period of the project, WP2 being essentially on trial setup, this section is not applicable, neither to other WPs.
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