Action plan 2014-2016

Grid of our tasksTREAT-NMD has always worked to a clearly defined "description of work", with agreed deliverables, milestones and expected achievements. This milestone-driven approach clearly drove the network's progress forward, therefore it was considered crucial to maintain this momentum by establishing new goals and defining the priorities and direction for future collaborative work across the NMD field.

The first ‘Action Plan’ built around the network’s core tools and resources has now been updated and the details of the outcomes achieved since the end of our EU funding can now be found here.

The TREAT-NMD Executive Committee, Taskforce and Secretariat have worked on updating and defining a new set of priorities in the form of this second work plan document that will take the network through to 2016. As well as the tasks described in the Action Plan, additional projects led by network participants will continue to make use of the network tools. Anyone interested in contributing to these tasks or proposing new areas of activity for the network is invited to contact the named coordinator.



Animal Model - Standard Operating Procedures

Markus Rüegg

Implementation of standardized protocols and guidelines for DMD and SMA

A closer collaboration with TACT (Prof. Dominic Wells and Prof. Annamaria de Luca) will allow identifying those procedures that are frequently not applied and that therefore may need to be revisited, as well as those new experimental procedures worth standardizing for the benefit of research and improvement of quality. Available protocols will be kept updated.

Expansion to other disease areas

With the residual AFM funding for 2014, protocols presently in preparation will be finalised and JoVE protocols will be published. Links to protocols available at EuroBioBank will be established. In addition, a study on mouse models for the merosin-deficient MDC1A (the most common CMD), with assessment of common outcome measures and their variability and recommendation for animal handling and experimental design will be finalized and submitted for publication.

Discussion with stakeholders

Besides the regular reviewing of existing SOPs and the expansion to animal models of other diseases, TREAT-NMD aims at initiating a discussion with stakeholders from different areas on how to improve the quality in reporting results of preclinical efficacy assays and  how to increase their significance for patient trials. If you are interested in contributing to these efforts, please contact Raffaella.


Marco Crimi

Samples availability

Approximately 15,000 new samples are collected each year

Services for Scientists

Training sessions can be organised upon request:

Primary muscle cell culture (at University of Munich, Germany) Contact Dr. Peter Schneiderat

DNA extraction techniques (at Second University of Napoli, Italy) Contact Prof. Luisa Politano


Alessandra Ferlini

Discovery of new biomarkers

The discovery task (using both targeted and Omics approaches) will increase the number of exploratory biomarkers to be further validated. However, since this task is high demanding, sharing strategies and defining common criteria will increase the possibility to have data quickly usable in clinical practice.
Therefore, it would be useful to build up a map of the ongoing research project across EU, USA and other countries, in order to maximise the opportunities to work together and to share data and knowledge.

Biomarker Validation

This is an extremely important task requiring high cooperation in terms of sharing data, databases and biosamples. Techniques and platforms would also benefit from having common plans in order to accelerate the validation and subsequent development programs. It is recognised that there is a need for longitudinal samples for validation of markers to be also linked to natural historu studies. Well defined functionally and repeated functional tests need to be done.

Non-, low-invasive biomarkers

There is an agreement on the need to identify biomarkers in fluids (plasma, serum, urine) to reduce drastically the invasiveness (muscle biopsy) in NMD clinical trials.
This implies intense research on discovery and also validation, as well as the need for large, homogeneously and clinically defined patient cohorts for validation. It is, therefore, imperative to organise non/low invasive, routine, longitudinal samples collections in NMDs. This effort would need a coordination to facilitate both actions and the dialogue among all centres.

Surrogate biomarkers

A surrogate biomarker is a tool that could be used to accelerate the process of making the drug available on the market. It can be defined as “a laboratory measurement or physical sign that is used in therapeutic trials as a substitute for a clinically meaningful endpoint that is a direct measure of how a patient feels, functions, or survives and is expected to predict the effect of the therapy.” The primary difference between a biomarker and a surrogate marker is that a biomarker is a “candidate” surrogate marker, whereas a surrogate marker is a test used, and taken, as a measure of the effects of a specific treatment. However, the regulatory authorities will only accept a surrogate endpoint when a strong correlation with clinical benefit has been convincingly shown by robust data. An accompanying biomarker can be used to support, integrate and anticipate a clinical outcome measure, which remains the gold standard as endpoint in that specific trial. Pharmacokinetic and pharmacodynamic biomarkers are also very important and can support the primary endpoint in clinical trials by confirming the drug mechanism (what the drug does to the body and what the body does to the drug, respectively).
To facilitate biomarker clinical application for rare diseases, the dialogue with regulatory authorities is required. This is an action included in the COST Action BM1207.

Genetic modifiers

Aa accurate and specific disease stratification would facilitate patients enrolment in clinical trials. Genetic modifiers are genetic entities (generally SNPs) that define factors which can modify the disease features and improve the disease definition in term of prognosis. Identifying genetic modifiers requires large well defined patient cohorts for discovery and validation.

Care & Trial Site Registry - CTSR

Jan Kirschner

Expansion of CTSR

The objective for the next few years is to win many new sites that treat neurodegenerative diseases, so that the CTSR can also be an asset for researchers and industry working in this field. The CTSR will continue to recruit more institutions caring for neuromuscular patients, too. The aim is to have all important medical centers with expertise in neuromuscular diseases both for children as well as for adults in Europe and North America registered into the CTSR. Therefore, a continuing effort will be put into publicising the CTSR.

Data quality

There will be further work on the data curation to avoid duplication of data entry. Duplicate sites need to be identified, contacted and merged. The registered users will be encouraged to update or complete the data for their site.
In larger sites often more than one investigator is active in the field. Therefore, the roles and rights of the users will be revised, so that one user can administrate the rights of the other users of his site and several users can change and update data.
Also, to prevent duplicate entries, anyone wishing to register will be presented with a list of sites in their country. Only if they cannot find their site on the list, they could open a new site.

Collaboration with research networks and patient organisation

It is further planned to work with research networks and patient organisations that might use the CTSR to monitor activities of the centers in their network. For example, if sites agree, a patient organisation could get access to the data entered by the sites they work with and they could also use the CTSR to add specific questions for their sites. This will be made possible by a flexible construction of the database so that a subset of questions might only be visible to specific sites.

Quality of sites

There will be a joint effort to make quality of sites more visible. If a center is certified as a center of expertise by a national or international organisation or health authority this should be visible in the CTSR along with a link to the appropriate website and quality criteria that have been used. Using existing national and international designation processes seems more appropriate than developing new quality control criteria. This would mean that for example MDA sites or CINRG sites can easily be identified or searched for in the CTSR.

Ethical Issues - PEC

Elizabeth Vroom

In 2013 the PEC decided to continue to be responsive and proactive regarding ethic issues in translational research in NMD. To identify, discuss and respond to questions and organise a conference call at least every 6 month or more often if needed.

PEC responses can be found here on the TREAT-NMD website.

Harmonising Research Efforts through Networking

Annemieke Aartsma-Rus

Organisation of regular meetings

Using COST funding 2 or 3 workshops on exon skipping will be planned each year. The topics will be chosen by partners involved in this work as needed.

Meetings on “Brain delivery of exon skipping compounds” (Madrid January 2014, organised by Aurélie Goyenvalle, Matthew Wood and Annemieke Aartsma-Rus) and “Antisense oligonucleotide chemistry and toxicology” (Stockholm April 2014, organized by Samir el Andaloussi, Mike Gait and Annemieke Aartsma-Rus) have already taken place.

Exchange of scientists between laboratories

Exchanging scientists between laboratories is a good way to facilitate and enhance networking and to harmonise the field. Within COST Actions there is funding available for short term visits of (early stage) researchers to another laboratory (5 – 90 days, see for more information). All researchers working in countries (not Institutes) linked up to a COST Action are eligible for this. Within the TREAT-NMD Alliance, there are currently two COST Actions active, one on exon skipping (, coordinated by Annemieke Aartsma-Rus) and one on MRI (coordinated by Volker Straub). If you are considering applying for an exchange visit using COST funding, please visit the websites of the respective Actions to see whether you are eligible.

Harmonisation of biochemical outcome measures (dystrophin quantification) - Francesco Muntoni

University College London and Leiden University Medical Center are now embarking on a similar effort to compare protocols to quantify exon skipping levels. This will be sponsored by COST.

MRI - Standard Operating Procedures

Volker Straub

The work that TREAT-NMD has started on MRI/MRS as outcome measures in neuromuscular diseases has been taken on by a comprehensive working group that applied for funding through the European COST program. The project proposal entitled “Applications of MR imaging and spectroscopy techniques in neuromuscular disease: collaboration on outcome measures and pattern recognition for diagnostics and therapy development” was funded for 4 years and is chaired by Prof Volker Straub (Newcastle University) and co-chaired by Prof Pierre Carlier (IoM, Paris). The start date of the program was 1 January 2014. Additional information is also available on the following websites: MYO-MRI and COST ACTION BM1304.

The main aim of the imaging program is to advance novel MRI and MRS techniques for both diagnosis and quantitative monitoring of neuromuscular diseases through sharing of expertise and data, joint development of protocols, opportunities for young researchers and creation of an online atlas of muscle MRI and MRS.

Secondary objectives will be achieved via four Working Groups (WGs), each of which has a specific focus, defined outcomes and agreed deliverables.

Improvement of diagnosis and understanding of muscle pathology

Knowledge about the onset of muscle pathology detected by imaging, about the degree of progression, the spectrum of selective involvement across the whole body and about modifiers of these parameters is still very sparse for the majority of NMD. This lack of information might delay the diagnosis of patients with NMD and impede our understanding of disease mechanisms.

Specific objectives: 1.1
: Hold 2 WG meetings per year that coordinate the collection of an agreed number of standardized MR images for defined diseases. 1.2: Establish and validate a secure Information Technology (IT) platform to share medical images between experts. 1.3: Establish an online inventory of muscle MR images with associated standardised clinical and genetic data from NMD prioritized by the consortium (including a spectrum from pre-symptomatic to advanced, whole-body images, where appropriate cardiac images). 1.4: Define regions of interest (ROI) for each disease, indicating the optimal muscle to biopsy or to be used for outcome measurements in a clinical trial setting (showing most reliable change over time). 1.5: Develop a user friendly digital NMD atlas of muscle MR images with public access.

Development of multicentric outcome measures (OMs)

The most important reason why quantitative muscle MRI and MRS is currently not applied routinely across trial sites in multicentric studies is because of the lack of standardized and validated MR protocols for both data acquisition and data analysis. Trial participants therefore either need to all travel to a single centre or there is a risk that data is not comparable across centres. Protocols may need to be tailored for specific diseases. There is also a global lack of young researchers, (MR physicists and radiographers) with expertise in this area, and given its rapid growth it is essential to encourage new researchers to specialise in this field. Enabling STSMs for young researchers to gain expertise in different departments is crucial to catalyse development of expertise in the “next generation”.

Specific objectives: 2.1:
Hold 2 expert WG meetings per year that serve to develop SOPs for imaging protocols relevant for quantitative muscle imaging in natural history studies and clinical trials. 2.2: Publish optimised protocols for Dixon acquisition (Iterative Decomposition of water and fat with Echo Asymmetry and Least-squares estimation, IDEAL vs non-IDEAL, and fat spectrum simulation) and T2 acquisition using new approaches (partially Spoiled Steady State Free Precession, pSSFP, acquisitions) validated in a multicentric, cross-platform setting. 2.3: Hold 1 training school per year for MR staff from different centres at a central location, coordinated by the Action’s Dissemination and Training Committee (DTC). 2.4: Offer up to 4 STSMs per year for ESRs to train in muscle imaging at centres of excellence. ESRs from Eastern Europe will be encouraged to make use of the offer as will those who are working in neuromuscular centres with an interest in clinical trials. Applicants are selected by the DTC. 2.5: Provide expert site visits for onsite training on outcomes of WG1 and WG2 to ensure implementation of the relevant protocols. 2.6: One international conference on neuromuscular imaging as a show case for European translational research in rare diseases.

Exploration of new contrasts, new targets and new imaging techniques for NMD

New imaging techniques and contrast agents evolve with the development of improved MR technology and need to be tested against established protocols for their added value in the quantitative assessment of muscle pathology.

Specific objectives: 3.1:
Hold 2 expert consensus WG meetings per year to confidentially share pre-clinical and clinical data with the intention to develop joint protocols for new imaging techniques. 3.2: Publish joint reports on experimental validation of new contrasts relevant for the diagnosis and/or assessment of NMD and recommendations for their application by non-experts.

Exploration of strategies for muscle imaging texture analysis

Muscle architecture disorganization is a frequent end-stage feature of chronic NMD and particularly of muscular dystrophy. These structural changes translate into abnormal dispersion of the NMR signal distribution within muscles. The NMR signal heterogeneities result in increased standard deviation of muscle signal intensities. This very simple index has been shown to identify dystrophic muscle in animal models and to normalize when dystrophin expression is restored. However it does not take into account possible particular spatial distribution of muscle signal intensities. Texture analysis algorithms may reveal topographical patterns and improve diseased muscle characterization.

Specific Objectives: 4.1:
Hold Working Group meetings of experts to define strategies of muscle texture analysis and to define the best NMR contrast for these techniques to be applied. 4.2: Compare results obtained with different approaches and determine their merits for monitoring disease evolution. 4.3: Publish joint reports and manuscripts on the relative performances of all techniques tested.

Diagnostics for neuromuscular disorders and new gene identification

Kathryn N North & Nigel G Laing

Establishing and providing next generation sequencing diagnostic services

Each country needs to design and deploy next generation sequencing (NGS) diagnostics to suit its own health system. It is our opinion, however, that NGS diagnostics should be organised in each country as a network of centres of next generation sequencing excellence. These next generation sequencing centres must be allied with networks of clinical and pathological excellence. This requires a network of clinicians and pathologists, expert in each of the groups of diseases. The sequencing and clinical and pathological centres of excellence do not need to be co-located, though this is advantageous, but must have clear, efficient and effective communication.

Costs of next generation sequencing diagnostics

It is noteworthy that whole exome sequencing or next generation sequencing of a large targeted gene panel is cheaper than the gold standard Sanger sequencing, that molecular diagnostics has relied on for so long, of single large genes.
Sequencing a targeted panel of genes is always going to be cheaper than obtaining the same depth of coverage through whole exome sequencing or whole genome sequencing.
Questions of cost per patient will be an overriding factor for health services in each country.Each country needs to work out how to fund NGS diagnostics within its health system.
Equity of access to next generation sequencing diagnostics, as with any new high tech procedure, is an important question for health systems, and health systems in each country will have to dealing with questions of equity of access to next generation sequencing diagnostics, each in their own way.

The availability of next generation sequencing diagnostics places pressure on current practice and ethics

Research has been carried out into the use of whole exome or whole genome sequencing of newborns in newborn intensive care units. This raises questions in relation to changing currently accepted ethical practice of not testing for genetic status, including carrier status, until the age of majority, when the patient or family member can decide for themselves what they want to know about their genetics.

Next generation sequencing diagnostic also raises the possibility of spreading preconception carrier screening to the entire population, whereas it is currently largely confined to ethnic groups with high levels of carrier status for recessive disease.
Certain applications of next generation sequencing diagnostics may therefore push the boundaries of acceptable medical practice.

A number of the initiatives we propose are currently being investigated in various collaborations. This includes investigation of molecular diagnostics by exome sequencing and sequencing of targeted gene panels in the European Union Framework Program 7 project “NEUROMICS” and by NEUROMICS Australia. In Australia, different methods of establishing next generation sequencing nationwide, including funding options, are currently being explored by Neuromics Australia and the Australasian Neuromuscular Network.

Outcome Measures

Eugenio Mercuri

Refining existing measures /natural history data

Long term longitudinal studies are being collected in DMD boys using the NSAA and 6MMWT, two measures already used in DMD clinical trials, to obtain better information on the progression of the disorder in patients at different ages and different severity and to establish how these measures can predict important clinical endpoints such as loss of ambulation.

More work is also needed to coordinate this effort and to establish the possible effects of regional differences and of different standards of care across countries and also to implement the training and improve inter observer reliability across centres.
Similar results are being collected in SMA.

Identification of new clinical measures

Development of a revised upper limb module for SMA

Work is in progress to extend the upper limb module for SMA measure, initially developed for weak non-ambulant type II SMA, by adding a number of new activities in order to reduce ceiling effect. Preliminary data on the revised upper limb module are ready to be submitted for Rasch analysis.

Assessment of upper limbs in DMD

Work is in progress to establish longitudinal changes using the PUL and the relationship between possible changes and a number of variables such as age, baseline values and type of mutation. Cross validation with other measures is also needed.

Development of new methods of assessment for young infants with DMD.

A protocol that could be used to assess the early phases of motor and general aspects of development in infants affected by DMD is being proposed and is now being piloted.

Myotools /accelerometer

New tools to assess pinch (MyoPinch), grip (MyoGrip) and the ability of patients to produce repetitive flexion/extension movements of wrist and fingers (MoviPlate) have been increasingly used in natural history studies and in some of the forthcoming studies. Further work is in progress to establish their suitability in SMA and in other disorders.

Improving methods of analysis

There are plans to run workshop and use conference calls to define conceptual frameworks behind each scale (disease specific).

Bring expert opinion together for workshops to review the analysis, construct and content of the scales. Use new psychometric tests, such as Rasch analysis, to conduct in-depth analysis of how the scale is working.

Use workshops and expert opinion to apply clinical sensibility to the Rasch analysis.

Establish a Rasch analysis team which would include a funded coordinator, consultancy advisor, staff responsible for data input and data cleaning.

Identification of non-clinical measures

The work on quantitative imaging and pattern recognition is still ongoing and further work is needed. Funding would be required to:

  • run workshop / use conference calls to bring expert opinion together to finalise the preliminary results obtained after the first workshops
  • plan further activities and improve the knowledge on how to standardise and disseminate the use of muscle MRI in a multicentre setting
  • agree how to collect data more systematically and provide common protocols for children and adults to be used in different centres in order to obtain longitudinal data in untreated patients
  • develop differential diagnoses for patterns of skeletal muscle pathology and to develop collaborative projects. Improving our knowledge on pattern recognition would not only help in the diagnostic approach to muscle diseases but would also provide us with useful information about the general pathophysiology of these diseases and help to select muscles for quantitative MRI assessments and outcome measure development.

Patient Registries

Jan Verschuuren

Coordination of the Patient Registries

The coordination and oversight of global patient registries for DMD, SMA and create the global DM1 and FSHD registries.

TGDOC information on the TREAT-NMD website

To gather further information from the TGDOC members, such information on clinical or research activities and include this information on the TREAT-NMD website.

Support the establishment of additional national registries for DMD, SMA, DM1, FSHD and other diseases

To continue provide advice to the new starting patient registries. To encourage the use of the core datasets.

Collaboration with MDA and other patient organisations to help develop patient registries to link additional data types

To continue the discussion on collaboration with the MDA on the patient registries and explore future collaborations with regards to the CTSR, standards of care and biobanks.

Registry utilisation for industry-sponsored studies

To continue to utilise the registries for the industry-sponsored studies using an established cost recovery model to assist with long term sustainability has been devised and implemented.

Data quality assurance

To continue to improve and then sustain the quality and completeness of the current dataset and ensure annual updates are achieved.

Surveillance registry platform for DMD and other conditions

To continue work on the development of a centralised disease specific post-marketing surveillance database that will allow drug treatments to be carefully tracked and monitored in separate secure modules once marketing approval is granted. Enable the link between the existing patient registries and this centralised database.

Utilisation of registries for academic studies and spin-off projects

To increase academic usage of registries and develop a standardised cost recovery model for academia.

Utilisation of registries for patient information, education and participation

To improve communication with TGDOC members and curators by sending out more regular updates and relevant information in between the TGDOC and Curators’ meetings. The relevant information in could then be disseminated by the curators to the patients. In this way the registries to contact patients with information relevant to their disease with the aim of enhancing the bond that currently exists between patients and TREAT-NMD.

Regulatory Interactions - Issues

Annemieke Aartsma-Rus, Steve Lynn & Nathalie Goemans

Within the COST Action on exon skipping there is funding for several smaller and larger workshops to discuss regulatory issues for clinical development of exon skipping for rare diseases.

A small workshop is planned in 2014 to discuss exon skipping challenges and biomarkers with a regulatory expert.

A larger workshop similar to the one organized in 2009 is foreseen for 2014/15.

Furthermore, it is anticipated that TREAT-NMD will respond on an ad hoc basis to regulatory issues that come up.


Dominic Wells

Review Meetings

TACT will continue to hold review meetings every 6 months.

Reaching out with TACT model to other rare disease groups

TACT is committed to spreading the model for accelerating drug discovery in rare diseases based on our experience. To this end we will regularly review and publicise TACT activities and will continue to reach out to other rare disease groups via personal contacts and relevant conferences. The current examples are:

  1. A paper describing the TACT model and achievements has been submitted as a commentary to Science Translational Medicine
  2. TACT members hosting a pre-conference tutorial on the TACT model for therapeutic review in rare diseases at the ERCD meeting in Berlin in May 2014.
  3. Members of other rare disease networks to attend TACT as observers covered by Confidential Disclosure Agreements. A member of the Beyond Batten Disease Foundation attended the meeting in May 2014.


TACT will seek funding to ensure a minimum of 3 year stability – core funding for a co-ordinator and twice yearly meetings. Various members of the Core committee and the Secretariat will be tasked with approaching specific organisations for funding.

TREAT-NMD Secretariat

Website & communications resources

The TREAT-NMD Secretariat is responsible for:

  • continued updating, maintenance and development of the TREAT-NMD website
  • publishing and distribution of the monthly TREAT-NMD newsletter
  • development of the social media communications across the network
  • updating and maintenance TREAT-NMD’s Intranet area and mailing lists
  • monitoring, analysis and dissemination (when required) of the amount of internet traffic to the website
  • processing new membership applications to the TREAT-NMD Alliance when required
  • providing advice and assistance to associates and collaborators who want to include information on the network website
  • continually monitoring developments in technology - implementation will be considered if deemed to be 'of value' to the network
  • making available up-to-date TREAT-NMD promotional materials to various bodies, committees and individuals associated with the network

Support service to the TREAT-NMD Alliance and its Committees

The TREAT-NMD Secretariat will continue to provide an efficient and coordinated support service to the TREAT-NMD Alliance, specifically to the TREAT-NMD Executive Committee, TREAT-NMD Global Database Oversight Committee (TGDOC), and the TREAT-NMD Advisory Committee for Therapeutics (TACT).

Management of industry interactions
The TREAT-NMD Secretariat will continue to act as the first point of contact within TREAT-NMD with regards to industry interactions.

Liaison with registries
The TREAT-NMD Secretariat will continue to manage communication with the TGDOC members and registry curators. The Secretariat will provide support to coordinate studies and enquiries coming from industry and academic researchers to the global registry. The Secretariat will work together with the TGDOC chair on the planning and organisation of the TGDOC and Curators meetings.

Liaison with patient organisations
The TREAT-NMD Secretariat will continue to liaise with patient organisations.

Organisation of regulatory interactions
The TREAT-NMD Secretariat will continue to be responsible for planning and organisation of workshops and meetings with regards to regulatory issues.

Publications related to the network
The TREAT-NMD Secretariat will continue to work on the publications related to the activities of the network.

12 Apr 2017