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TREAT-NMD is a European neuromuscular network awarded by the European Commission (contract number EC 036825) following successful lobbying efforts by groups such as the AFM and ENMC to address the fragmentation currently hindering translational research for cutting edge therapies in rare neuromuscular diseases (NMD). By bringing together experts from different European centres (Table (Table1)1) and working with teams from across the world, it is aiming to accelerate the clinical application of promising treatments for rare NMD. Bringing promising cutting edge therapies into clinical settings is currently delayed by the lack of standardised protocols for preclinical animal studies, molecular diagnoses and patient assessment and management. TREAT-NMD is addressing this fragmentation by establishing a common road map for the progression of cutting edge therapies from laboratory to clinic, from the assessment of cellular and animal models, via issues of delivery, production and toxicology, to relevant clinical outcome measures. This is underpinned by the integration and establishment of pan-European patient databases and biobanks and their global extension. The TREAT-NMD Coordination Centre (TNCC) is developing and integrating organisations and networks comprising the top researchers, clinicians and industries working in Europe in partnership with patient organisations in order to deliver the dream of treatments for these devastating disorders. Technological, educational and communication resources (www.treat-nmd.eu) have been developed as a durable resource co-ordinated by the TNCC. A strong educational programme will also provide the next generation of experts with the necessary background and expertise to maintain this leading position, and integrate the voices of patient organisations in the development of future research plans. Cutting edge treatments currently under development for muscular dystrophies and spinal muscular atrophy have been specifically targeted in this process, while future developments for other disease groups have been benefiting from the durable infrastructure of the TNCC, which will act as the portal for future pharmaceutical developments in the neuromuscular field.
Knowledge of disease causing genes has begun to allow the elucidation of the molecular pathological mechanisms underlying NMDs, leading to plans for specific gene based therapies or targeted pharmaceutical approaches. Some of these treatment options are beginning to move to human studies. Examples include antisense oligonucleotide treatment and stop codon suppression for Duchenne Muscular Dystrophy (DMD), myostatin inhibition in a range of muscular dystrophies, gene therapy approaches to DMD and pharmacological approaches to survival motor neuron gene (SMN) upregulation in Spinal Muscular Atrophy (SMA). These developments, while universally welcomed amongst scientists, clinicians and patient organisations, have exposed the lack of harmonisation of approaches to possibly beneficial therapeutics in NMD, which is hindering a smooth move into clinical trials.
TREAT-NMD is addressing this lack of harmonisation by creating a model in which the development of the tools of the Network through a long-term vision will bring delivery of new treatments while supporting optimal care for patients. The components of the TREAT-NMD model are illustrated in Figure Figure1.1. Individual partners (Table (Table1),1), working with international collaborators, are responsible for the delivery of each of these components of the network which address specific bottlenecks in therapy development and delivery including:
As part of the TREAT-NMD project, the network has been working with international groups to generate and disseminate care standards for SMA and DMD. These collaborative projects have led to the publication of précis of care standards via the TREAT-NMD website in multiple languages. The TREAT-NMD care and trial site network offers a unique opportunity to develop international harmonisation to aid implementation of internationally agreed care standards and disseminate best practice Europe-wide. The Rare Diseases Task Force has noted the substantial national variation in implementation of care through expert centres in European countries and recognises the high added value of collaboration at a European level to harmonise access to expert care for patients across Europe. One method of implementing this is via the establishing of “European Reference Networks" for rare diseases. The public health ramifications of this strategy place it beyond TREAT-NMD’s current remit as a translational research network; nonetheless, the infrastructure being established by TREAT-NMD makes it ideally placed to implement such a network for rare inherited neuromuscular disorders.
As part of its “trial-readiness" strategy, TREAT-NMD has been creating a registry of clinical sites across Europe (and beyond) which have expertise in neuromuscular disease or see neuromuscular patients. As of May 2009, the registry included detailed information on more than 150 clinical trial sites worldwide. In total, these sites can identify over 11,000 neuromuscular patients mapped to a set of diagnostic categories (currently DMD, SMA, CMD and LGMD). Mapping the location, expertise and patient cohorts of these clinical centres is proving key to finding sites capable of running upcoming clinical trials. However, this network of sites with neuromuscular expertise is not only valuable in terms of clinical trials, but also as a platform for disseminating best practice in patient care, for example:
One of the key TREAT-NMD infrastructures built up in the last 2 years is a global patient registry for DMD and SMA comprising more than 20 national patient registries worldwide. The DMD registries now hold more than 9,000 individual patient entries with standardized items and consent facilitating and accelerating clinical research and clinical trials while giving patients improved access to relevant information on standards of diagnosis and care.
Most innovative therapies for patients suffering from rare NMDs are expected to act on gene-specific molecular pathways. In some areas, the specific mutation will determine the applicability of a particular therapeutic technique. Therefore, patient registries for NMDs need to be gene-based and annotating each patient’s mutation correctly is of high importance. Clinical information needs to be captured in a standardized way and updated regularly. For ease of use, and to respond to the need for regular updating, a core set of mandatory data are generated for each disorder. Participation of disease experts is essential for curation of genetic and clinical information and adherence to the TREAT-NMD charter provides assurance of best practice in regulatory and ethical domains. Access to the data in the global registry is regulated by an international oversight committee.
TREAT-NMD is now working with other groups to support similar developments for other rare NMDs such as the Congenital Muscular Dystrophies (with Cure CMD) and Myotonic Dystrophy (with the Marigold Foundation), and others representing several genetic entities. For some of these disorders, leading scientists have set up local registries or private databases that may not be generally available to the research community, and may use different tools and practices (an inventory is available at www.treat-nmd.eu/registries/docs/rare_inventory.pdf). These experts were invited by ENMC and TREAT-NMD to participate in a workshop to encourage collaborative action towards gene-based patient registries for rare, inherited muscle disorders in Europe and worldwide.
The workshop concluded that harmonizing practices, joining forces and merging experience on gene-based patient registries may facilitate research into rare inherited muscle disorders, support upcoming clinical trials, and deliver standards of care (3). Several specific recommendations were made:
TREAT-NMD is committed to delivering innovative treatments for rare neuromuscular diseases, starting with muscular dystrophies and spinal muscular atrophy, from laboratory development to clinical practice via the generation of a durable and sustainable network coordination centre. Although the roots of the network are within the EU 6th framework programme, the collaborations and work of the network now extends globally with members all across the world. Engagement with industry, patient groups and academia is growing with the realisation that the challenges of the new therapeutic era in NMD requires an increasing commitment to collaboration (4). More information on all aspects of the network, including how to become a member, and how to contribute to its activities can be found at www.treat-nmd.eu.