Archive for: 2016

Location: Heemskerk

This workshop was co-sponsored by:

Consensus reached on a global FSHD registry. Global FSHD consortium created

Lay Summary

If you are an individual with FSHD, or a family member, you may have been asked to join a patient registry. Perhaps you are wondering what a registry is?

Disease registries are an essential tool for advancing research to understand a disease, improve patient care, and develop treatments. Typically, registries collect patient contact information, and demographic and diagnosis data. In addition, registries may collect varying amounts of data about your health and symptoms. The data will be anonymized and accessible only by authorized individuals, to protect the privacy of patients and families who participate.

In the FSHD field, there are patient registries in at least 13 countries. On the one hand, that’s great news. On the other hand, having data on this rare disease scattered across so many registries that work in isolation is a cause for concern. Ideally, FSHD patient data from around the world should be collected in a single global registry or a federation of national registries that could talk to one another, so that we have data from as many patients as possible, gathered in a uniform way using the latest standards for diagnosing and describing the condition.

A group of registry curators worked with the FSHD Champions, an international alliance of FSHD patient advocacy organizations, to organize an international workshop to discuss how to move toward this vision of a global FSHD registry. We all agreed that the key goals for this registry are to:

1. Accelerate research to understand and treat FSHD;
2. Empower patients to gain insights from the data about their condition and improve their health and quality of life.

This second point is very important. Traditionally, registries have not given information back to patients. Doing so takes considerable thought and work, but we all feel strongly that providing this information to patients and families is an obligation we owe to the patient community.

Over the three-day workshop (November 18-20, 2016) supported by the European Neuromuscular Center (ENMC), 23 individuals from the U.S., Canada, U.K., France, Italy, Spain, the Netherlands, Czech Republic, Australia, New Zealand, representing academia, industry, and patient advocacy groups, gathered to review current FSHD registries.

The participants of the 225^th ENMC workshop on “A global FSHD Registry Framework”

We discussed issues in clinical and genetic diagnosis, and ideas for how to evolve from the current 13 registries toward a global network with a way to aggregate data from multiple registries. There was a powerful desire among the participants to collaborate and arrive at a consensus on a number of essential topics. We are happy to report that we delivered on our aims, and more.

The workshop attendees agreed on an updated list of “core data elements” (information that are considered fundamental for the description of disease in each subject) that all registries should collect, and drafted a set of questions that will enable patients to supply this data to registries. We plan to publish the new core data elements in the Neuromuscular Disorders journal and distribute them to all FSHD registry curators.

Very importantly, while FSHD patients show a very wide range of symptoms and severity, the new core data elements focus on a small subset of signs that are mostly likely present in an FSHD patient. This ensures that the registry will not exclude any FSHD patient, while limiting the number of questions that patients would need to answer about their clinical status.

We also agreed on a genetic definition of FSHD that reflects our latest knowledge of FSHD genetics. This allows for “non-penetrant” and “asymptomatic” individuals to be defined as carriers of FSHD based on their genetics, but who have no symptoms or have such mild symptoms that the individual does not notice them. This is important to isolate elements (genetic or environmental) that can interfere with the appearance of disease symptoms. It also excludes patients who appear to have FSHD but lack of what it is now considered the essential genetic basis for FSHD.

In addition, we agreed that FSHD registries should serve as a platform for research. By time-stamping patients’ updated information (rather than overwriting old information with new), a registry can track changes in patients’ health and symptoms over time. Researchers can send surveys to registry participants to gain insight into a wide range of topics, from pain management, the effects of exercise, diet, and medications, the impact of pregnancy and menopause, and so on. We agreed that such research surveys should be shared among the registries so that they can be used in different populations.

Buoyed by this success, we went even further. Dr. George Padberg proposed that an international consortium be formed to continue the work. Workshop organizers Rossella Tupler (Italy), Baziel van Engelen (The Netherlands), Hanns Lochmuller (UK), and June Kinoshita (USA, patient advocacy representative) were asked lead the new consortium, joined by Drs. Rabi Tawil (USA).

The new organization will be called the FSHD Consortium. The name leaves open the possibility of expanding beyond registries to drive international collaboration on a variety of future research studies and initiatives.

Establishment of the global registry and FSHD Consortium will enable us to achieve greater clarity on the nature of FSHD and on factors that can make a difference to patients’ health and quality of life.

Acknowledgements: We thank the European Neuromuscular Center for a generous grant to support the workshop. The FSH Society, FSHD Stichting, and Friends of FSH Research provided additional support.

A full report of this workshop is published in Neuromuscular Disorders (pdf)

List of FSHD Champions members:

Location: Naarden

Translation of this report:
French

This workshop was co-sponsored by:

Organizers:

Diana Ribeiro (London, UK), Caroline Le Guiner (Nantes, France), Fulvio Mavilio (Evry, France), George Dickson (London, UK).

Workshop Description:

The 223rd ENMC workshop entitled “AAV (Adeno-Associated Virus) Microdystrophin Gene therapy: Trial Ready for Duchenne Muscular Dystrophy (DMD)” took place from the September 16th to 18th September 2016 in Naarden, The Netherlands. A multidisciplinary group of 23 persons from 7 countries (UK, USA, Germany, France, Netherlands, Belgium, Iceland and Ireland) attended the workshop, including 14 clinical and basic science researchers, 3 industry participants, 2 patients, and 4 representatives from the following DMD patient organisations: AFM, MDUK, Action Duchenne, Join our Boys and Living with Duchenne. It is unique, since an ENMC workshop on gene therapy for DMD has never been organized before. The discussions were divided in 4 sessions, encompassing the following topics: background and other examples of AAV gene therapy; preclinical development of microdystrophin AAV vectors; AAV vector GMP production, toxicology and immuno-toxicology; DMD gene therapy clinical trial design and execution. The aim of the workshop was to share, receive, collate and report on the expert opinions in the field on: (i) current ongoing or near-horizon AAV gene therapy trials, (ii) development of AAV microdystrophin vectors, (iii) production and toxicology of AAV vectors, (iv) immunogenicity of AAV vectors and transgenes, and (v) DMD Gene therapy clinical trial design and execution.

Workshop Outcomes:

Virus-mediated gene therapy applications to restore dystrophin expression are widely considered as a promising treatment avenue to directly address the underlying genetic cause of DMD. Many different viral vectors exist, each with specific properties. Adeno-associated virus (AAV) is non-pathogenic and has been well characterised in pre-clinical studies and in recent clinical gene therapy trials, for example for spinal muscular atrophy and haemophilia. There are various challenges involving AAV gene therapy both in general and for the DMD gene. Lab-based genes encoding the full-sized dystrophin protein are generally too large to be accommodated into AAV gene therapy vectors. For this reason, there have been a range of so-called microdystrophin genes artificially designed, which are small enough to fit into an AAV vector, and yet retain much if not all of the functionality of the normal sized dystrophin can be discarded without losing much of its function. These approaches were discussed in detail. The distribution of viral vectors to the skeletal muscle, diaphragm and heart to deliver the treatment and expression of microdystrophin was also discussed in detail. Two types of AAV vectors or serotypes (AAV8 and AAV9) were described for microdystrophin delivery and seem to be currently best suited and practical for DMD gene therapy. These variant vectors and microdystrophins have been studied in the mouse, rat and dog animal models of DMD with significant positive results, in terms of reduced degeneration of muscle tissue, scar tissue, and improved muscle functionality and stability, and improved clinical parameters (movement, gait and breathing). Duration of microdystrophin expression and clinical improvements were observed for at least 2 years after a single administration of an AAV gene therapy vector. Effective gene therapy targeting widespread muscles has been shown to require relatively large doses of AAV vectors to be administered which challenges production methods and may limit the number of people that can be recruited into clinical trials. Scaling up of AAV vector production from lab-based levels to semi-industrial pharmaceutical grade production takes significant investment to meet the stringent standards related to purity, potency and safety that are required for human clinical trials. Different methodologies to generate the required amount of purified product for DMD trials are currently being evaluated were discussed in terms of efficiency and practicalities of production. The safety of, and immune response to, AAV gene therapy vectors and microdystrophin products were extensively discussed. While no adverse immunological responses are observed generally in animal studies, prior and ongoing clinical trials in humans have shown that low-level and transient elevations in serum liver enzymes may occur most likely due to immune system reactions to AAV surface protein (called the capsid). Such responses in human subjects have been below the level to generate serious clinical concerns, but have nevertheless been managed by transient mild immunosuppression using steroid drugs (glucocorticoids). It was discussed that any DMD patients recruited into AAV-microdystrophin gene therapy trials will likely be already receiving steroid treatments and that this was considered an advantageous situation although steroid dose levels might have to be adjusted temporarily. It was also discussed that either due to pre-existing exposure to AAV in individuals prior to gene therapy, or following an initial gene therapy treatment, the presence of antibodies to AAV in patients would present a barrier to efficient re-administration of second and subsequent doses. It was noted that approaches to prevent and/ or circumvent this effect were under development but would likely prove difficult. Discussion of trial designs indicated that they would follow a standard approach in the field with initial small scale safety and dose-escalation studies (Phase I and Phase II), with primary outcomes of safety and tolerability, and secondary outcomes monitoring microdystrophin expression, immune parameters, MRI scans and clinical tests of muscle function. Due to the unusual circumstances in AAV gene therapy trials where a first treatment may preclude secondary higher dose treatments, it was noted and discussed that in dose-escalation safety studies, careful consideration of the initiating dose, and patient recruitment and ethical consent would be required. A full report of this ENMC workshop will be published in Neuromuscular Disorders in the first half of 2017.

Participants:

Eduard Ayuso (Nantes, France), Anna Buj-Bello (Evry, France), Serge Braun (Paris, France), Jeff Chamberlain (Seattle, USA), Marinee Chuah (Brussels, Belgium), George Dickson (London, UK), Dongsheng Duan (Missouri, USA), Ward Greve (The Netherlands), Caroline Le Guiner (Nantes, France), Michael Linden (London, UK), Fulvio Mavilio (Evry, France), Anna Mayhew (Newcastle, UK), Francesco Muntoni (London, UK), Paula Naughton (Dublin, Ireland), Guðjón Reykdal Óskarsson (Iceland), Diana Ribeiro (London, UK), Jude Samulski (Florida, USA), Laurent Servais (Paris, France), Volker Straub (Newcastle, UK), Thierry VandenDriessche (Brussels, Belgium), Jenny Versnel (London, UK), Jim Wilson (Philadelphia, USA).

A full report will be published in Neuromuscular Disorders.

Location:Naarden, The Netherlands

Organizers: M. M. Reilly (UK), D. Pareyson (Italy), J. Burns (Australia), D. Singh (UK).

Participants: Mary M Reilly (London, UK); Davide Pareyson (Milan, Italy); Dishan Singh (Stanmore, UK); Joshua Burns (Sydney, Australia); Michael Shy (Iowa City, US); Matilde Laurá (London, UK); Jonathan Baets (Antwerp, Belgium); Gita Ramdharry (London, UK); Adnan Manzur (London, UK); Isabella Moroni (Milan, Italy); Luca Gaiani (Imola, Italy); Paul Gibbons (Sydney, Australia); Glenn Pfeffer (Cedars Sinai, US); Wolfram Wenz (Heidelberg, Germany); Jan Willem Louwerens (Nijmegen, the Netherlands); Per Henrik Agren (Stockholm, Sweden); Viola Altmann (Nijmegen, the Netherlands); Peter Briggs (Newcastle upon Tyne, UK); Nicolò Martinelli (Milan, Italy) who was able to attend with the Young Scientist Award, made possible by the ENMC Company Forum (see www.enmc.org); Karen Butcher (Christchurch, UK); Fillippo Genovese (Modena, Italy); Marco van der Linden (Eindhoven, the Netherlands).

This workshop was co-sponsored by the CMT UK and INC

Description of the workshop

The 221st ENMC workshop entitled “Foot surgery in Charcot-Marie-Tooth disease (CMT)” took place from  the 10th of June to the 12th of June 2016 in Naarden, The Netherlands. A multidisciplinary group of 22 participants from 8 countries (UK, Italy, Germany, Belgium, Australia, USA, Sweden and the Netherlands) attended the workshop, including clinical researchers, orthopaedic surgeons (expert in foot and ankle surgery), physiotherapists and three patient representatives from CMT UK, ACMT-RETE and Dutch Neuromuscular Disease Association. They shared ideas and experiences related to surgery in CMT and identified new research areas for the future. It was unique, since a meeting on surgery and CMT with neurologists, orthopaedic surgeons and patient representatives has never been organized before.

Background

Foot deformities in CMT patients are common.  A cavo-varus deformity (the typical high arched foot seen in CMT), which represents the most frequent deformity, may increase the level of disability of these patients due to instability and foot pain. Over the years many surgical procedures have beenadvocated for the treatment of foot deformities in CMT. However, the lack of well-documented clinical indications and proven results mean we do not know the optimal surgical treatment of such deformities.

Furthermore, in the orthopaedic literature most of the studies reporting the clinical outcomes after different techniques for treatment of CMT foot deformities use a broad set of clinical scores and are relatively short term, leading to difficulties in comparing studies on the same condition.

Aims

The purpose of this workshop was to provide physicians and orthopaedic surgeons involved in the management of CMT foot deformities with an opportunity to review the surgical interventional techniques from an evidence-based and expert perspective and to promote collaborative multidisciplinary research that produces high-quality studies. Therefore, one of the primary goals of this workshop was to agree some basic principles for foot surgery in CMT patients, including types of procedures, indications and outcomes as well as identify areas for future research.

Discussions and achievements

The first part of the workshop was dedicated to a review of the international contemporary practices in CMT treatment by different participants and a comprehensive review of the literature. This part included an introductory presentation by Dr. Singh focusing on the most frequent surgical approaches to treat foot deformities in CMT patients.

In the second and main part, leading experts gave presentations on foot surgery techniques for CMT patients and a discussion was held regarding all approaches.

In the final day the discussion focused on the timing of surgery, the optimum follow up protocol and the identification of the main research questions going forward.

The following key points were achieved

1. Decision on timing and type of surgery should be taken in a multidisciplinary team, including the neurologist and the orthopaedic surgeon.
2. The main broad aim of surgery is to achieve a stable well-balanced foot.
3. A follow-up protocol is being developed to adopt in the clinical setting and which will be  suitable for future research purposes.
4. The critical research question going forward is to standardize a follow up protocol in an international setting to allow proper comparison of surgical techniques and to allow proper long term follow of outcomes.
5. A working group was formed to take the actions identified forward

The participants of the 221^st ENMC workshop on foot surgery in CMT

A full report is published in Neuromuscular Disorders (pdf)

Location: Heemskerk, The Netherlands

This workshop was co-supported by The Joshua Frase Foundation and Cure CMD

Organizers:

Peter Hackman, Folkhälsan Institute of Genetics, University of Helsinki (Finland)
Bjarne Udd, Neuromuscular Research Center, Tampere University (Finland)
Carsten Bönnemann, NINDS/NIH (USA)
Ana Ferreiro, Unité de Biologie Fonctionnelle et Adaptative, Université Paris Diderot  (France)

The goal and purpose of this ENMC workshop was to establish an international database of TTN (Titin gene) mutations, variations and their clinical presentations, to be able to determine if particular genetic variants of the gene are the cause of disease. Titin is a giant protein, that functions as a molecular spring responsible for the structural integrity and passive elasticity of the muscle. TTN mutations have to date been reported to be the cause of various diseases collectively termed titinopathies, including a range of skeletal muscle and cardiac diseases.

We brought together worldwide leaders in the Titin myopathy field, Titin family advocates, as well as representatives from other successfully developed groups. Some attendees are already collaborating together to identify disease causing genes and their clinical descriptions.

Nederland, Heemskerk, 30 april 2016.
ENMC. Groepsfoto.
Foto: Jeroen Poortvliet.

Discussion

“Titin is complex and our need for answers is urgent.” said Titin patient representative Sarah Foye.  After welcoming remarks by Prof. Bjarne Udd and the ENMC Managing Director, Foye opened the meeting by sharing several patient stories to convey patient perspectives.

The meeting then went on to discuss clinical presentations as well as genetic variations of cases from multiple clinicians and researchers. In the sharing spirit of the conference, people presented various cases that have not yet been published in the medical literature. There is a wide range of clinical symptoms that include things like muscle weakness, rigid spine, upper and lower body contractures (tight joints), breathing problems, heart disease and more. The age when symptoms start ranges from birth to adulthood. It became clear that the range of Titin symptoms is multifaceted and varied.  Dr. Ana Ferreiro suggested using the term “congenital titinopathies” to describe the whole spectrum of infantile-onset muscle diseases, with or without heart involvement, associated with TTN mutations.  Dr. Carsten Bonnemann commented that when diagnosing titinopathies clinicians need to consider genetic information (“genotype”), physical features (“phenotype”), microscopic lesions of the muscle cells (“histiotype”) and functional defects (“physiotype”).

The meeting covered different methods of making a genetic diagnosis. The tools for analysis of whether these variants are disease causing or not were reviewed. The group then assessed several databases in existence to see if they would meet the needs. Due to its large size and intricate nature, determining whether a TTN gene variant causes disease or not is a tough challenge. In addition, the current computer tools available are not adequate to meet this need. Thus, a Titin-specific database is necessary.

Specific database requirements were then discussed.  The database needs to include the ability to make an accurate genetic diagnosis as well as to capture a good clinical picture of symptoms.

Outcomes:

• Attendees agreed that a Titin-specific database is needed.
• The group drafted clinical questions to include in the database.
• Platforms for housing the database were presented and discussed.
• Patient/family experiences were portrayed and appreciated.
• A collaborative spirit was strengthened among attendees.
• A commitment to move forward to making a difference for families with titinopathies was renewed.

• “Plan B” platform alternatives were mentioned in case the “RD-Connect platform” be deemed unsuitable.

Key deliverables and who is taking the lead:

• The clinical questions on PhenoTips were drafted for the database.  Final touches to these questions will be made within 60 days. (Ferreiro, Saravese, Hackman, Udd)
• A pilot version of the database based on the RD-connect platform will be tested and data from 100 samples will be uploaded by June 30^th 2016. (Saravese, Hackman, Udd, Evangelista)

• After the RD-Connect pilot has been evaluated an on-line meeting will be held in September to discuss the experiences and the execution of follow up actions. (All, Foye to organize online meeting logistics)
• If a decision is made based on the pilot study to use RD-connect, then the groups which attend the workshop will submit their data into the database. (All)
• A computer program for analyzing Titin variants currently named, “Titin Viewer” developed by Isabelle Richard, has been drafted and will be piloted by 30^th June 2016. (Hackman, Udd, Saravese, Beggs and other interested parties)

Future meetings:

• Online meetings as needed to move the database forward.
• A new ENMC follow up workshop to decide further steps based on the experiences with the utility of the database will be applied for in one year, after the full report has been published in the journal of Neuromuscular Disorders. In this follow up workshop decisions on the wider access to submit data to the database, curation of data submitted from outside the consortium and integration of the cardiomyopathy part will be made.
• Participants in this workshop were: Bjarne Udd, Neuromuscular Research Center, Tampere University (Finland); Peter Hackman, Folkhälsan Research Center (Finland); Ana Ferreiro Unité de Biologie Fonctionnelle et Adaptative (France); Carsten Bonnemann, NIH/NINDS (USA); Alan Beggs, Boston Children’s Hospital/ Harvard Medical School (USA); Mathias Gautel, King’s College London (UK); Mark Davis, PatheWest Laboratory (Australia); Teresinha Evangelista, Newcastle University (UK); Marco Savarese (via the ENMC Young Scientist Award), Folkhälsan Research Center (Finland); Jelena Nikodinovic Glumac, Clinic for Neurology and Psychiatry for Children and Youth (Serbia); Jocelyn Laporte, IGBMC (France); John Edward Smith, University of Arizona (USA); Isabelle Richard, Genethon (France); Henk Granzier, University of Arizona (USA); Raphäel Schneider, IGBMC (France); Heinz Jungbluth, King’s College (UK); Sarah Foye, Titin family representative, Congenital Muscle Disease International Registry (USA); Alison Rockett Frase, patient representative, Joshua Frase Foundation (USA).Thank you to the ENMC and our sponsors who helped fund with non-European travel expenses. A full report will be published in Neuromuscular Disorders.

A full report is published in Neuromuscular Disorders (pdf).

This workshop was made possible with the generous support from :

Organisers

James Dowling, Heinz Jungbluth, Ana Ferreiro, Francesco Muntoni.

Description of the workshop:

The 217^th ENMC workshop entitled “RYR1-Related Myopathies” took place from the 29^th to the 31^st of January 2016 in Naarden, The Netherlands. A multidisciplinary group of 20 individuals from 7 countries (UK, USA, Italy, Switzerland, France, Netherlands and Canada) attended the workshop, including 17 clinical and basic science researchers, an RYR1 patient, a patient’s parent and representatives from the RYR1 Foundation (www.ryr1.org), the advocacy group for patients affected by RYR1-related conditions.

Patient Representative quote:

“As a parent of a child with a severe congenital neuromuscular condition, I must convey my sincere gratitude to the ENMC for organising the workshop into RYR1-related myopathies at Naarden.  This forum provided the perfect platform for the worlds leading experts to present their latest research, share ideas and develop theories in a collaborative way.  It is truly reassuring to see first hand how so many dedicated individuals are working together with the ultimate objective of finding effective treatments and cures for those that are affected by this and other similar conditions.”

Background:

RYR1 myopathies are due to a change or mutation in the RYR1 gene. This mutation in the RYR1 gene is usually inherited from one or both parents, who may or may not be affected by the disease. There are two types of inheritance patterns for changes in this gene: autosomal dominant and autosomal recessive. “Recessive” means that both “copies” of the gene must have mutations for the patient to be affected; if only one copy is defective, the person (parent or unaffected sibling) will be a carrier and not be affected clinically (that means they will have no signs or symptoms). “Dominant” means that even if only one copy of the gene is defective, the patient and any relative (parent or sibling) carrying the same faulty copy will be affected by the disease.

The term “congenital myopathy” refers to a group of muscle conditions with muscle weakness beginning at birth or in early childhood. Mutations or changes in the RYR1 gene are the most common genetic cause of congenital myopathies. The RYR1 gene encodes for the ryanodine (RYR1) receptor, a channel in muscle cells that regulates the flow of calcium, a critical component of muscle contraction. A reduced number and/or abnormal RYR1 channels lead to dysfunctional muscle contraction and weakness. There is a wide range of symptoms for RYR1-related muscle weakness, but those are typically either non-progressive or very slowly progressive.

Common symptoms include weakness of the eye muscles (in particular in recessive forms) and generalized muscle weakness, typically affecting the muscles closest to the torso of the body.  Some individuals experience muscle cramping and pain, difficulties exercising, and intolerance to heat. There are typically no heart problems and intelligence is not affected.

At this time, no cure exists for RYR1 myopathies

Discussions and Achievements:

Leading experts gave multiple presentations during the course of this weekend workshop into RYR1-related myopathies. The main presentation themes and discussion points have been summarised below:

• Presentations were conducted on the correlations that exist between muscle disease characteristics and RYR1 sequence variants.  It was made clear that better understanding these correlations is essential for clinicians to be able to provide families and patients with accurate information on disease diagnosis, prognosis and to develop effective treatments moving forward.  A number of examples were provided to illustrate real-life similarities and patterns amongst:
  • Patients that are affected by the disease from a young age (early onset myopathy)
  • Patients that developed muscle disease symptoms later in life (adult onset myopathy)
  • Patients within the same family that have an RYR1 myopathy of varying severity
  • Patients of certain ethnic backgrounds
  • Patient muscle tissue sample correlation analysis and implied disease severity
  • Correlations between RYR1 muscle disease and Malignant Hyperthermia susceptibility (MHS), an inherited tendency to develop severe, potentially life-threatening reactions to certain anaesthetics and muscle relaxants.

• A number of presentations were also dedicated to the basic science of RYR1 myopathies.  Specifically, recent advances in the ability to model the crystal-like structure of the ryanodine receptor at extremely high resolutions, has enabled researchers to observe the workings of the receptor in incredible clarity. In turn, this has significantly improved our understanding of how the receptor is actually impacted by different variants in the RYR1 gene.  This level of understanding is essential in the quest to find new effective treatments, which can improve the function of the ryanodine receptor and alleviate disease symptoms. The development of Rycals, pharmacological compounds with the potential to modify defective RYR1 function, was discussed as one such new treatment that may help to properly regulate the flow of calcium from the ryanodine receptor to the muscle. This treatment has been tested on mice that have an RYR1 myopathy and has been shown to improve ryanodine receptor function and increase muscle strength. It is expected that human clinical trials of Rycals will commence sometime next year.
• Information was also provided on drugs that are in clinical trials or that are already FDA approved, and which may be used as treatments in the not too distant future for patients suffering from an RYR1-related myopathy.  These drugs include:

• • N-Acetlylcysteine (NAC)
    • This drug has been shown to reduce oxidative stress in zebra fish that are suffering from an RYR1 myopathy.  Evidence was shown that this drug may help to increase endurance, stamina and improve muscle function in affected zebrafish. This drug has been used to treat varying conditions in humans for many years, seems to have relatively few side effects and is inexpensive. A clinical trial of NAC in humans with RYR1-related myopathies is currently underway and preliminary findings seem positive. The clinical trial is due to be completed in 2017 and official results will be published shortly thereafter.
  • AICAR
    • It was suggested that AICAR may help to increase cell energy release and improve muscle function in those affected by muscle weakness due to RYR1 mutations.  However, relatively few studies have been conducted which analyse its side-effects and the drug would need to be administered in high concentrations to be effective, which may be cost prohibitive as it is expensive.
  • Dantrolene
    • Information was provided which showed that Dantrolene is an effective treatment for Malignant Hyperthermia (MH) but may also be of benefit to patients that have a MH-related RYR1 mutation with additional symptoms such as exertional rhabdomyolysis (i.e. severe muscle breakdown provoked by exercise).
  • CRISPR
    • CRISPR is a gene therapy tool, which is recognised to have huge potential. However, it is recognised that there are significant hurdles to overcome before this treatment will be ready for human clinical trials. Efficiency of gene editing mechanisms, eliminating off target effects, the removal of CAS9 after editing and reducing the cost of creating customised treatments are seen to be the main challenges. Currently, this gene editing tool is being tested in RYR1 affected mice and preliminary results on whether this has improved the mouse phenotype should be available later this year. Although it will be many years before CRISPR will be available as a treatment that can correct genetic variants in humans, its huge potential is clear.

Next steps/key deliverables

• It was explained that a particular challenge to clinical trials for rare neuromuscular diseases is the lack of a central global database or register that lists affected patients and their symptoms. This makes it difficult for pharmaceutical companies to understand the breadth of the disease and to make contact with suitable clinical trial candidates. As a result, a key deliverable was to establish a central register of those patients affected by an RYR1 related myopathy and to accurately capture their symptoms.
• The need to provide RYR1 patients with access to consensus care guidelines and disease information resources was listed as a key deliverable.
• The participants discussed potential for further collaborations, in particular concerning modelling of RYR1 variants to ascertain there precise effects on the ryanodine receptor structure and function. Systematic capture of symptoms of RYR1-related myopathies (for example, increased bleeding, bowel and bladder dysfunction) that are not strictly related to skeletal muscle dysfunction was identified as another area where further collaborative work is needed.

Participants

Robert Dirksen (USA), Susan Hamilton (USA), Andrew Marks (USA),  Katy Meilleur (USA), Sheila Riazi (Canada), Francesco Zorzato (Italy), Susan Treves (Switzerland), Heinz Jungbluth (UK), Carsten Bönnemann (USA),  James Dowling (Canada), John-Paul Cutajar (UK), Julian Faure (France), Isabelle Marty (France), Caroline Sewry (UK), Phil Hopkins (UK), Ana Ferreiro (France), Francesco Muntoni (UK), Mike Goldberg (USA), Nicol Voermans (Netherlands), Jennifer Ryan (USA).

A full report is published in Neuromuscular Disorders (pdf)