Edition 2: July 2017

Hello, and welcome to the second Myotubular and Centronuclear Myopathy (MTM & CNM) Registry newsletter, and thank you for your continued support and participation. 

The MTM & CNM Registry is managed by the John Walton Muscular Dystrophy Research Centre at Newcastle University in the UK, funded by the Myotubular Trust, and is part of the global TREAT-NMD Neuromuscular Network.

I hope you find this newsletter useful and informative. Please contact me if you have any questions or comments - I would love to hear from you.

Jo Bullivant (Registry Curator)

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In this edition:


1. Overview of the MTM & CNM Patient Registry:

1a. An introduction to the registry data
1b. Important reminders about registrations
1c. The registry in different languages

2. Making sense of clinical trials:

2a. How do clinical trials work?
2b. Jargon-buster
2c. How registries can help
2d. What happens after the clinical trials?
2e. Online learning

3. MTM & CNM treatments in development

3a. AT132 gene therapy for XLMTM (Audentes Therapeutics)
3b. Dynacure: therapeutic strategies for CNM (IGBMC and Ionis Pharmaceuticals
3c. PI3 Kinase Inhibition for XLMTM (Dr James Dowling)
3d. VAL-0620 enzyme replacement therapy for XLMTM (Valerion Therapeutics)

4. New genes associated with the centronuclear myopathies

4a. CACNA1S (work by the IGBMC Research Centre in France)
4b. SRPK3 (work by the Institute of Genetic Medicine at Newcastle University in the UK)

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1. Overview of the MTM & CNM Patient Registry

The MTM and CMN Patient Registry is an international, patient reported database of patients with myotubular or centronuclear myopathy. We also register female carriers of X-linked myotubular myopathy. Registration is done through the website, and participants create an online account so they can log in to view or update their information at any time.

1a. An introduction to the registry data

We currently have over 200 registrations from 32 different countries worldwide - and as you can see in the chart below, this number is steadily growing:

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The USA and the UK are the largest cohorts by quite a margin, however Germany, Poland, Australia, Spain and the Netherlands are also well represented:

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We collect a wide range of data from registry participants:

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Almost half of the registry participants reported a diagnosis of myotubular myopathy, and 15% registered as female carriers of x-linked myotubular myopathy:

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1b. Important reminders about registrations

Already registered? 

If you joined the registry before May 2016 we will be contacting you soon to arrange the new facility of online access to your registration.

If you registered after May 2016, I will be contacting you to remind you how to update your consent, or to provide any missing information.

You can log in from this page: mtmcnmregistry.org/join-now

(Don’t worry if you can’t remember your log in details. Your username is your email address, and you can reset your password if needed via the “Forgotten your password?” link.)

New registrations:

We welcome the registration of:

• Patients with a diagnosis of myotubular myopathy or centronuclear myopathy, confirmed via genetic testing or muscle biopsy: Please register online at www.mtmcnmregistry.org

• Female carriers of X-linked myotubular myopathy: please email Jo Bullivant.

• Any patient who is deceased but had a confirmed diagnosis: please email Jo Bullivant.

1c. The registry in different languages

The updated registry is currently available in English and German, and will soon also be available in Spanish, Polish, Italian and French. This is a gradual and careful roll-out because all of the information and consent forms are being translated by professional translators and then checked by medical professionals, researchers or expert patients before we implement them. 

Languages will be automatically displayed according to the language setting of your PC browser. If your browser is set to a language that isn’t currently available, the registry will be displayed to you in English. 

If you would like to be notified when a particular language becomes available, please email Jo Bullivant.

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2. Making sense of clinical trials

Clinical trials are research studies that involve patients or healthy people, and they are designed to test the safety and effectiveness of treatments (e.g. a new drug) in a controlled setting. We have put together a collection of resources to help you better understand the world of clinical trials.

2a. How do clinical trials work?

Our MTM & CNM Registry website contains a thorough overview of how clinical trials work, including information about the different phases, what the risks can be, how and why to participate, the importance of consent, and some suggested questions for you to ask if you are considering taking part.

2b. Jargon-buster

There are many different acronyms and terms used when talking about clinical trials. Global healthcare company Novartis have put together this Glossary of clinical trial terms to help improve understanding of a complex area. 

2c. How registries can help

Clinical trial recruitment: Patient registries allow people who may be eligible for clinical trials to be contacted quickly and easily. This is especially important for rare neuromuscular conditions, since without a patient registry, finding enough patients for a trial could take years, delaying the testing of potential therapies.

Feasibility: Information from registries can help companies to evaluate the possibility of conducting a particular clinical trial, and can speed up the trial planning process.

Research: As well as directly supporting clinical trials, registries allow research and questionnaires on care and disease progression (also called natural history) to be conducted, which improves our understanding of a condition and its prevalence. In some cases, just the knowledge that registry data exists can encourage or inspire new research.

2d. What happens after the clinical trials?

Even after a drug has been proved safe and effective in clinical trials, there can be a long approval process to get through before the drug gets into clinics. The MTM-CNM Family Connection have produced this useful Basic overview of the FDA (USA) drug approval process. It is a similar process in other geographic areas of the world.

2e. Online learning

If you would like to learn more about this topic, there are a series of webcasts on medical research and development available from EURORDIS (“The Voice of Rare Disease Patients in Europe”). Topics include:

• How medical research develops into clinical drugs

• When and why to do clinical research

• Clinical trials in non-standard situations

You can access the webcasts here.

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3. MTM and CNM treatments in development

Here we take a quick guided tour of the current research landscape in MTM and CNM:

3a. AT132 gene therapy for XLMTM (Audentes Therapeutics)

How does it work?
The AT132 treatment involves administering a modified (functional) version of the MTM1 gene into XLMTM patients, leading to long-term expression of the protein myotubularin. Studies in animal models have demonstrated that a single administration improved disease symptoms and survival rates, with no significant adverse events or safety findings.  

What is happening now?
In April 2017, the US FDA (Food and Drug Administration) approved AT132 for use in human clinical trials. The approval means that Audentes have been able to initiate their Phase 1/2 study, called ASPIRO, and will soon begin the process of enrolling patients to the US trial sites (not all of these sites have been announced yet). This will be a multi-national study, so they will also be opening sites in Europe.

How can I find out more?

• Audentes have produced these Commonly Asked Questions and Answers about AT132.

• Read the latest press release on the Audentes website or take a look at their pipeline information on AT132.

• Check the ClinicalTrials.gov website for the latest publicly available information on the ASPIRO clinical trial.

• If you have specific questions* and would like to speak to someone at Audentes, you can contact Kim Trant at patientadvocacy@audentestx.com, or call +1 415 805 1049

* Please be aware that outside of the US, some national regulations might require that your doctor contacts Audentes on your behalf.

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3b. Dynacure: therapeutic strategies for centronuclear myopathies (IGBMC - Institute of Genetics and Molecular and Cellular Biology, and Ionis Pharmaceuticals)

How does it work?
The balance of the myotubularin and dynamin proteins in muscles is very important. In MTM and CNM patients this balance is disrupted, and more dynamin is found in their muscles than those of healthy people. Reduced dynamin levels in mice with MTM1, BIN1 and DNM2 mutations resulted in the treated mice having more strength than before the treatment, and surviving as long as healthy mice.

What is happening now?
Because of the promising pre-clinical results, in October 2016 the project was turned into a start-up biotech company called Dynacure, who are dedicated to developing a human drug to be tested in clinical trials in the near future. In parallel, other important investigations, such as testing different methodologies for targeting DNM2, or assessing if such an approach can also rescue other forms of centronuclear myopathies, are ongoing.

How can I find out more?

• Read the lay person summary of this research by Dr Cowling from IGBMC; “New therapy to cure several CNM?” on page 3 of this ZNM – Zusammen Stark! Newsletter.

• Read this Myotubular Trust news article about the launch of the Dynacure company and their grants towards this work.

• Read the recently published article "Antisense oligonucleotide-mediated Dnm2 knockdown prevents and reverts myotubular myopathy in mice"

• Visit the Dynacure website.

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3c. PI3 Kinase Inhibition for XLMTM (Dr James Dowling, Sick Kids, Toronto)

How does it work?
This is a small molecule based therapy for MTM, which means it could be administered orally, or without the need for injections. Dr Dowling’s work has shown that the loss of the MTM1 enzyme in MTM patients results in the accumulation of a specific phosphoinositide (lipid) called PI(3)P. Their hypothesis is that reducing or rebalancing levels of PI(3)P in the body may reverse or prevent many of the problems that affect the muscle in this condition. If such a therapy works it could be used to complement other treatments.

What is happening now?
Dr Dowling and his team have developed a prioritised list of 15 drugs that are predicted to achieve the desired action, and they are currently being tested in animal models. Results to date are very encouraging and this work was published in the high impact journal JCI (Journal of Clinical Investigations) in August 2016.

How can I find out more?

• Read Dr Dowling’s lay summary of PI3 Kinase Inhibition on the Myotubular Trust website.

• Read the JCI journal article “PIK3C2B inhibition improves function and prolongs survival in myotubular myopathy animal models”.

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3d. VAL-0620 enzyme replacement therapy for XLMTM (Valerion Therapeutics)

How does it work?
Myotubularin is the name of the enzyme missing in patients with Myotubular Myopathy. The goal of VAL-0620 is to replace the myotubularin enzyme, thereby reversing or preventing the myopathy and respiratory symptoms in patients.

What is happening now?
VAL-0620 is currently at the pre-clinical stage and results so far are promising. Valerion are working towards initiating pharmacology studies to assess dosage and safety, with a view to progressing towards clinical studies in humans.

How can I find out more?

• Read more information about VAL-0620 on the Valerion website.

• Read the journal article “Enzyme replacement therapy rescues weakness and improves muscle pathology in mice with X-linked myotubular myopathy”.

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4. New genes associated with the centronuclear myopathies

4a. CACNA1S

Dr Jocelyn Laporte's team at the Institute of Genetics and Molecular and Cellular Biology (IGBMC) have identified and characterised a novel gene implicated in centronuclear myopathy; CACNA1S. This important breakthrough could uncover new potential research avenues, as well as giving hope to families who currently do not have a genetic diagnosis.

By high-throughput sequencing of the DNA of 11 patients who did not have a genetic diagnosis for their myopathy, the researchers revealed that all of them had mutations in the same gene. These mutations are widespread in the gene and are either from recessive or dominant transmission. The gene CACNA1S was already well studied because of its implication in other diseases, but this is the first time it has been associated with a congenital myopathy.

To find out more:

• Read the news article on the IGBMC website.

• Read the published article in the Acta Neuropathologica journal.

4b. SRPK3 - a new candidate gene for congenital myopathy

Ana Topf’s team at Newcastle University in the UK have recently identified a new X-linked gene associated with congenital myopathy; SRPK3. Patients first present symptoms in childhood with walking difficulties and delayed milestones. Weakness is slowly progressive and mainly of the lower limbs, with no bulbar (speech/swallowing), ocular (eye) or facial involvement. Creatine kinase levels in the blood are normal or mildly elevated, and muscle biopsy shows core-like areas and increased number of internal nuclei. Presentation is otherwise unremarkable.

Through international collaborations and data sharing, the team at Newcastle identified a total of six families carrying loss of function mutations in this gene, resulting in absent or reduced expression of the protein.  

This work is still ongoing and has not yet been published. 

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Goodbye for now

Thank you for taking the time to read this newsletter. We are always looking for new ideas for content, and we believe the best people to give these ideas are the people who read it. So if you have any feedback on this newsletter or ideas for the next one, we would love to hear from you. Please contact me, Jo Bullivant, at mtmcnmregistry@treat-nmd.eu