Edition 3: April 2018

Welcome 

Welcome to our anniversary edition of the MTM and CNM Patient Registry Newsletter! This month we are celebrating five years since the beginning of this international, patient-reported database of patients with Myotubular or Centronuclear Myopathy. The registry collects clinical and genetic data on patients who have been diagnosed with these ultra-rare genetic conditions, and on female carriers of x-linked myotubular myopathy. Here are the key facts:

•Information in the registry is collected directly from the participants (or from a parent or guardian if the patient is under 18). We also welcome registration of deceased patients, if their family wishes to contribute their data.

•Online registration is available to all of these groups, and it can be done in English, German, Spanish, Polish, Italian or French.

•In its first five years, the registry has evolved, transferring to a new online platform which means that participants create a password-protected account and can log in to view or edit their data online whenever they wish.

 Please do come and have a look around the website at www.mtmcnmregistry.org, where you can find more information and register online. If you are already part of the registry, it would be great if you could log in to have a look through your information and update it if needed.

 The purpose of the registry is to...

… to this end, it is most important that the registry holds the most up-to-date information possible, especially regarding the genetic diagnosis. A copy of your genetic report can be uploaded to the registry or sent to the registry curators Jo Bullivant or Lindsay Murphy.

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 Muscular Dystrophy UK, and is part of the global TREAT-NMD Neuromuscular Network.

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

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In this edition:

1. Overview of the MTM & CNM Patient Registry

1a. Who has registered?

1b. Registrations over the last five years

1c. Registration categories

1d. Disease diagnoses

1e. Gene mutation causing disease

1f. Important reminders about registrations

1g. The FDA Embraces ‘Real World’ Data in Clinical Trials

 

2. Current clinical trial and research activity

2a. Respiratory Muscle Function in Untreated X-Linked Myotubular Myopathy (XLMTM)

2b. Prospective Natural History Study of Patients with Myotubular Myopathy and other Centronuclear Myopathies

2c. Molecular and Genetic Studies of Congenital Myopathies

2d.Recensus Study: A Medical Chart Review of Patients with X-Linked Myotubular Myopathy (XLMTM)

2e. Inceptus Study: A Clinical Assessment Study in X-Linked Myotubular Myopathy (XLMTM) Subjects

2f. Aspiro Study: Gene Transfer Clinical Study in X-Linked Myotubular Myopathy

 

3. Potential treatments in development

3a. Gene replacement therapy – AT132 by Audentes Therapeutics

3b. Enzyme replacement therapy – VAL-0620 by Valerion Therapeutics

3c. Antisense oligonucleotide (ASO) knockdown – Dyn-101 by Dynacure

3d. PIK3C2B inhibition - from the research group of Dr James Dowling

3e. Repurposing of known drugs - from the research group of Dr James Dowling

 

4. Recent papers of interest

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1. Overview of the MTM & CNM Patient Registry

 1a. Who has registered?

The registry currently has 228 participants from 34 countries, with the greatest number of registrations coming from the USA, UK and Germany.

1b. Registrations over the last five years have steadily increased, year on year.

1c. Registration categories: male patients are the largest category making up nearly two-thirds of the total registrations. Female patients and female carriers account for 15% each of the registrations, closely followed by the fourth category of deceased patients.

1d. Disease diagnoses: Approximately half of the registry participants have been diagnosed with X-linked Myotubular Myopathy. Centronuclear Myopathy accounts for the smaller percentage. The registry collects disease-specific data to promote research and focus interest into this ultra-rare group of conditions.

1e. Genetic mutation causing disease: Mutation in the MTM1 gene, in patients and in female carriers, accounts for approximately half of the known genetic mutations in the registry. Mutations in DNM2 are present in 8% of registry participants, followed by smaller percentages of RYR1-, BIN1- and TTN-related mutations.

1f. Important reminders about registrations

New registrations are warmly welcomed from all patients with X-Linked Myotubular Myopathy or Centronuclear Myopathy, from female carriers of X-Linked MTM and from relatives wishing to register a deceased family member. Please click here to discover more about the registry and to register.

Already registered? We are currently contacting participants who joined the registry before May 2016 to arrange transfer to the new online platform – if we haven’t already been in touch, we will shortly! For participants already registered, please log in here - 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.

1g. The FDA Embraces the value of ‘Real World’ Data from Patient Registries in Clinical Trials

The opinions and needs of rare disease patients are increasingly shaping the design of clinical trials for new therapies. A recent article in Muscular Dystrophy News Today describes how Commissioner Scott Gottlieb of the U.S. Food and Drug Administration (FDA) is encouraging a move away from traditional, randomised clinical trials with placebo-controls, towards an approach influenced by meaningful end-points and ‘real-world’ data, as well as natural disease histories. In rare diseases, the FDA is increasingly engaging with patient advocacy groups and recognising the value of the data held in Patient Registries, which gather data on very small patient populations, frequently including disease natural history and progression.

The full article may be found here.

 

Remember; our registry is only as useful as the data within it, so please make sure you keep your information up to date, and contact us if you have any questions or problems.

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2. Current clinical trial and research activity

 Here are summaries of some of the current studies being held to help advance our understanding of Myotubular and Centronuclear Myopathy.

2a. Respiratory Muscle Function in Untreated X-Linked Myotubular Myopathy (XLMTM)

This is a longitudinal study which aims to assess the severity and progression of respiratory muscle function in X-linked myotubular myopathy (XLMTM). The study is recruiting patients aged between zero and fourteen years and is gathering information from medical history, physical tests and quality of life assessment, collected over two or three visits. The study is sponsored by, and carried out at, University of Florida, USA, in collaboration with Audentes Therapeutics. It began in October 2015 and is due to end in December 2018. More information about this study may be found here.

 

2b. Prospective Natural History Study of Patients with Myotubular Myopathy and other Centronuclear Myopathies

This natural history study seeks to recruit twenty patients with CNM, who possess mutations in genes MTM1, DNM2 or BIN1. The intention of the study is to collect information over at least a one year period to characterize the disease course of CNM and determine which outcome measures are the most appropriate to assess the effectiveness of potential therapies. The study is being held by sponsor Institut de Myologie, France, in collaboration with Dynacure and is an extension of the European part of an original study, initially sponsored by Valerian Therapeutics. The extension began in May 2017, is being held at sites in Belgium, France, Germany, Italy and Spain and is expected to close in May 2019. More information about this study may be found here.

 

2c. Molecular and Genetic Studies of Congenital Myopathies

Boston Children's Hospital and Harvard Medical School, USA, in collaboration with the Muscular Dystrophy Association, are conducting a molecular and genetic study of congenital myopathies, including MTM and CNM. This long-term study began in August 2003 and is intended to close in 2050 with the final enrolment number of 4000 participants. It seeks to better understand the genes and proteins involved in muscle functioning and disease by the analysis of genetic data and that collected from medical notes. More information about this study may be found here.

Read more about Professor Alan Beggs’s laboratory at Boston Children’s Hospital here.

 

2d. Recensus Study: A Medical Chart Review of Patients with X-Linked Myotubular Myopathy (XLMTM)

RECENSUS is a retrospective medical chart review designed to further characterize XLMTM and to identify possible outcome measures for use in subsequent clinical trials. The international study is sponsored by Audentes Therapeutics and began in September 2014. The data gathered so far demonstrate the significant medical burden for children living with XLMTM, as well as their families and caregivers. More information about this study may be found here.

Read more about the Recensus Study in this Muscular Dystrophy News article.

 

2e. Inceptus Study: A Clinical Assessment Study in X-Linked Myotubular Myopathy (XLMTM) Subjects

INCEPTUS is a prospective, observational, natural history study of patients with XLMTM aged less than four years old, designed to characterize the disease presentation of each participant prior to potential enrolment in the ASPIRO gene therapy clinical trial. Sponsored by Audentes Therapeutics, INCEPTUS is intended to provide a longitudinal baseline and within-patient control for ASPIRO. The study began in July 2016. More information about this study may be found here.

 

2f. Aspiro Study: Gene Transfer Clinical Study in X-Linked Myotubular Myopathy

ASPIRO is a clinical trial to determine the safety and preliminary effectiveness of AT132, a gene therapy product candidate being developed to treat XLMTM by Audentes Therapeutics. AT132 carries a functional copy of the human MTM1 gene within a modified viral vector (AAV8) and has received Rare Paediatric Disease and Fast Track designations from the Food and Drug Administration (FDA).The Phase 1/2 clinical study is recruiting XLMTM patients aged five years or younger, genetically confirmed as XLMTM and requiring ventilator support. The study includes three ascending-dose groups and a delayed-treatment control group. Various outcome measures are being monitored, including motor function, respiratory strength and endurance, time off ventilator, survival, quality of life and adverse events. The first patient was enrolled in August 2017 and, in January 2018, Audentes Therapeutics announced preliminary data in the first three patients to receive AT132. Additional data will be shared periodically as the study and long-term patient follow-up continues. More information about this study may be found here.

Information from Audentes about AT132 may be found here.

Read the Interim Report press release from Audentes to the MTM & CNM community here.

Read Audentes’ letter to the patient community here.

View the slideshow of the first interim Audentes report here.

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3. Potential treatments in development

3a. Gene replacement therapy is currently being developed for the treatment or prevention of disease in patients who carry specific genetic mutations. The therapy involves the delivery of a healthy copy of the mutated gene into the cells in a patient's body that need it most. This healthy gene is tailored to respond to molecular signals within particular cell types, so that the gene's protein product is preferentially made in desired cell types. For example, in the Audentes Therapeutics investigational gene therapy product for XLMTM (AT132), the healthy MTM1 gene carries a signal to encourage its expression in muscle cells. AT132 is currently being studied in a Phase 1/2 clinical trial, designed to deliver a healthy copy of the MTM1 gene in the treatment of XLMTM. A guide to gene therapy can be found here.

Information from Audentes about AT132 may be found here.

Read the original research article Gene Therapy Prolongs Survival and Restores Function in Murine and Canine Models of Myotubular Myopathy (Science Translational Medicine, 2014) written by the research group of Ana Buj-Bello.

 

3b. Enzyme replacement therapy seeks to provide specific, functional enzymes (proteins that facilitate particular biochemical reactions) in patients who are unable to make their own. For example, Valerion Therapeutics are currently developing a therapy for the provision of the myotubularin enzyme in XLMTM patients with the aspiration of improving muscle function and respiratory symptoms and reversing the muscle pathology observed in patients. Valerion’s therapy, VAL-0620, is a protein created by the fusion of myotubularin with a bespoke delivery antibody which enables tissue-specific drug delivery. The company reports that the VAL-0620 development programme continues to progress.

A description of enzyme replacement can be found here.

Information about VAL-0620 can be found here.

Read the original research article Enzyme replacement therapy rescues weakness and improves muscle pathology in mice with X-linked myotubular myopathy (Human Molecular Genetics, 2013) written by the research groups of Alan H. Beggs and Ana Buj-Bello.

 

3c. Antisense oligonucleotide (ASO) knockdown is a therapeutic method that seeks to reduce the expression of a particular gene. Antisense oligonucleotides are short, synthetic, chemically modified strands of nucleotides. When introduced into a cell, they bind with a specific, complementary cellular RNA, the ‘go-between’ messenger from a gene to its protein product. Binding of a cellular RNA with a specific ASO causes its breakdown within the cell and thereby prevents the expression of a specific protein. ASOs are widely used in tissue culture and in animal models, and are more recently approved for use in clinic. French company Dynacure are currently developing their use in the therapy of CNM. One of the genes implicated in several forms of CNM is dynamin 2 (DNM2): dynamin 2 protein is present in greater abundance in the muscles of patients with CNM carrying mutations in MTM1. Also, the dynamin 2 protein has a presumed increased activity in muscles from patients with CNM carrying a DNM2 mutation. Dynacure’s product Dyn101, developed in collaboration with the Institute of Genetics and Molecular and Cellular Biology (IGBMC) and IONIS Pharmaceuticals, USA, is an ASO that targets the messenger RNA of dynamin 2. Within both mouse models (Mtm1- and Dnm2-related CNM), this targeted reduction of dynamin 2 protein led to disease improvement. The company reports that the Dyn101 development programme continues to progress.

Read more about ASO technology on the Ionis website.

Information about Dyn101 can be found here.

Read the original research articles Reducing dynamin 2 expression rescues X-linked centronuclear myopathy (Journal of Clinical Investigation, 2014) and Antisense oligonucleotide-mediated Dnm2 knockdown prevents and reverts myotubular myopathy in mice (Nature Communications, 2017), written by the research groups of Jocelyn Laporte and Belinda Cowling.

 

3d. The laboratory of Dr James Dowling has been investigating the effect of PIK3C2B inhibition on the MTM disease process. Within healthy muscle, the enzyme myotubularin modifies the molecule PI3P. In the muscle of MTM disease animal models, the PI3P molecule tends to accumulate due to the lack of functional myotubularin and it has been speculated that this build-up has some bearing on the development of MTM disease. PIK3C2B is an enzyme responsible for the formation of PI3P. James Dowling’s group engineered the muscle-specific removal of PIK3C2B in a mouse model of MTM. This lowered the amount of accumulated PI3P and had the exciting effect of both completely preventing and reversing the MTM disease process. The team then treated a different group of MTM mice with a chemical that blocks the effect of PIK3C2B and observed both improved motor function and prolonged lifespan. This suggests that PIK3C2B inhibition offers a promising potential treatment strategy for MTM.

PI3P - phosphatidylinositol-3-phosphate              PIK3C2B - class II phosphoinositide 3-kinase

Read the original research article PIK3C2B inhibition improves function and prolongs survival in myotubular myopathy animal models (Journal of Clinical Investigation, 2016) written by the research groups of John Dowling and Ana Buj-Bello.

 

3e. The repurposing of known drugs for the therapy of MTM is another approach being explored by Dr James Dowling’s group. They investigated more than 1000 FDA-approved drugs in a high throughput drug screen in a zebrafish model of MTM and identified a number of potentially interesting drugs that had a positive effect on zebrafish appearance and swim behaviour. The group has selected the most exciting and potentially translatable drug to investigate further. The second drug of interest was serendipitously discovered during their PIK3C2B study. The two drugs selected for further investigation are commonly used in children for conditions other than muscle disease. Though acting in different ways, both drugs have been observed to improve the MTM disease process. The team are now investigating the effect of these drugs on the MTM mouse. A benefit of drug repurposing is that the drug has an established safety record which potentially leads to its clinical development and testing for the treatment of MTM in a more timely and cost effective manner. In addition, the drugs may be applicable to the broader range of patients with centronuclear and X-linked myotubular myopathy and of different ages.

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4. Recent papers of interest

Single Intramuscular Injection of AAV-shRNA Reduces DNM2 and Prevents Myotubular Myopathy in Mice (Molecular Therapy, February 2018) written by the research groups of Jocelyn Laporte and Belinda Cowling.

 

Intravenous Administration of a MTMR2-Encoding AAV Vector Ameliorates the Phenotype of Myotubular Myopathy in Mice (Journal of Neuropathology & Experimental Neurology, February 2018) written by the research groups of Michael Lawlor and Ana Buj-Bello.

 

Successful use of non-invasive positive pressure ventilation in a patient with the severe form of X-linked myotubular myopathy (Brain and Development, January 2018) written by the research group of Tatsuya Fujii.

 

Downregulation of myostatin pathway in neuromuscular diseases may explain challenges of anti-myostatin therapeutic approaches (Nature Communications, November 2017) written by the research groups of Julie Dumonceaux and Ana Buj-Bello.

 

A multicenter, retrospective medical record review of X-linked myotubular myopathy: The recensus study (Muscle Nerve, November 2017) written by many contributors including study sponsor Audentes Therapeutics.

 

A natural history study of X-linked myotubular myopathy (Neurology, September 2017) written by the research groups of Alan Beggs and James Dowling.

 

Affected female carriers of MTM1 mutations display a wide spectrum of clinical and pathological involvement: delineating diagnostic clues (Acta Neuropathologica, December 2017) written by many contributors including by the research group of Jocelyn Laporte.

 

Insights from genotype-phenotype correlations by novel SPEG mutations causing centronuclear myopathy (Neuromuscular Disorders, September 2017) written by the research group of Sebahattin Cirak.

 

Grand paternal inheritance of X-linked myotubular myopathy due to mosaicism, and identification of necklace fibers in an asymptomatic male (Neuromuscular Disorders, September 2017) written by the research group of A. Oldfors.

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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 Jo Bullivant or Lindsay Murphy.

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