National conversation on rare diseases

The Minister for rare disease at the Department of Health and Social Care, Baroness Blackwood, recently announced a national conversation to understand how we can better care for people living with rare disease.

This survey aims to identify the major challenges faced by rare disease patients and the people and organisations that care for them. The themes identified in the survey will feed into a framework to follow the current UK Strategy on Rare Diseases, which runs until the end of 2020.

The survey is seeking input from the rare disease community across the UK, including patients, families and carers, rare disease medical professionals and GPs, clinical academics and industry experts.

You must be living currently in the UK and over 16 years to take part in the survey. If you are under 16 years and are living with a rare disease, please ask a family member or carer to fill in the survey for you.  For further information see below.

The deadline for responses is Friday 29 November 2019.

Audentes news 2019

May 2019

In May Audentes released new data at the American Society for Gene and Cell Therapy (ASGCT) to include more positive feedback about their AT132 gene therapy trial programme (ASPIRO), which is aimed at patients with x-linked myotubular myopathy (MTM1) aged up to five years.

Outcomes from nine patients in total were shared at the meeting. Chairman and Chief Executive Officer of Audentes, Matthew R Patterson said “We are excited to share today’s results and are working hard toward our goal of making AT132 available to patients living with XLMTM globally as rapidly as possible. We look forward to important next steps for the program, including selection of the optimal dose and further discussions with regulators in the U.S. and Europe regarding possible pathways to license applications.”

October 2019

In October Audentes presented new positive data from ASPIRO, the clinical trial evaluating AT132 in patients with X-Linked myotubular myopathy, at the 24th International Annual Congress of the World Muscle Society. The data was presented  by Dr James J Dowling from the Toronto Hospital for Sick Children. Dr Dowling said “The new ASPIRO data shared today builds upon the encouraging efficacy and safety profile seen to date with AT132. Treated patients across both dose cohorts show significant reductions in ventilator dependence and the progressive attainment of developmental motor milestones, suggesting that AT132 has the potential to deliver transformative benefit to patients and families living with XLMTM.”

Natalie Holles, President and Chief Operating Officer of Audentes said “We remain focused on our goal of rapidly progressing AT132 toward global regulatory approvals. Importantly, we have fully enrolled 14 patients into the ASPIRO dose escalation cohorts, and plan to complete enrolment of the ASPIRO pivotal expansion cohort imminently. ”

November 2019

In November the organisation reported its third quarter 2019 financial results and provided a corporate update. Matthew R Patterson, Chairman and Chief Executive Officer stated “AT132 continues to show a promising safety and efficacy profile in patients with XLMTM, with the first seven treated patients now ventilator independent.  Beyond AT132, we are excited about the significant momentum building across our entire pipeline of development candidates.”

Share your experience with x linked myotubular myopathy (xlmtm): a survey for the US X linked myotubular myopathy community

Also in November, Audentes Therapeutics  launched the xlmtm parent and caregiver community survey in the US.  Initially the survey is live for US based families, with UK and German versions coming in early 2020.

Families and caregivers economic and quality of life impact of xlmtm study.

The survey aims to gather important data related to the quality of life and economic impacts of xlmtm and to create a more thorough understanding of the quality of life and economic impact of xlmtm on families and caregivers. The results of this survey will be published and shared with the xlmtm community and may be shared with health policy makers and insurance companies to support patient access to future treatments. 

More detailed information about the study is available below.

Share your experience

Audentes logo.


Graduate researcher

Allison Welter from Farmington, Minnesota has recently featured in a short film about the Graduate Research Programme (GREP) at the Mayo Clinic Graduate School of Biomedical Sciences. Her younger brother Andy is a high school senior and is diagnosed with myotubular myopathy – you can read about Andy in this issue of Our World too.

Since the age of 12 Allison knew she  wanted to discover drugs and therapies to treat or cure diseases like her brother’s. Her experience includes a freshman scholarship known as the Blugold Fellowship, at University of Wisconsion-Eau Claire, a programme designed to carve out undergraduate research opportunities for students as soon as they enrol, during which she spent more than three years studying plant genome sequencing. In addition. Allison secured a summer internship at Boston Children’s Hospital and Harvard Medical School, where she assisted in a lab that studies myotubular myopathy.

Allison says ‘Doing undergraduate research at University of Wisconsin-Eau Claire helped prepare me to be more independent working here at Mayo Clinic. I felt more comfortable being an independent scientist after doing research for so long and the time in Boston allowed me to network with the amazing Harvard faculty. It was a really great experience.’

Since the film was made, Allison has moved on to her Ph.D. studies in molecular pharmacology and experimental therapeutics.

Further information

Read more about Allison below.

Kyle kayaks

Kyle Grant, who lives in the rural State of Vermont in the USA and is diagnosed with myotubular myopathy, has been enjoying adaptive kayaking.  Below, his mum Betsy tells Our World more.

Kyle in kayak.

The activity is organised and led by a physical therapist and volunteers at the Northeast Disabled Athlete Association. Funds were raised, kayaks with adaptations were purchased and a single location was found. Grant funds also greatly assisted.  The short film below gives more information about the organisation.

Each kayak has a paddle that is mounted on a fitting that goes on the front of the kayak, so the paddle never falls into the water out of reach. Floats or outriggers as they are also known, are mounted on the back of the kayaks. These ensure safety so no one can tip it over. Lastly, an accessible location with calm water was chosen.

Kyle in kayak.

A hoyer lift is used to transfer into the kayak seat. Cushions and supports are added as needed. The freedom each person has, in being able to paddle themselves out on open water, is priceless. One participant said “when I’m out here, I’m not disabled”. What a wonderful opportunity!

Kyle in kayak.

Kyle participates in this summer program once a week from late June until late August. He can bring his medical equipment with him and is not alone or far from shore. His strength improves as the weeks go by. Bright sunshine, a boating experience, a feeling of independence and normalcy, make this activity worth every bit of effort!

Research news 2017

During 2017 The Information Point reported on a number of research stories and these can be found below.

Characterisation of a new class of congenital myopathies

With the support of funding from the Myotubular Trust, the team of Jocelyn Laporte, have identified a novel gene, named CACNA1S, implicated in centronuclear myopathy. This is a very important breakthrough as it highlights potential new avenues for research.

High-throughput sequencing of the DNA of 11 patients who did not have a genetic diagnosis for their centronuclear myopathy, revealed to researchers that all of the patients had mutations in the CACNA1S gene. Surprisingly, 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 the gene has been associated with a myopathy and will give hope to families who currently do not have a genetic diagnosis.

Centronuclear myopathy: towards the development of a therapy 

After identifying Dynamin 2 as a potential therapeutic target in congenital myopathies, the team of Jocelyn Laporte at the IGBMC has managed to specifically modulate the level of this molecule and to cure almost all signs of disease. These results published on 7 June 2017 in the journal Nature Communications provide excellent perspectives for therapeutic development.

The centronuclear myopathies, which include centronuclear myopathy (CNM) and myotubular myopathy (MTM), are rare genetic diseases characterised by a very disabling muscular weakness and early death. There are several genetic causes of CNM, in particular mutations of genes coding for myotubularin (MTM1) or dynamin2 (DNM2), proteins that regulate the organisation of muscle fibres.

Three years ago, researchers from Jocelyn Laporte’s team demonstrated in myopathic mice lacking MTM1 that decreasing the level of DNM2 by genetic cross improved the clinical signs of the disease (Cowling et al., 2014). Animals that previously died of the myopathy by two months of age, instead survived two years, a normal lifetime for mice. This proof-of-concept published in 2014 identified DNM2 as a new therapeutic target, generating a large interest for therapeutic development. This required however that an injectable compound targeting DNM2 could be developed for clinical use.

Hichem Tasfaout, Belinda Cowling and Jocelyn Laporte at the IGBMC have collaborated with Ionis Pharmaceuticals, a world leader in antisense oligonucleotides (ASO) technology. ASOs are synthetic RNA fragments that can bind very specifically to target messenger RNAs to promote their degradation.

These researchers have demonstrated that injections of ASOs targeting DNM2 messenger RNA in myopathic mice effectively reduced the level of DNM2 and restore muscle function, either to prevent development of the disease (injection before onset of symptoms) or to revert the signs of the myopathy (injections in a severely affected animal). Treatment resulted in improved muscle function and increased lifespan, using a chemistry and dose that can be translated to patients.

These very promising results contributed to the creation of the start-up company Dynacure, which aims to transform this approach into clinical trials. This study was financed by SATT Conectus and the National Research Agency (ANR).

Myotubular Trust 2017 research grant award

In October 2017 the Myotubular Trust announced its 2017 grant award to Dr James Dowling of Sick Kids Toronto. The grant will allow Dr Dowling and his team to investigate the effectiveness in myotubular myopathy of two existing drugs currently licensed for use in children who have other conditions which have been identified by Dr Dowling’s team as showing encouraging signs of improving the symptoms of myotubular myopathy.

This three year grant from Myotubular Trust and supported by our friends at ZNM – Zusammen Stark! will allow Dr Dowling and his team to investigate the effectiveness of these drugs, either alone or to complement other therapies. Repurposing medicines that are safe and have been used and studied in children is a very exciting goal for rare diseases. We are delighted to be making our 2017 grant of £216,000 to Dr Dowling to pursue this promising project.

“Because these drugs have previously been used in children, we feel that the pathway for clinical development and testing of them can be feasibly accomplished in a timely and cost effective manner” – Dr Dowling.

Continuation of previous grant – PI(3)P levels

During the course of this grant, Dr Dowling’s laboratory will also continue to develop on previous awards by the Myotubular Trust. Loss of MTM1 results in the accumulation of a lipid called PI(3)P in someone with myotubular myopathy. This project will continue to develop inhibitors of PI(3)P that work well in humans and can be translated to clinical use.

“Furthermore, we believe these therapeutic strategies may be applicable to the broader range of patients with centronuclear and myotubular myopathy” – Dr Dowling.

Further information

To read more about this research see below.

Researchers in the Dowling laboratory


Titin mutations cause centronuclear myopathy

This story first appeared in the Information Point newsletter Our World in 2013, when Sarah Foye, Lindsay Swanson, MS, CGC and Elizabeth Torosian told the The Information Point about the discovery that mutations in the Titin (TTN) gene can cause centronuclear myopathy.

As you may know, the congenital myopathies are a group of inherited disorders (passed down from parent to child) that affect the structure of muscles. The class of myopathies known as centronuclear myopathy (CNM) have historically been named due to the muscle cells appearance under the microscope. The nuclei of muscle cells affected by CNM tend to be found in the center of the cell, unlike in healthy muscles where the nucleus is found on the edge of the cell. These internalized nuclei are what give CNM it’s name, but there are several genes known to cause various forms of CNM. These genes are MTM1, DNM2, RYR1, BIN1 and TTN however some genes still remain unknown.

New gene discoveries are taking place as muscle disorder researchers learn more about CNM and more technologies become available. One new technology being utilized in the research lab of Dr Alan Beggs includes whole exome sequencing (WES) and whole genome sequencing (WGS). These new technologies, which can be less expensive than traditional genetic sequencing, allow researchers to look at larger chunks of the human genetic code.

Using this technology, the Beggs Lab, along with a group of collaborators, discovered that mutations in the Titin (TTN) gene can cause CNM. Titin, the largest known protein in the human body, is coded by the TTN gene. It is a structural protein that acts as a molecular spring within the muscle cell, as seen in the drawing to the right. Although Titin has long been known to be a structural protein within the muscle cell, examination of the gene TTN has been limited due to it’s gigantic size. However, the use of new genetic testing methods like WES and WGS have allowed researchers to understand more about Titin and the TTN gene. You can read more about this in the article below.

Beggs et al, used the new genetic testing methods to screen a group of subjects who were diagnosed with CNM by muscle biopsy but tested negative for mutations in all genes known to cause CNM. Through this process, they identified that TTN mutations were likely the genetic cause in five individuals with CNM. You can read more about this in the article below:

However, there still remains a large category of people diagnosed with CNM whose genetic cause remains unknown. With new gene discoveries and new technologies, it can be expected that people can jump from the ‘unknown’ category into a category with a known gene. New clinical testing can help ease the diagnosis by testing for many genes simultaneously. The University of Chicago Genetic Services Laboratories is now offering a state of the art test in which multiple congenital myopathy genes can all be tested at once. Known as next generation sequence genetic testing. This type of testing is faster and cheaper than prior testing methods. This panel includes the TTN gene. If you or a family member have been diagnosed with MTM or CNM but never had a genetic mutation identified or confirmed through a clinical lab, please consider discussing this with your doctor or a genetic counselor.

One final point to note is that TTN mutations are known to cause a heart problem known as adult onset dilated cardiomyopathy. This can have important clinical implications for people who may have CNM caused by a TTN mutation and may be another important reason to have the genetic testing done. Additionally, any person with heart problems and a congenital myopathy may strongly consider TTN as a possibly cause.

International collaboration

Since 2011 the Myotubular Trust has been funding a grant to Dr Jocelyn Laporte at IGBMC in France to use next generation gene sequencing technology to find some of the other genes that cause myotubular and centronuclear myopathy. Jocelyn Laporte says ‘The team in Strasbourg is supported by Myotubular Trust to identify genes linked to myotubular and centronuclear myopathies using the novel genome sequencing approach. Due to this support the lab were able to participate to an international collaborative study that culminated in the identification of mutations in Titin in patients presenting with centronuclear myopathy. Titin is the largest protein of the human body and acts as a molecular spring during muscle contraction and relaxation. Other families with centronuclear myopathy that have previously eluded genetic diagnosis may turn out to be linked to this same gene. Researchers can now use this finding to better establish diagnosis and understand how these myopathies occur’.

The discovery of the Titin protein’s role in this condition is a great example of the power of international collaboration between leading neuromuscular research teams. This is really good news for our community

Genetic testing

If you have been diagnosed with myotubular myopathy but have never had your MTM1 mutation identified of confirmed in a clinical laboratory, you may want to consider enrolling in the MTM Genetic Testing study.

For European patients, where the culprit gene has not been identified via genetic testing, retesting can be requested via a clinician, as most diagnostic laboratories in Europe are currently validating these novel sequencing technologies. In Europe, such a request for re-testing must be made via a clinician, rather than directly to a laboratory and testing is free in some countries.