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Solid Biosciences announces new preclinical data about gene transfer

 

One of the objectives of our team is to inform you about new treatments. Here’s the latest news from a recent Solid Bioscience press release about SGT-001, the Company’s lead microdystrophin gene transfer candidate. Enjoy reading and thank you for sharing these articles within the DMD community.

 

Solid Biosciences announces new preclinical data at the American Society of Gene and Cell Therapy Annual Meeting

Solid Biosciences Inc. announced new preclinical data from its gene therapy development programs for Duchenne muscular dystrophy (DMD). New data for SGT-001 further demonstrate its potential to produce long-term and body-wide microdystrophin expression that correlates with significant improvements in muscle function.

 

“Solid remains steadfast in our mission to bring important therapies to patients with DMD, where a significant unmet need exists. These data further support the investigation of SGT-001 as a potential new treatment option for those living with this devastating disease, as well as reinforce our commitment to advancing cutting-edge innovations through our next generation gene therapy pipeline,” said Carl Morris, Ph.D., Chief Scientific Officer of Solid Biosciences.

 

 

About SGT-001

SGT-001 is a novel adeno-associated virus* (AAV) vector-mediated gene transfer under investigation for its ability to address the underlying genetic cause of DMD. SGT-001 is a systemically administered* candidate that delivers a synthetic dystrophin gene, called microdystrophin, to the body. This microdystrophin encodes for a functional protein surrogate that is expressed in muscles and stabilizes essential associated proteins.

  • Adeno-associated virus > is a small virus which infects humans and some other primate species. Link
  • Systemically administered > Systemic forms of administration affect the whole body (in general).

Data from Solid’s preclinical program suggests that SGT-001 has the potential to slow or stop the progression of DMD, regardless of genetic mutation or disease stage. SGT-001 is based on pioneering research in dystrophin biology by Dr. Jeffrey Chamberlain of the University of Washington and Dr. Dongsheng Duan of the University of Missouri.

 

Status

SGT-001 has been granted Rare Pediatric Disease Designation or RPDD in the United States and Orphan Drug Designation in both the United States and European Union. The Phase I/II clinical trial for SGT-001, IGNITE DMD, is currently on clinical hold. Microdystrophin gene transfer trial on hold

 

About Solid Biosciences

Solid Biosciences is a life science company focused solely on finding meaningful therapies for Duchenne muscular dystrophy (DMD). Founded by people touched by the disease, Solid Biosciences is a center of excellence for DMD, bringing together experts in science, technology and care to drive forward a portfolio of candidates that have life-changing potential. Currently, Solid Biosciences is progressing from programs across four scientific platforms: corrective therapies, disease-modifying therapies, disease understanding and assistive devices. For more information, please visit this website: www.solidbio.com.

 

About DMD

Duchenne muscular dystrophy (DMD) is a disease that almost exclusively affects boys and whose incidence is 1 in 3,500. It is extremely rare that Duchenne muscular dystrophy (DMD) will affect girls. Those affected are usually diagnosed around the age of five, but symptoms may be visible from early childhood. It is a degenerative disease of the muscles caused by a genetic mutation. The Duchenne muscular dystrophy (DMD) – for which no treatment is currently available – directly affects skeletal muscles. Without treatment, the consequences of the disease are dire for those afflicted and their families.

 

To know more

SOLID BIOSCIENCES INITIATES CLINICAL TRIAL FOR GENE TRANSFER

GLOBE NEWSWIRE: Solid-Biosciences-Announces-New-Preclinical-Data-at-the-American-Society-of-Gene-and-Cell-Therapy-Annual-Meeting

STAT3 a new research to treat DMD

Canadian Research series

This video series of interviews features Canadian scientists who work on solutions for Duchenne muscular dystrophy (DMD). We wish to connect you – the DMD community – with these scientists. You’ll be delighted to learn about their motivation and dedication to this cause. In turn, they appreciate knowing more about our community, because we’re the people who are impacted by their discoveries. We hope that the interviews will help to foster an understanding of scientific concepts that aren’t always easy to grasp.

 

Meet the Gunning Group

We met and interviewed Patrick Gunning, Ph.D., who leads the Gunning Group, and one of his Ph.D. students, Yasir Raouf. Professor Gunning holds a Canada Research Chair in Medicinal Chemistry and is Director of the Centre for Medicinal Chemistry, Department of Chemical and Physical Sciences, at the University of Toronto’s Mississauga campus.

The Gunning Group is a team of scientists who pursue projects that focus on drug discovery. They work at the molecular level to design new drugs. Their goal is to develop better treatments and diagnostic options for devastating and under-explored human diseases. One of those diseases is DMD.

Dr. Gunning: “Yasir and myself are very motivated to try and see whether a STAT drug would work in DMD,”

 

What to know about STAT3

Their research targets STAT3, a protein that plays an essential role in cell regeneration. STAT3 is a transcription factor that controls or regulates, to some extent, how cells proliferate or grow and divide.

That’s very relevant to DMD, says Yasir Raouf. In DMD, muscle cell regeneration is poor. “Usually in humans, when your muscle cells die, they regenerate, and you get new muscles. If you have DMD, that regeneration is slow or nonexistent.”

If you can control STAT3, you can control the regenerative capacity of muscle cells, he believes.

 

What’s the timeline for development of this treatment?

Over the last decade, the Gunning Group developed a STAT3 drug that inhibits this protein. Over the next two years, they plan to test its effectiveness in mouse models. They will study how it affects muscle cell proliferation in mice over an extended period. For this work, they will collaborate with Dr. Michael Rudnicki, Professor and holder of a Canada Research Chair in Molecular Biology at the University of Ottawa.

 

Words of hope for the DMD community

Dr. Gunning has a message for families in the DMD community: “It’s very important to raise awareness for this disease.”

He urges families to highlight to the industry that people need help and new drugs to treat this orphan disease. “If money and efforts in research are put towards this disease, I’m very confident that academics like myself or industry can find something that will spare the lives of these children.”

Yasir Raouf hopes that we will soon live in a world that has cured DMD.“That’s what I hope for. That’s what I work for.”

 

More about the Gunning Group: http://www.gunninggroup.ca

 

Connect to our Canadian Research Series

An effective way to be informed and to receive our videos right out of the box is to sign up here for our newsletter.

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Capricor initiates HOPE-2 clinical trial

One of the objectives of our team is to inform you about new treatments. Here’s the latest news from a recent press released by Capricor which announces the clinical trial HOPE-2. Enjoy reading and thank you for sharing these articles within the DMD community.

CAP-1002 aim to maintain or improve cardiac and skeletal muscle function

Capricor’s lead candidate, CAP-1002, is a cell therapy that is currently in clinical development for the treatment of Duchenne muscular dystrophy (DMD). CAP-1002 is an allogeneic product, meaning that it is manufactured from donor heart tissue and then stored until needed for use. CAP-1002 consists of allogeneic cardiosphere-derived cells, or CDCs, a unique population of cells that contains cardiac progenitor cells. CAP-1002 has been shown to exert potent immunomodulatory activity and alters the immune system’s activity to encourage cellular regeneration. CDCs have been the subject of over 100 peer-reviewed scientific publications and have been administered to approximately 140 human subjects across several clinical trials.

Status by the FDA

CAP-1002 has been granted orphan drug designation by the FDA for the treatment of DMD.

About the HOPE study

Capricor’s previous clinical trial, the HOPE-Duchenne trial, evaluated the safety and efficacy of a single dose of CAP-1002 in boys and young men with heart disease related to Duchenne muscular dystrophy. It found CAP-1002 was safe, well tolerated and demonstrated significant and sustained signals of improvement in cardiac and skeletal muscle function.

HOPE 2

Participants in the HOPE-2 trial will be randomized to receive either placebo or CAP-1002, delivered intravenously every three months for a total of 4 administrations. Participants will be followed for a yearlong period following randomization, and an open-label extension (OLE) study is planned. The trial evidence should suggest an appropriate risk/benefit profile of CAP-1002 in the medical indication. Capricor – HOPE-2

Where is the trial?

The medical center in Sacramento is the first site in the nation to begin enrolling and treating participants. Approximately 12 to 15 investigative sites are expected to participate in the trial.

About Capricor

Capricor Therapeutics is a clinical-stage biotechnology company focused on the discovery, development and commercialization of first-in-class biological therapeutics for the treatment of rare disorders. Capricor’s lead candidate, CAP-1002, is an allogeneic cell therapy that is currently in clinical development for the treatment of Duchenne muscular dystrophy.

What is DMD?

Duchenne muscular dystrophy (DMD) is a disease that almost exclusively affects boys and whose incidence is 1 in 3,5000. It is extremely rare that Duchenne muscular dystrophy (DMD) will affect girls. Those affected are usually diagnosed around the age of five, but symptoms may be visible from early childhood. It is a degenerative disease of the muscles caused by a genetic mutation. The Duchenne muscular dystrophy (DMD) – for which no treatment is currently available – directly affects skeletal muscles. Without treatment, the consequences of the disease are dire for those afflicted and their families.

For more information:

Rare Disease Report

GlobeNews Wire – Press Release

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Edasalonexent: Positive results and no side effects

One of the objectives of our team is to inform you about new treatments. Here’s the latest news from a recent Catabasis press release about edasalonexent. Enjoy reading and thank you for sharing these articles within the DMD community.

The MoveDMD trial through 48 weeks of edasalonexent treatment

 

“ We believe that these effects will ultimately translate to boys with Duchenne maintaining functional abilities longer.”

Said Jill C. Milne, Ph.D., Chief Executive Officer of Catabasis, in a press release this week.

The fact that no evidence of side effects or safety has been observed after more than 37 patient-years of exposure to treatment is also encouraging.

What is Edasalonexent?

Edasalonexent (CAT-1004)  is being developed as a potential foundational disease-modifying therapy for all patients affected by DMD, regardless of their underlying mutation. It is an investigational oral small molecule. Edasalonexent inhibits NF-kB, a protein that is activated by DMD and drives inflammation and fibrosis, muscle degeneration and suppresses muscle regeneration.

You can watch our video here to have a more in-depth explanation about the basis of this treatment.

 

Positive results:

Statistically significant improvement was observed compared to the off-treatment control period. These improvements show a slowing of disease progression and are in addition to the improvements found in all assessments of muscle function through more than a year of edasalonexent treatment.

What’s next?

Catabasis is preparing for a Phase 3 trial that will enroll approximately 125 boys with DMD between the ages of 4-7 years old regardless of mutation type and who have not been on steroids for at least six months. It is planned to be a single, global, placebo-controlled Phase 3 trial with two boys receiving edasalonexent for every one boy receiving placebo. After 12 months in the trial, all boys are expected to receive edasalonexent in an open-label extension.

Approbation in the US: FDA Status

The FDA has granted orphan drug, fast track and rare pediatric disease designations and the European Commission has granted orphan medicinal product designation to edasalonexent for the treatment of DMD. For a summary of clinical results reported to-date, please visit www.catabasis.com.

About DMD

Duchenne muscular dystrophy (DMD) is a disease that almost exclusively affects boys and whose incidence is 1 in 3,500. It is extremely rare that Duchenne muscular dystrophy (DMD) will affect girls. Those affected are usually diagnosed around the age of five, but symptoms may be visible from early childhood. It is a degenerative disease of the muscles caused by a genetic mutation. The Duchenne muscular dystrophy (DMD) – for which no treatment is currently available – directly affects skeletal muscles. Without treatment, the consequences of the disease are dire for those afflicted and their families.

For more information:

More information about the trial:  DMDtrials@catabasis.com and Catabasis -clinical trials

More: Portrait of Duchenne – edasalonexent cat-1004 – La Force DMD

Press release: www.catabasis.com

Business Wire: www.businesswire.com

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A clinical trial on utrophin modulation is completed

One of the objectives of our team is to inform you about new treatments. You can catch up on the last news in the latest press release by Summit Therapeutics company about ezutromid, a utrophin modulation. We wish you a happy reading and thank you for sharing those articles within the DMD community.

“PhaseOutDMD” clinical trial for ezutromid is completed

“We believe the early improvements seen in muscle health in the interim data from PhaseOut DMD indicate ezutromid is reducing DMD disease severity. In the full trial results, we aim to see continued utrophin modulation and sustained changes in magnetic resonance parameters. These results, if positive, could form the basis of a regulatory filing of ezutromid, bringing this universal treatment to patients more rapidly.”

Said Dr. David Roblin, Chief Medical Officer and President of R&D of Summit.

What is “PhaseOutDMD”?

PhaseOut DMD is a Phase 2 open-label, multi-centre trial of the Company’s utrophin modulator, ezutromid, in patients with DMD. Previously announced 24-week interim data from PhaseOut DMD showed evidence of activity across three different measures. Specifically, ezutromid:

• Maintained the production of utrophin, a naturally occurring protein that can potentially substitute for dystrophin, as measured by muscle biopsy;

• Significantly and meaningfully reduced muscle damage, as measured by muscle biopsy; and

• Significantly reduced muscle inflammation, as measured by magnetic resonance.

What is utrophin?

The human body naturally produces utrophin, a protein, when a muscle is first forming or when a muscle is repairing. As a muscle matures, dystrophin replaces utrophin. However, in people with Duchenne muscular dystrophy (DMD), dystrophin does not function properly. Utrophin is functionally and structurally similar to dystrophin. Preclinical trials that have simulated sustained utrophin production have shown that it could potentially replace dystrophin in people with Duchenne muscular dystrophy (DMD). The replacement of dysfunctional dystrophin with functional utrophin might have a highly positive impact on muscle performance.

Summit Therapeutics believes that utrophin may slow or even stop the progression of DMD.

 

This video explains what is utrophin.

About Summit Therapeutics

Summit is a biopharmaceutical company focused on the discovery, development and commercialization of novel medicines for indications for which there are no existing or only inadequate therapies. Summit is conducting clinical programmes focused on the genetic disease Duchenne muscular dystrophy and the infectious disease C. difficile infection. Further information is available at www.summitplc.com and Summit can be followed on Twitter (@summitplc).

What is DMD?

Duchenne muscular dystrophy (DMD) is a disease that almost exclusively affects boys and whose incidence is 1 in 3,5000. It is extremely rare that Duchenne muscular dystrophy (DMD) will affect girls. Those affected are usually diagnosed around the age of five, but symptoms may be visible from early childhood. It is a degenerative disease of the muscles caused by a genetic mutation. The Duchenne muscular dystrophy (DMD) – for which no treatment is currently available – directly affects skeletal muscles. Without treatment, the consequences of the disease are dire for those afflicted and their families.

Useful links

Here are a few additional links including the initial news release of the Summit Therapeutics company.

Link to the news release: www.summitplc.com

Link to additional information on utrophin modulation:

Positive data about utrophin modulator – La Force DMD

Portrait of Duchenne – Utrophin modulator – La Force DMD

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Portrait of Duchenne – Every action counts!

A chance encounter launched groundbreaking DMD research

When Max Sedmihradsky was two-years-old, he received the DMD diagnosis. The news was devastating beyond words for his parents Kerry and Andrew. After a moment of profound sadness, Andrew came up with the idea for Max’s Big Ride. Every year he cycles between Ottawa and Hamilton, Ontario, with Max in front of the cargo bike. The ride aims to raise funds and awareness for Duchenne muscular dystrophy.

Andrew works at the University of Toronto, where the researcher Patrick Gunning also works. Andrew took the chance to reach up to him to see if he would do some research for DMD. At that time, Patrick Gunning reached out to his graduate students to start a research on DMD. They found out that the cell they are working on, “Stat 3”, plays a decisive role in DMD. A year later, after this chance encounter, the Gunning Group received a $300,000 grant and are performing ground-breaking research for DMD. This is the story of Max’s Big Ride and the Gunning Group.

 

 

Quotes from video

Magic happened

Andrew Sedmihradsky: “You know, it’s the very random kind of thing that happened and the fact that I work in the building where there is a man who potentially could have the cure for Duchenne is tremendous”

 

Kerry Sedmihradsky: “Patrick Gunning is a researcher at the University of Toronto where Andrew works. And Andrew attended a talk which mention the research that Patrick was doing and for what he has told me, he is kind of the rock star of researchers at the University of Toronto”

 

Patrick Gunning, Associate Professor: “Would you be interested in looking at developing drugs for Duchenne?’’ And I said: “Well, we are typically oncology based and I don’t think that the targets that we make drugs for are involved in Duchenne.” I asked my graduated student Yasir to investigate whether STAT proteins in particular were involved in Duchenne.”

 

A ride of hope: Max’s Big Ride

Andrew Sedmihradsky: “You know, a few days into it, we just went on a family trip to the museum and I remember in the gift shop seeing a card that said: “Falling down is part of life but getting up is living.  It really responded to me, it resonated with me. I think that’s kind of the attitude that we’ve adopted you know, from that point forward. And you know, you have to fight, and we’re determined as a family to do so. To try and beat this.”

 

Kerry Sedmihradsky: “So, he worked out the route between Hamilton and Ottawa which is 600 km with Max riding in the front of the Cargo bike and it’s been a really, really positive experience for our family.”

 

Groundbreaking research with the Gunning Group

Yassir, Graduated student: “It’s very rare that we get to see what we do have an impact. So yeah, my motivation is, just all the young children that have Duchenne and if I can do anything, you know one percent that I can do to try to push this a little bit more, maybe five years later someone pushes it more and hopefully, we live in a world soon where Duchenne is something that is normal and we can cure it.”

 

Join the fight!

Duchenne muscular dystrophy (DMD) is a rare disease with no cure. Orphan drugs that target its causes are being developed now. We need your help. Research is the only hope. And research needs funding.

For the past 20 years, Canadian families in the DMD community have been raising funds for and awareness of DMD. Their actions and successes have funded current research. Now that new treatments are emerging, families need to unite and be heard to access new treatments quickly.

 

Bruce Babington, our own La Force athlete, will cycle across Canada in July 2018 to raise funds and awareness for DMD. Our part is to tell their story.

 

Sharing these stories is one step forward towards the cure.

  • We invite you to share this story with your community.
  • Encourage Bruce’s challenge: to cycle from Quebec to British Columbia in 24 days! Make a donation /Here
  • Donate to our organization, so we can continue to help get closer to treatment.  /Here

 

For more information:

About Max’s Big Ride:  Max’s Big Ride / Here

About the Gunning group: The Gunning Group  / Here

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New DMD exon-skipping therapy on the way

Following positive results obtained in Phase I/II trial of SRP-4053 (Golodirsen), Sarepta Therapeutics has announced a plan to submit a new drug application (NDA) for accelerated approval of Golodirsen in patients with Duchenne muscular dystrophy (DMD).

According to results of the clinical study, Golodirsen significantly boosted dystrophin protein production in 25 boys with confirmed deletions of the DMD gene amenable to exon 53 skipping. This mutation affects about 8 percent of all DMD patients.

 

What is Golodirsen?

Golodirsen uses exon-skipping technology and works by binding to exon 53 of the dystrophin sequence to exclude, or skip, this part of the sequence. This helps produce a smaller but functional form of dystrophin protein.

 

Positive results

Golodirsen showed potential to treat Duchenne muscular dystrophy (DMD) in a first clinical trial of DMD patients. Press release

 

Why do we need to skip an exon?

DMD is caused by specific errors (mutations) in the gene that codes for dystrophin. Dystrophin is a protein that plays a crucial role in the function of muscle cells and protects them from damage as muscles contract and relaxes. These mutations in the dystrophin gene lead to a lack of dystrophin protein in muscles. Without enough dystrophin, muscles gradually grow weaker until they can’t move at all, and eventually breathing and heart function are lost.

The condition is universally fatal, and death usually occurs before the age of 30 generally due to respiratory or cardiac failure.

 

More about Golodirsen

Golodirsen uses Sarepta’s proprietary phosphorodiamidate morpholino oligomer (PMO)* chemistry and exon-skipping technology to skip exon 53 of the DMD gene. Golodirsen is designed to bind to exon 53 of dystrophin pre-mRNA, resulting in exclusion, or “skipping,” of this exon during mRNA processing in patients with genetic mutations that are amenable to exon 53 skipping. Exon skipping is intended to allow for the production of an internally truncated but functional dystrophin protein.

Golodirsen is one of the investigational candidates currently being evaluated in the ESSENCE study, a global, randomized double-blind, placebo-controlled study evaluating efficacy and safety in patients amenable to skipping exons 45 or 53.

*a phosphorodiamidate Morpholino oligomer (PMO), is a type of oligomer molecule (colloquially, an oligo) used in molecular biology to modify gene expression. 

 

More about clinical trial

 ESSENCE: Phase III Study

Purpose: The main objective of this study is to evaluate the efficacy of SRP-4045 and SRP-4053 compared to placebo in Duchenne muscular dystrophy (DMD) patients with out-of-frame deletion mutations amenable to skipping exon 45 and exon 53 respectively.

Location: United States, Europe, Canada, Israel

For more information, please visit www.clinicaltrials.gov or www.essencetrial.com

 

Sources:

Clinical Trials

Muscular Dystrophy News

Investor Relations

Wikipedia

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Canadian Research osteoprotegerin (OPG)

Meeting with professor Jérôme Frenette about osteoprotegerin (OPG).

We are producing a video series of interviews with Canadian researchers working on DMD. We have met many professors, and our videos will be coming up soon.  We wish to connect you, the DMD community, with the professors. You will be delighted to know their deepest motivation and devotion. They love to know your face; you are the people that will be impacted by their discovery. Also, the video is a very good medium to offer an understanding of scientific concepts which are not always so easy to grasp.

 

Video series coming up…

We met and interviewed professor Jérôme Frenette of the Rehabilitation Department of Laval University who is currently working on a potential treatment for Duchenne muscular dystrophy. He presented some very promising work with his team at the University Hospital Center of Quebec on osteoprotegerin (OPG).

 

Interesting information about OPG

• OPG is a protein well known for its protective role against osteoporosis, where its name comes from, osteoprotegerin.
• OPG reduces damage and inflammation.
• OPG eases Duchenne muscular dystrophy, especially in fast-twitch skeletal muscle.
• OPG can simultaneously treat osteoporosis and muscle degeneration in patients with DMD.
• Dystrophic muscles can be protected without correcting the dystrophin gene. The team from the Faculty of Medicine at Laval University in Quebec City has just demonstrated that this protein could be a new avenue of treatment for Duchenne muscular dystrophy (DMD).

 

Get connected to our Canadian Research Series

An effective way to be informed and to receive our videos right out of the box is to sign up here for our newsletter.

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PORTRAIT OF DUCHENNE – REPURPOSING EXISTING DRUGS FOR DMD

Steve J. Winder, PhD

Professor of Molecular Cell Biology, Director of Postgraduate Teaching, Director of External Relations, Department of Biomedical Science, The University of Sheffield, United Kingdom

In this sixth interview of our series “Portrait of Duchenne”, La Fondation La Force talks with Steve Winder, Professor of Molecular Cell Biology, Director of Postgraduate Teaching, Director of External Relations, Department of Biomedical Science, The University of Sheffield, United Kingdom. He has been working on aspects of Duchenne muscular dystrophy (DMD) for more than 20 years. He has worked on this project for the last 3 or 4 years.

 

Why repurpose existing drugs for DMD?

Developing a brand-new drug takes an enormous amount of time, money and effort. Delays and barriers mean that translation of a promising molecule into an approved drug often takes more than 14 years. It is crucial to advance strategies to reduce this time frame, decrease costs and improve success rates. Drug repurposing or re-positioning is one such strategy. This is what Steve Winder and his team of researchers are exploring; in this case, cancer drugs that affect muscle and which may be useful in the treatment of DMD.

 

In the video, Professor Steve Winder answers our questions about repurposing existing drugs for DMD

 

  • Can you explain the process of drug repurposing?

Ok, so repurposing is taking a drug that’s already been approved for clinical use in one disease and working out whether it’s suitable and effective to use in another disease. A good example would be something like aspirin, which you take for headaches because it’s a painkiller, but these days a lot of people also take the aspirin to prevent heart attacks, because it thins the blood. So, the drug has a primary effect, but it also has what I would call a side effect. And sometimes these side effects can be really useful. So, this is what we are trying to do with a series of drugs that might be useful in treating Duchenne muscular dystrophy. So, in this case, it’s cancer drugs, but they have other effects in the muscle, which may be useful for the treatment of Duchenne muscular dystrophy.

 

  • What drugs are you repurposing in your current research?

So, these drugs that we’re working with are a group of anti-cancer drugs that are mostly used to treat chronic myeloid leukemias, which are genetically based leukemias that occur reasonably common. And, the advantage of these drugs is, because the disease, as its name says, is chronic myeloid leukemia, the disease is long-lasting, so the drugs are given for long periods of time, So, they’ve been designed to be well-tolerated or the ones that are in clinical use are well-tolerated and can be given for, you know, 10s of, well, there are examples, certainly, of people being given these drugs for 10s of years. So, from that point of view, if you were going to treat a boy with DMD, it would probably be a life-long treatment, so they need to be well-tolerated, low side effects, and so on. So, these drugs would be particularly suited to that.

 

  • What effect could this approach have for DMD?

So, these drugs are inhibitors of signaling processes in the muscle that are altered when dystrophin is absent. The drug is not going to reverse the disease. If it were to work 100%, it would stop the disease from getting any worse. That’s the best it could do. But if you started treatment early, then obviously, you would preserve most of the muscles for the boys. And they act on inhibiting signaling pathways that are turned on aberrantly in the muscular dystrophy process. So it’s targeting things directly in the muscle that are altered as a consequence of the loss of dystrophin in the muscle tissue.

 

  • How long before this type of treatment is available?

We need to satisfy ourselves in the preclinical stages. So this is working with animal models of the disease, such as the MDX mice that have a mutation in the dystrophin gene, the same as boys with Duchenne muscular dystrophy. But the drugs that we’re testing (must) work as we expect them to work and actually have some benefit in the mouse before we then have the confidence to actually go forward and use them in boys with Duchenne muscular dystrophy in a proper clinical trial.

 

  • How do you envision the future for people with DMD?

In the last 5 years, even in the last 2 years, there’s just been an explosion of new potential treatments for Duchenne: some of which people have been working on for a very long time and others which have really just almost come out of nowhere. So, I think, in terms of potential treatments for Duchenne, they, I think, are looking really, really, really positive. I mean, when I originally started work on this, the prospects for treatment seemed completely bleak and no hope 20 years ago, but now, there’s all sorts of things, different approaches. I am confident, in the next few years, we’ll see real benefits to lots of boys with Duchenne.

 

 

Interesting links

About The University of Sheffield

About drug repurposing for DMD

 

To receive the next interview in our series “Portrait of Duchenne”, please subscribe to our newsletter.

 

 Acknowledgements

We thank Action Duchenne, who received us with open arms to conduct a series of interviews.

More information about next event: conference 2017

 

 

 

PORTRAIT OF DUCHENNE – GENE THERAPY AND EXON SKIPPING

Professor George Dickson

 

Professor of Molecular Cell Biology, Royal Holloway University of London

In the third interview of our series “Portrait of Duchenne”, La Fondation La Force talks with George Dickson, Professor of Molecular Cell Biology at the Royal Holloway University of London. He has spent most of his career studying neuromuscular disease and muscle cell biology, contributing to, the first cloning of an intact dystrophin gene, the discovery of the role of cell adhesion molecules in muscle stem cell fusion, the first identification of utrophin and the first description of exon skipping in Duchenne muscular dystrophy (DMD).

Our journey at La Fondation La Force travels the road of discovery with families, researchers, pharmaceutical companies and more. Our mission is finding the best new experimental treatments and the most promising research for children and adults with Duchenne muscular dystrophy (DMD). In November 2016, we went to the 14th Action Duchenne International Conference in London, UK, to meet with the international DMD community on your behalf.  We hope this series of interviews will bring hope and inspiration to Canadian families.

Developing new treatments for DMD

For the past decade, Dr. Dickson’s team has been involved in developing exon-skipping drugs, specifically for exons 53, 45 and 46. They did not work on developing the exon 51-skipping drug eteplirsen  (Exondys 51™; Sarepta Therapeutics Inc.), which is approved for use in the USA, but did contribute to early clinical trials in the UK.  They also work in parallel on developing gene therapy tools called recombinant dystrophin genes.

 

 

In the video, Professor George Dickson answers our questions about gene therapy & exon-skipping drugs.

 

1— Can you explain the basis of gene therapy?

R: It’s really very simple. Many genetic conditions are caused by the damage and, basically, the absence of particular genes. In DMD, it’s the dystrophin gene. Perhaps one way of treating those conditions – one very simple, one obvious way – would be to replace the missing gene with a version which has been created – a functional version that’s been created in the laboratory. That is basically the aim of gene therapy.

 

2— Which treatments are you working on in your laboratory?

R: In the case of Duchenne, we’ve been involved for maybe 10 years now in developing some of these exon-skipping drugs, not exon 51, not the eteplirsen, which has now been approved, but some of the others that are coming through behind for exon 53 and 45 and 46. We have reagents that we’ve developed that are in clinical trial. And, at the same time, we’ve worked on developing the gene therapy tools for DMD– which are called recombinant dystrophin genes, the largest genes that allows us to plan ahead for clinical trial.

 

3— When do you think the damaged DMD gene could be replaced?

R: It’s difficult to say. The honest truth is we have the genes. They are lab-based genes. We have systems to deliver the genes, and we know that the gene therapy is very active in experimental models and perhaps animal models of DMD. Now we have to scale up the process and run clinical trials of that technique in patients with Duchenne muscular dystrophy. Those clinical trials, for example, if they began right now, and we are planning to start very soon with those trials, maybe within the next 12 months, but if they began right now, they probably would take 2 or perhaps 3 years to complete and get the final results from them. So 3 years to test the product and then perhaps another year or 2 years to get official authorization for the new drug, the new medicine, to be used in patients. So in honesty, we are looking 2,3 years, perhaps 5 years ahead. But hopefully the gene therapies will be tested in patients with Duchenne muscular dystrophy well before, that perhaps, within 18 months I would say.

 

4— What is exon skipping?

R: Well, to try and explain it simply: the way the cell works with genes, the gene is actually separated into a number of fragments. You can imagine this like a linear jigsaw puzzle, and these fragments have to be joined together to produce the proper gene product. If there is a change in one of the fragments, which affects the way the gene works, which causes, shall we say, Duchenne muscular dystrophy or other genetic diseases, one potential way is to persuade or induce the muscle tissue to ignore the damaged fragment and join together fragments on either side. Now, a jigsaw puzzle, as you can imagine, if you don’t fit the right pieces together, will not work, so exon skipping is designed to try and ensure that the fragments that are brought together in the gene, avoiding mutation, are functionally active and, basically, that involves a medicinal product, which is a very small piece of nucleic acid, which masks the damaged jigsaw puzzle piece and allows others to come together in a functional way.

 

5— How do you envision the future for people with DMD?

R: My dream, I suppose you would call it that, what I feel we’re all working towards, is a situation, like in many diseases, where a combination of three of four medicines will allow Duchenne to become a disease which perhaps isn’t cured – cured is a difficult word in medicine – but what happens mostly in medicine is that conditions are managed to improve very, very much the quality of life of patients with the illness, with Duchenne muscular dystrophy. So a combination of drugs available to pediatricians to treat boys with Duchenne muscular dystrophy and produce a very significant improvement in their disease and in their quality of life. That would be fantastic, already.

 

 

 

Up next:

Our next portrait: Ellen Welch, group leader biology at PTC Therapeutics talks about ataluren (Translarna™).

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Acknowledgements

 

We thank the Action Duchenne UK team, who received us with open arms and gave us access to all key speakers at their conference. Because of their generosity, we can spread this hopeful information to the Canadian DMD community.

 

To know more about the Action Duchenne conference:

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Special Thanks to Daniel K Cooper and Allain Lagadic