New gene therapy for Duchenne muscular dystrophy

Audentes Therapeutics, Inc., a leading Adeno-associated virus (AAV)* based genetic medicines company focused on developing and commercializing innovative products for serious rare neuromuscular diseases; announced it had expanded its scientific platform and pipeline to advance vectorized antisense treatments for the treatment of Duchenne muscular dystrophy (DMD) and myotonic dystrophy type 1 (DM1).

The Gene Therapy Market

Very promising and strong from its first successes, gene therapy benefits from active research and its development intensifies. Generating both hope and caution, it is about to prove its potential. The history of gene therapy is 30 years old. In 1999, the first clinical trials were carried out by the team of Professor Alain Fischer, at Necker Hospital for Sick Children, on young patients with severe immune deficiency (so-called “bubble children”).

The developments are long and require the creation of companies and industrial partnerships.


Gene therapy is now a real “promise” for patients and not just a “hope”.


In 2016, the U.S. Food and Drug Administration (FDA) approved the first drug to treat DMD, Sarepta’s Exondys 51. It was a long, dramatic and controversial approval journey involving numerous public hearings, internal FDA battles and letters from Congress and leading DMD physicians to the agency.

These deals mark the entry of gene therapy into mainstream drug development. Roche recently acquired Spark Therapeutics for $4.8 billion. Spark developed a gene therapy for rare eye disease and hemophilia. And in 2018, Novartis acquired AveXis for $8.7 billion. AveXis has a gene therapy for spinal muscular atrophy (SMA).


Audentes Therapeutics Partners with Nationwide Children’s Center

Published on April 8, 2019

Audentes Therapeutics, Inc., a leading Adeno-associated virus (AAV)* based genetic medicines company focused on developing and commercializing innovative products for serious rare neuromuscular diseases; today announced it had expanded its scientific platform and pipeline to advance vectorized antisense treatments for the treatment of Duchenne muscular dystrophy (DMD) and myotonic dystrophy type 1 (DM1).

To accelerate these promising new programs, Audentes has entered into a licensing agreement and will collaborate with Nationwide Children’s Hospital, utilizing the expertise of Kevin M. Flanigan, M.D. and Nicholas S. Wein, Ph.D., two recognized leaders in the field of genetic medicines for neuromuscular diseases.


Matthew R. Patterson, Chairman and Chief Executive Officer – «Today’s announcement represents a significant step forward in expanding our scientific platform and deepening our pipeline of product candidates for neuromuscular diseases with high unmet medical need.

We see tremendous potential in combining AAV with validated oligonucleotide-based approaches to treat diseases that are not amenable to traditional AAV-based gene replacement.

We believe this approach, combined with our in-house large-scale cGMP (current good manufacturing practice) manufacturing capability, can deliver best-in-class therapies for the treatment of Duchenne muscular dystrophy and myotonic dystrophy.»


Dr. Flanigan, Director of Nationwide Children’s Center for Gene Therapy – «We are excited to be collaborating with Audentes to advance these novel, highly differentiated approaches for DMD and DM1…»


Audentes and Nationwide Children’s are collaborating to develop AT702, an AAV-antisense candidate designed to induce exon two skipping for DMD with duplications of exon 2 and mutations in exons 1-5 of the dystrophin gene. Audentes is currently conducting additional preclinical work and expects to commence a Phase 1/2 study at Nationwide Children’s in the fourth quarter of 2019.

The Audentes approach

Separate from the Nationwide Children’s collaboration, Audentes is also conducting preclinical work to advance AT751 and AT753, additional vectorized exon skipping candidates, to treat DMD patients with genotypes amenable to exon 51 and exon 53 skipping. Both AT751 and AT753 utilize the same vector construct backbone as AT702, enabling a potentially accelerated path into clinical development. With these initial programs, Audentes is targeting more than 25% of patients with DMD and has plans to leverage its vectorized exon-skipping platform to develop further product candidates to address up to 80% of DMD patients over time.

This approach combines the delivery power of AAV with the precision tools of antisense oligonucleotides, or ASOs, to develop potential best-in-class therapeutic candidates for these devastating neuromuscular diseases.

Adeno-associated virus (AAV)*

Adeno-associated virus (AAV) is a small virus that infects humans and some other primate species. AAV is a very attractive candidate for creating viral vectors for gene therapy, and for the creation of isogenic human disease models.

Vectorized exon skipping uses an AAV vector

Vectorized exon skipping uses an AAV vector to deliver an antisense sequence designed to induce cells to skip over faulty or misaligned sections of genetic code, leading to the expression of a more complete, functional protein. For the treatment of DMD, this approach has the potential to provide significant advantages over microdystrophin gene replacement strategies that produce a substantially truncated protein, which may limit the degree and durability of disease correction, as well as existing ASO therapies, whose efficacy is limited by poor biodistribution to muscle tissue.

Antisense therapy (ASO)

Antisense therapy is a form of treatment for genetic disorders or infections. When the genetic sequence of a particular gene is known to cause a particular disease, it is possible to synthesize a strand of nucleic acid (DNA, RNA or a chemical analogue) that will bind to the messenger RNA (mRNA) produced by that gene and inactivate it, effectively turning that gene “off”. This is because mRNA has to be single-stranded for it to be translated. Alternatively, the strand might be targeted to bind a splicing site on pre-mRNA and modify the exon content of an mRNA.

About Audentes Therapeutics, Inc.

Audentes Therapeutics (Nasdaq: BOLD) is a leading AAV-based genetic medicines company focused on developing and commercializing innovative products for serious rare neuromuscular diseases. We are leveraging our AAV gene therapy technology platform and proprietary manufacturing expertise to develop programs across three modalities: gene replacement, vectorized exon skipping, and vectorized RNA knockdown. Our product candidates are showing promising therapeutic profiles in clinical and preclinical studies across a range of neuromuscular diseases. Audentes is a focused, experienced and passionate team driven by the goal of improving the lives of patients. For more information regarding Audentes, please visit www.audentestx.com.


About Nationwide Children’s Hospital

Named to the Top 10 Honor Roll on U.S. News & World Report’s 2018-19 list of “Best Children’s Hospitals,” Nationwide Children’s Hospital is one of America’s largest not-for-profit freestanding pediatric health care systems providing wellness, preventive, diagnostic, treatment and rehabilitative care for infants, children and adolescents, as well as adult patients with congenital disease. Nationwide Children’s has a staff of more than 13,000 providing state-of-the-art pediatric care during more than 1.4 million patient visits annually. As home to the Department of Pediatrics of The Ohio State University College of Medicine, Nationwide Children’s physicians train the next generation of pediatricians and pediatric specialists. The Research Institute at Nationwide Children’s Hospital is one of the top 10 National Institutes of Health-funded freestanding pediatric research facilities. More information is available at NationwideChildrens.org.


Myotonic dystrophy

Myotonic dystrophy is the most common form of adult-onset muscular dystrophy, with a worldwide prevalence of 14 per 100,000 population. More on muscle.ca


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Phase 3 PolarisDMD trial of edasalonexent is now open for enrollment in Canada

Catabasis is enrolling boys ages 4 to 7 (up to 8th birthday), any mutation type, who have not been on steroids for at least the past six months.


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. By inhibiting NF-kB, edasalonexent has the potential to decrease inflammation and fibrosis, promote muscle regeneration, and slow disease progression. Edasalonexent was designed as a stand-alone therapy and may also enhance the efficacy of dystrophin targeted therapies.


Potential bone health benefits of edasalonexent

Why is bone health so important in Duchenne?

Boys with Duchenne are at an increased risk of bone fractures and should be monitored yearly to check for fractures. Early detection is critical. Strong bones are essential to help boys grow taller! Some therapies used to treat Duchenne have an additional negative impact on bone health and can increase the frequency of long bone and spine fractures.

Catabasis believes that edasalonexent has the potential to benefit bone health, which is why they are studying it in their Phase 3 PolarisDMD trial. Because edasalonexent is an NF-kB inhibitor, it has the potential to reduce inflammation and promote muscle regeneration, and that can strengthen bones. Catabasis will perform x-rays and body scans at the beginning and end of the study to check on bone health!


PolarisDMD in Canada

If you’d like to learn more, contact Catabasis at DMDtrials@catabasis.com. Catabasis is also sharing updates on edasalonexent @CatabasisPharma on Facebook, Twitter and Instagram if you are interested in the latest updates. Get the story behind the PolarisDMD experience! – Here


  • Children’s Hospital-London Health Sciences Centre, this site is expected to be enrolling soon
    • Principal Investigator: Craig Campbell
  • Children’s Hospital Eastern Ontario, this site is expected to be enrolling soon
    • Principal Investigator: Hugh McMillian


  • Alberta Children’s Hospital is actively recruiting
    • Principal Investigator: Jean Mah


  • Sainte-Justine Hospital, this site is expected to be enrolling soon
    • Principal Investigator: Cam-Tu Nguyen


Sources and for more information

More about Catabasis: www.catabasis.com

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

Blog post La Force

More information about the Polaris DMD trial: Catabasis – Polaris DMD

Phase III Study of Edasalonexent in Boys With Duchenne Muscular Dystrophy (PolarisDMD)



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Sarepta Therapeutics announces positive results from the ESSENCE study

Sarepta Therapeutics, Inc., a leader in precision genetic medicine for rare diseases, announced positive results from its interim analysis of muscle biopsy endpoints comparing casimersen treatment to placebo in the ESSENCE study.

ESSENCE is a global, randomized double-blind, placebo-controlled Phase 3 study evaluating the efficacy and safety of casimersen and golodirsen in patients amenable to skipping exons 45 or 53, respectively.

After soliciting feedback from the FDA, Sarepta conducted an interim analysis for levels of dystrophin protein expression in those patients who are amenable to exon 45 skipping to determine the potential for a New Drug Application (NDA) filing based on dystrophin as a surrogate endpoint. With these results, the Company intends to work toward submission of an NDA for casimersen in the middle of 2019. News release


“We are pleased to see that the anticipated exon skipping after treatment resulted in a statistically significant mean increase of dystrophin protein, as measured by western blot*.” -Professor Francesco Muntoni, University College London

“This is the third exon-skipping agent to have shown a statistically significant increase in dystrophin production, and reinforces our confidence in the exon-skipping approach for treating Duchenne patients with amenable mutations.” -Professor Francesco Muntoni, University College London

“The casimersen results and submission of our application for golodirsen earlier this year further validate our RNA* research engine. If golodirsen and casimersen are approved, nearly a third of the boys and young men living with DMD in the United States could benefit from our RNA therapies. We continue to advance toward our ultimate goal of profoundly improving the lives of as many patients around the world with DMD as possible.” -Doug Ingram, Sarepta Therapeutics’ president and chief executive officer


ESSENCE is a global Phase 3 study evaluating the efficacy and safety of casimersen and golodirsen in patients amenable to skipping exons 45 or 53, respectively. Golodirsen and casimersen rely on the same approach than Exondys 51.

Positive results

The interim analysis found a statistically significant increase in dystrophin production in casimersen-treated participants compared to baseline and placebo. Golodirsen and casimersen rely on the same approach than Exondys 51.

Submitting to the FDA

Based on positive results, the company intends to schedule a pre-NDA (New Drug Submission) meeting with FDA (Food and Drug Administration) US and plans to submit an NDA for casimersen in the middle of 2019.

Key findings from the interim analysis include:

  • Dystrophin protein increased to 1.736%. By comparison, treatment with Exondys 51 was shown to result in dystrophin levels of 0.93% of normal after 180 weeks.
  • A statistically significant difference in the mean change from baseline to week 48 in dystrophin protein was observed between the casimersen-treated arm compared to the placebo arm.
  • A statistically significant positive correlation between exon 45 skipping and dystrophin production was observed.
  • The study is ongoing and remains blinded to collect additional efficacy and safety data.

Sarepta exon skipping therapy

  • Exondys 51 > skipping exon 51 = 13% DMD patients
  • Golodirsen > skipping exon 53 = 8% DMD patients
  • Casimersen > skipping exon 45 = 8% DMD patients

For a better understanding

* The western blot is a widely used analytical technique in molecular biology, immunogenetics and other molecular biology disciplines to detect specific proteins in a sample of tissue homogenate or extract.

* Ribonucleic acid (RNA) is a polymeric molecule essential in various biological roles in coding, decoding, regulation and expression of genes. RNA and DNA are nucleic acids, and, along with lipids, proteins and carbohydrates, constitute the four major macromolecules essential for all known forms of life. Like DNA, RNA is assembled as a chain of nucleotides, but unlike DNA it is more often found in nature as a single-strand folded onto itself, rather than a paired double-strand.

Duchenne muscular dystrophy (DMD) is caused by a lack of dystrophin

Dystrophin is a protein found in muscle cells that, while present in minimal amounts, is crucial in strengthening and protecting muscle fibers. A devastating and incurable muscle-wasting disease, DMD is associated with specific errors in the gene that codes for dystrophin, a protein that plays a critical structural role in muscle fiber function. Progressive muscle weakness in the lower limb’s spreads to the arms, neck and other areas of the body. The condition is universally fatal, and death usually occurs before the age of 30 generally due to respiratory or cardiac failure.

RNA-targeted therapeutics are powerful tools

Humans have about 22,000 genes, which contain the blueprints for producing proteins that perform essential functions in the body.

Proteins are molecular workhorses involved in almost every function in our bodies, and defective proteins often result in disease. More specifically, some diseases may be caused by the over-production of one or more proteins, while other diseases are caused by protein deficiencies.

Proteins are produced in cells, where genes in the DNA are “transcribed” into RNA templates, which are then processed and “translated” into proteins by  the cellular machinery.

RNA-targeted therapeutics direct the cellular machinery involved in making proteins. These drugs can be designed to increase or decrease the production of a protein involved in a disease.

By working at the genetic level, RNA-targeted therapeutics are powerful tools with the potential to address diseases that otherwise could not be treated with traditional small molecule or biologic drugs.

Watch Sarepta video here

What is Exon Skipping

Mutations in the dystrophin gene are one cause of DMD. Most commonly, one or more exons (a portion of a gene) are missing, and the remaining exons don’t fit together correctly. (Think of a zipper that doesn’t work correctly, because teeth are missing.)

Because of this error, cells cannot make the dystrophin protein that muscles need to work properly. Without it, muscle cells become damaged and, over time, are replaced with scar tissue and fat.

To fix the broken genetic machinery, scientists are developing drugs that skip over parts that contain missing or defective exons. In this way, the machine can produce a less defective dystrophin protein, which may improve muscle function in children with exon mutations.

Sarepta investigational therapies in the ESSENCE study use a technique referred to as exon skipping. Skipping a specific exon next to the mutation is intended to allow the body to make a shortened form of the dystrophin protein.


Sarepta Therapeutics, Inc.

Clinical Trials

Biopharma Dive

Cure Duchenne



Idebenone for Duchenne muscular dystrophy

February 25, 2019

Santhera Pharmaceuticals announces results from the SYROS study.


The primary objective of this study was to evaluate the long-term evolution of the respiratory function in patients who maintained treatment with idebenone for up to 6 years compared to their preceding off-idebenone period.


Respiratory Function in DMD

In boys and men with DMD, weakness of respiratory muscles leads to a progressive decline in their ability to move air into/out of their lungs, leading to sleep disturbances and respiratory infections, especially when patients have lost their ability to walk. Studies estimate 55-90% of patients with DMD die from pulmonary complications.

Acute respiratory failure can occur due to:

  • Compromised respiratory dysfunction complicated by mucus plugging and further weakening of inspiratory/expiratory muscles
  • Repeated cases of pneumonia, hospitalizations and intubations

Decreased ability to cough leads to retained secretions and high risk of recurrent respiratory tract infections.


The result of this study, which is consistent with outcomes from the pivotal DELOS study, demonstrated that:

  • Switching to and maintaining long-term treatment with idebenone reduced the annual rate of decline in the forced vital capacity percent of predicted (FVC%p) by 50%. Forced Vital Capacity is one of the tests of lung function. FVC is a kind of forced expiration. (Which reflects the strength of the respiratory muscles)
  • The treatment effect was consistently maintained year-on-year for up to 6 years.
  • These findings are further supported by consistent reductions in the rate of both inspiratory and expiratory respiratory function loss over the same period.
  • Prolonged treatment with idebenone also reduced the risk of important patient-relevant outcomes, including bronchopulmonary adverse events and hospitalizations due to respiratory causes.


“We are very excited to see that the significant treatment effect with idebenone observed in our 52- week Phase III DELOS study is maintained over the long-term. The new findings are highly relevant for DMD patients in respiratory decline who have an urgent need for a therapy to modify the declining course of respiratory function decline and ultimately delay the need for assisted ventilation.” -Kristina Sjöblom Nygren, MD, Chief Medical Officer and Head of Development at Santhera.


About idebenone

Idebenone is a synthetic molecular formula similar to coenzyme Q10. Chemically, it is an organic compound of the family of quinones that can slow the loss of respiratory function.

Mitochondria are specialized structures in the human body that serve as batteries, powering various functions of the cell and the organism as a whole.

Mitochondria produce the energy necessary for the cell functioning through a process called “cellular respiration” which requires oxygen and provides energy. During cellular respiration, some toxic forms of oxygen (called oxygen free radicals) can be produced. These free radicals must be neutralized by other substances to avoid cellular damage.

Idebenone is expected to act as a neutralizer of these toxic forms of oxygen. Thus, idebenone is expected to have an antioxidant effect, and consequently prevent cellular damage.

Idebenone is optimized to dissolve in water and lipids and able to cross the mitochondrial membrane.

Idebenone is a medicine that is under investigation for the treatment of DMD. It has not yet been approved by the U.S. FDA, and the safety and efficacy continue to be evaluated in clinical trials.



Santhera’s Raxone® (idebenone) is authorized in the European Union, Norway, Iceland, Liechtenstein, Israel and Serbia for the treatment of Leber’s hereditary optic neuropathy (LHON) and is currently commercialized in more than 20 countries. For further information, please visit www.santhera.com. Raxone® is a trademark of Santhera Pharmaceuticals.

Santhera has been granted orphan drug designation for Raxone for the treatment of DMD in Europe and the US. The US Food and Drug Administration (FDA) has also granted rare pediatric disease designation and Fast Track designation for idebenone for the treatment of DMD. Furthermore, the UK’s Medicines and Healthcare Products Regulatory Agency (MHRA) designated idebenone as Promising Innovative Medicine (PIM) and as a suitable candidate for entry into Step II of the EAMS process.


About Santhera Pharmaceuticals

Santhera is a Swiss specialty pharmaceutical company focused on the development and commercialization of innovative medicines for rare and other diseases with high unmet medical needs. They are focusing on the development of treatments for neuro-ophthalmological, neuromuscular and pulmonary diseases that currently lack treatment options, such as Leber’s hereditary optic neuropathy (LHON), Duchenne muscular dystrophy (DMD), congenital muscular dystrophy (CMD) and cystic fibrosis (CF).



Santhera’s SYROS Study Shows Long-term Efficacy with Idebenone in Slowing Respiratory Function Loss in Patients with Duchenne Muscular Dystrophy





CRISPR & Duchenne muscular dystrophy

The success of CRISPR in a model of Duchenne muscular dystrophy

Original story from Duke University

Researchers at Duke University have shown that by using genome editing technology, CRISPR can safely and stably correct a genetic condition such as Duchenne Muscular Dystrophy (DMD). The study appears in the journal Nature Medicine. Links here


CRISPR/Cas9 is, by far, the most effective technique to correct DNA defects. Described as a “molecular toolkit,” this intelligent and sophisticated technique enables researchers to perform cut and paste” operations on DNA.


How does CRISPR work?

This technology works as follows:

  • CRISPR is a type of gene sequence found naturally in specific organisms, including viruses. It can recognize a particular DNA sequence, i.e., find the place on a DNA strand where a disease-causing genetic defect (mutation) lies.
  • Cas9 acts like a pair of scissors. It “cuts” DNA at a specific location, i.e., where an action is needed to repair or eliminate a genetic defect.
  • With this technology, researchers can remove a genetic mutation or insert a fix for a faulty gene sequence.
  • Using standard DNA repair mechanisms, the cell will then naturally reattach the severed DNA strands.


About Gersbach’s latest research

In 2016, Charles Gersbach, a Rooney Family Associate Professor of Biomedical Engineering, was in the first published positive results concerning the CRISPR technique likely to be translated into human therapy. Since then, many other examples have been released, and several genome editing therapies are targeting human diseases that are currently undergoing clinical trials, and others are underway.

Gersbach’s latest research focuses on a mouse model of DMD, that is unable to produce dystrophin.

The genetic cause of DMD

Dystrophin is encoded by a gene containing 79 exons responsible for producing a protein, called dystrophin. If one or more exons are disrupted or removed by a genetic mutation, the chain is not built, causing the muscle to deteriorate slowly. Most patients use a wheelchair before the age of 10 and do not live in their twenties or early thirties.


Gersbach has been working on potential genetic treatments for Duchenne muscular dystrophy since 2009. His lab was one of the first to begin focusing on CRISPR/Cas9. Cas9. CRISPR/Cas9 is used to cut into the dystrophin gene around the exons responsible for the genetic mutation that causes DMD. Then, the body’s natural DNA repair system, picks up the previously cut gene, to create an abbreviated version of the dystrophin gene.


“As we continue to work to develop CRISPR-based genetic therapies, it is critical to test our assumptions and rigorously assess all aspects of this approach. A goal of our experiments was to test some ideas being discussed in the field, which will help us understand the potential of CRISPR to treat genetic diseases in general and Duchenne muscular dystrophy in particular. This includes monitoring the long-term durability of the response in the face of potential immune responses against the bacterial Cas9 protein.” – Charles Gersbach


“It is widely believed that gene editing leads to permanent gene correction. However, it is important to explore theoretical possibilities that could undermine the effects of gene editing, such as losing treated cells or an immune response.”  – Charles Gersbach


The purpose of this new study

The purpose of this new study is to explore the factors that may alter the long-term effects of CRISPR/Cas9-based gene editing.

A single dose of the CRISPR therapy was administered intravenously to adult mice and newborn mice carrying a defective dystrophin gene. The following year, the researchers measured how many muscle cells had been successfully edited and what types of genetic modifications had been made, as well as the possibility of an immune response against the bacterial CRISPR protein, Cas9, which acts as the “scissors” that cuts into the gene.

An immune reaction against CRISPR

Other studies have reported that the mouse immune system can mount a response to Cas9, which could potentially interfere with the benefit of CRISPR therapies. Several groups have also said that some people have preexisting immunity to Cas9 proteins.


“The good news is that even though we observed both antibody and T cell responses to Cas9, neither appeared to result in any toxicity in these mice. The response also did not prevent the therapy’s ability to edit the dystrophin gene and produce long-term protein expression successfully.” – Christopher Nelson, a post-doctoral fellow in Gersbach’s lab.


Some results suggest approaches to face potential challenges. When two-day-old mice without a fully developed immune system are treated intravenously, no immune response is detected. Genome editing by CRISPR has remained stable and, in some cases, even strengthened in one year. We could imagine that administering therapy to infants would be a method of circumventing an undesirable immune response.

The immune system of the mouse works differently from the human immune system. Screening for DMD in newborns is not yet widespread; most Duchenne diagnoses occur when children are three to five years old. The suppression of the immune system during treatment might be an approach.


“We were pleased to observe that all the mice were doing well a year after treatment, but our results show that there needs to be more focus on the immune response as we move toward larger animal models,” – Christopher Nelson


Some studies have shown that CRISPR can cut out genetic sections much more significant than intended or that pieces of DNA can embed at the site of the cut.

To exhaustively map all the changes in the dystrophin gene, Nelson used a DNA sequencing approach. Surprisingly, many types of modifications have been made in addition to the intended removal of the targeted exon, including a high level of DNA sequence insertion.


“None of these edits would necessarily be a cause for concern in this case because the dystrophin gene is already defective. That being said, any unintended results could potentially take away from the efficiency of the gene editing you are trying to achieve, which supports the importance of designing ways to identify and mitigate alternative edits in future studies objectively. Moving forward, this phenomenon needs to be monitored carefully and better understood. Methods that avoid these alternative edits and increase the frequency of the intended edit will be important to maximizing the potential of genome editing to treat disease.”- Christopher Nelson


An encouraging step in the fight against DMD

Duchenne muscular dystrophy (DMD) results from an error in the “writing” of the dystrophin gene. In children with DMD, the dystrophin gene is corrupt—it contains a genetic defect (mutation). The gene is so badly “written” that the cellular machinery cannot accurately “read” the genetic instructions to produce dystrophin—a protein that’s essential for proper neuromuscular function.

Researchers are using CRISPR/Cas9 to remove the corrupt part of the genes (mutations). “Erasing” problem areas on a DNA strand may restore accurate protein decoding. With this technology, DMD researchers have been able to restore the production of dystrophin.

Researchers have found a way to transport this molecular toolkit aboard viruses with a particular attraction to muscle cells. They injected this mixture into mice models that could not synthesize dystrophin. After a few weeks, the rodents’ muscles began to produce dystrophin.

A brilliant idea!





(Also known as study 041)

The clinical trial of ataluren in nonsense mutation Duchenne muscular dystrophy (NMDMD)

Study 041 is a new clinical trial for boys and young men who are living with nonsense mutation Duchenne Muscular Dystrophy (nmDMD).

Who Can Enter Study 041?

To ensure that participants who enroll in Study 041 get the most benefit, and to ensure their safety, there are strict criteria around who is able to enter the study. Your doctor will help to decide whether you/your child can take part.

Main Inclusion Criteria

  • Documentation proving that you have undertaken a genetic test which shows you/your child has nmDMD.
  • You/your child is male and five years of age or older.
  • You/your child is able to walk at least 150 meters (165 yards) without help during a six-minute walking test.
  • You/your child is able to undertake certain timed tests.
  • You/your child has been on corticosteroid treatment (i.e. prednisone, prednisolone, or deflazacort) for at least 12 months immediately before the start of study treatment, with no significant change in dose within three months before the start of the study (other than for body weight change).


Trial Design

Stage One

Stage One of Study 041 is looking at how the investigational treatment, ataluren, affects the ability to walk and endurance in males aged five years and older with nmDMD, compared to placebo (a substance that looks and tastes the same as ataluren but does not actually contain the drug). The study will also look at the ability of participants to climb up and down stairs, walk/run certain distances, use their upper limbs and measure lung function. The safety of ataluren will also be assessed.

Stage Two

Stage Two of Study 041 will compare results in participants who started on ataluren from the beginning of the trial with those who started taking ataluren from the start of stage two. All participants will be involved in both stages of the trial.

If you/your child decides to enroll in Study 041, you may help drive a better understanding of nmDMD, as well as current and future treatments, which may benefit nmDMD patients in the future.


Frequently asked questions

What is ataluren?

Ataluren is an investigational therapy being studied for the treatment of people with nmDMD who are still able to walk and aged five years or older. It is administered three times per day, mixed with a liquid or semi-solid food and taken orally. People with nmDMD are unable to produce a protein, dystrophin, which helps keep muscles healthy. Without dystrophin, muscles become weaker over time. PTC Therapeutics is studying ataluren to determine if it helps the body produce dystrophin, which may help slow down muscle weakening.

Is ataluren safe?

Ataluren has been studied in over 1,000 patients in clinical trials. During these clinical trials, ataluren was found to be well-tolerated in patients with nmDMD and has demonstrated a favourable safety profile for this condition.

Will I need to pay anything to be involved in the trial?

No, all costs involved in the trial, including physical examinations, screening, laboratory and other tests, as well as the cost of the drug, will be covered by PTC Therapeutics, who is funding Study 041.

You may be reimbursed for all reasonable*costs for travel, meals and accommodation necessary for your visits to the study site the clinic, which will be approximately every 12 weeks for the first stage of the trial, and every 24 weeks for the second stage of the trial.

How will ataluren affect other treatments that I am taking?

If you/your child are/is taking any medications, then the doctor will advise you/your child of potential problems and discuss treatment options with you/your child. However, to participate in the trial you/your child must be taking treatments known as corticosteroids, and ataluren can be taken alongside these medications.

What happens if/when ataluren is approved in my country? Can I leave the trial?

If you/your child enroll in Study 041, we would like a commitment that you/your child will follow through with the study obligations, unless a doctor determines you/your child should discontinue for health or safety reasons. However, participation in this study is entirely voluntary, and if you wish to do so, you/your child are able to withdraw from the study at any point for any reason, or no reason.

What do I have to do to be involved in Study 041?

If you/your child would like to participate in the trial, before being enrolled, you/your child will need to discuss the trial with your doctor, and agree (consent) to being involved. You/your child will be asked to sign a consent form(s). The consent form(s) provides detailed information, which will outline the risks and benefits of participating in the trial. If you/your child have/has any questions about this information, talk to your doctor as it is important that you are fully informed. The consent form(s) also explains the basic facts about the trial in age-appropriate language. When you/your child signs these forms you will be given copies to keep.

The next step involves some checks to ensure that you/your child is eligible to participate in the trial. These checks, known as screening procedures, will include tests that are timed to assess your/your child’s ability to run/walk 10 meters, climb four stairs, descend four stairs, and stand up from lying down on your back within 30 seconds. These checks will take place in the two weeks before your/your child’s trial starts. A genotyping test, to ensure that you/your child has a nonsense mutation of the dystrophin gene, will be administered at baseline, or the start of the trial.

What do I have to do during Study 041?

If you/your child are/is accepted into the trial, you will be randomly assigned to either the ataluren group or the placebo group.

Ataluren or placebo is taken through the mouth. Every day for the duration of the trial, you/your child will need to prepare and take the medication or placebo three times a day: in the morning, at midday and in the evening.

Ideally, there should be about six hours between morning and midday doses, about six hours between midday and evening doses, and about 12 hours between evening doses and the morning dose on the next day.


For More Information

Email: patientinfo@ptcbio.com

Toll free: +1 (866) 282-5873

Ask for the original document: mcduberger@laforcedmd.com

Learn more

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New drug for DMD being reviewed by the FDA

Sarepta Announces FDA Acceptance of Golodirsen (SRP-4053) New Drug Application for Patients with Duchenne Muscular Dystrophy Amenable to Skipping Exon 53

Press release here: Sarepta.com


Sarepta Therapeutics, Inc. announced the Food and Drug Administration, Division of Neurology had accepted its New Drug Application (NDA) seeking accelerated approval for golodirsen (SRP-4053) and provided a regulatory action date of August 19, 2019. Golodirsen is a phosphordiamidate morpholino oligomer* engineered to treat those individuals with Duchenne muscular dystrophy (DMD) who have genetic mutations subject to skipping exon 53 of the dystrophin gene.

The company completed its NDA at the end of 2018 as part of a rolling submission and requested priority review, which was granted. The company previously received orphan drug designation for golodirsen.

The study demonstrated statistically significant results in favour of golodirsen on all biological endpoints.

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


Doug Ingram, president and chief executive officer, Sarepta: “If approved, golodirsen will serve up to another 8 percent of the Duchenne community, bringing us closer to helping as many Duchenne patients as possible.

We look forward to working with the FDA toward advancing this important therapy and rapidly bringing it to individuals with Duchenne who are amenable to exon 53 skipping.”


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. Exon skipping is intended to allow for the production of an internally truncated but functional 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. Death usually occurs before the age of 30 generally due to respiratory or cardiac failure.




News about Golodirsen, Skipping Exon 53

Sarepta Therapeutics completes submission of New Drug Application seeking approval of golodirsen in patients with DMD amenable to skipping exon 53

Press Release here

Golodirsen has been studied for the treatment of exon 53 amenable patients, approximately eight percent of patients with DMD. Submission represents ongoing advancement of the company’s proprietary PMO RNA-based platform.

Sarepta Therapeutics, Inc. announced today that it had completed the submission of its New Drug Application (NDA) seeking accelerated approval for golodirsen (SRP-4053), a phosphorodiamidate morpholino oligomer engineered to treat those patients with Duchenne muscular dystrophy who have genetic mutations subject to skipping exon 53 of the Duchenne gene.

If the golodirsen NDA is filed and granted accelerated approval, the company’s ESSENCE study (4045-301) could serve as a post-marketing confirmatory study. ESSENCE, which is underway, is a global, randomized double-blind, placebo-controlled study assessing the safety and efficacy of golodirsen and casimersen, their exon 45 skipping therapy.

“We are grateful for the patients and clinicians who have participated in the study with an aim to advance treatment for all patients with Duchenne,”
“Sarepta is committed to developing therapies to benefit the greatest possible percentage of patients affected by Duchenne. Our proprietary PMO technology remains central to our commitment to patients with Duchenne. Combined, EXONDYS 51® (eteplirsen), golodirsen, and casimersen have the potential to treat nearly 30 percent of patients with Duchenne.” Said DOUGLAS S. INGRAM, President & CEO

About Golodirsen

Golodirsen exon-skipping technology to skip exon 53 of the DMD gene. Exon skipping is intended to allow for the production of an internally truncated but functional dystrophin protein.

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 dystrophin

Dystrophin is a protein found in muscle cells that, while present in extremely small amounts (about 0.002 percent of total muscle protein), is crucial in strengthening and protecting muscle fibers. A devastating and incurable muscle-wasting disease, DMD is associated with specific errors in the gene that codes for dystrophin, a protein that plays a key structural role in muscle fiber function.

POLARIS DMD, a phase 3 trial on edasalonexent

One of the objectives of our team is to inform you about new treatments. Here’s the latest news about Polaris DMD, the clinical trial of edasalonexent, developed by Catabasis. Thank you for sharing these articles in the DMD community.


Maria Mancini, vice president of clinical operations at Catabasis: We named the trial ‘Polaris’ because it is the brightest star in its constellation and it’s also known as the North Star.


What is Polaris DMD?

Polaris DMD is a phase 3 trial of edasalonexent, a potential treatment for Duchenne muscular dystrophy (DMD), regardless of mutation type, is enrolling boys ages 4 to 7 in the U.S. Registration information is available here > Clinicaltrials.gov.

The Polaris DMD Trial is a one-year, randomized, placebo-controlled trial. Catabasis began evaluating patients on October 2 at several sites in the United States. Catabasis plans to conduct the trial at nearly 40 sites around the world. The results are expected in June 2020.


Joanne Donovan, M.D., Ph.D., Chief Medical Officer of Catabasis: We are very excited to advance edasalonexent through this potentially last phase of clinical development with the hope of providing a new treatment option to all boys affected by this disease. We believe that edasalonexent has great potential as a therapy to be taken on its own as well as in combination with other treatments.


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.


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.


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 Catabasis: www.catabasis.com

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

Muscular Dystrophy News: www.musculardystrophynews.com

More information about the Polaris DMD trial: Catabasis – Polaris DMD

Business Wire: www.businesswire.com


Tarantula venom for dmd

Here’s the latest news from the University of Buffalo (UB) about an experimental therapy called GsMTx4. Based on a molecule found in tarantula venom, this “protein” can prevent muscle mass loss and muscle damage in an animal model of Duchenne Muscular Dystrophy (DMD). Enjoy your reading and thank you for sharing these articles in the DMD community.

This research from UB, published last July in the magazine “Neuromuscular Disorders,” shows that this new drug significantly reduces the loss of muscle mass.


What Is GsMTx4?

GsMTx4 is a small protein, a peptide*, present in the venom of the tarantula. This protein works by preventing some ion channel activity in muscles without affecting the communication between nerve cells and muscle cells.

Frederick Sachs: “GsMTx4 represents an out-of-the-box treatment to slow the progression of DMD.”

 Thomas Suchyna noted in a previous study that in addition to protecting muscles, GsMTx4 protected against cardiomyopathy, a common cause of death in patients with DMD.

 Frederick Sachs: “Remarkably, we did not observe any side effects in mice in this study. The drug also has a long life so that subcutaneous injection may be needed only once a week.

The researchers concluded that GsMTx4 could also be complementary to other therapies, such as the anti-inflammatory agents and gene replacement strategies prescribed or studied in DMD.

GsMTx4 has already been licensed to Tonus Therapeutics and Akashi Therapeutics as a sublicence for further development.



By the spring of 2019, a new investigatory new drug application will be filed with the United States Food and Drug Administration (FDA). If successful, by 2020, Phase I/II studies in humans will be followed.

Manufactured by chemical synthesis, GsMTx4 is considered an ‘orphan drug,’ a designation that the FDA grants to promising therapies for rare diseases.


About DMD

Duchenne muscular dystrophy (DMD) is a disease that affects boys almost exclusively 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. 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.


More Links

University of Buffalo:: Promising new therapy spares muscle loss in Duchenne muscular dystrophy

These results were published in the study entitled, “GsMTx4-D provides protection to the D2.mdx mouse,” in Neuromuscular Disorders.

Neuromuscular Disorders



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