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The Future of Duchenne Muscular Dystrophy: Understanding the Science Behind Emerging Gene Therapies

  • Authors: Crystal M. Proud, MD; Eugenio Mercuri, MD, PhD; Laurent Servais, MD, PhD
  • CPD Released: 5/18/2022
  • Valid for credit through: 5/18/2023, 11:59 PM EST
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Target Audience and Goal Statement

This activity is intended for an international audience of non-US neurologists, pediatricians, and other healthcare professionals caring for patients with DMD. 

The goal of this activity is that learners will be better able to understand the rationale for gene therapy in DMD and the latest data.

Upon completion of this activity, participants will:

  • Have increased knowledge regarding the
    • Science of gene therapy in DMD 
    • Current approaches being investigated for gene therapy in DMD 
    • Clinical data on emerging gene therapies for DMD


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  • Crystal M. Proud, MD

    Director of Neurology and Neuromuscular Medicine
    Children's Hospital of The King's Daughters
    Norfolk, Virginia
    United States


    Disclosure: Crystal M. Proud, MD, has the following relevant financial relationships:
    Consultant or advisor for: AveXis/Novartis Gene Therapies; Biogen; Genentech/Roche; Sarepta; Scholar Rock
    Speaker or member of speakers bureau for: Biogen
    Contracted researcher for: AveXis/Novartis Gene Therapies; Biogen; CSL Behring; Fibrogen; Pfizer; PTC; Sarepta; Scholar Rock

  • Eugenio Mercuri, MD, PhD

    Professor of Pediatric Neurology
    Catholic University
    Rome, Italy


    Disclosure: Eugenio Mercuri, MD, PhD, has the following relevant financial relationships:
    Consultant or advisor for: Biogen; Italfarmaco; Novartis; Pfizer; PTC; Roche; Sarepta; Scholar Rock
    Speaker or member of speakers bureau for: Biogen; Novartis; PTC; Roche; Sarepta
    Research funding from: Biogen

  • Laurent Servais, MD, PhD

    Professor of Pediatric Neuromuscular Diseases
    MDUK Oxford Neuromuscular Centre
    University of Oxford
    United Kingdom


    Disclosure: Laurent Servais, MD, PhD, has the following relevant financial relationships:
    Consultant or advisor for: Affinia; Audentes; Biohaven; Biogen; Catabasis; Dynacure; Evox Therapeutics; Novartis; Roche; RegenexBio; Sarepta; Scholar Rock
    Speaker or member of speakers bureau for: Audentes; Biogen; Novartis; Roche
    Research funding from: Biogen; Novartis; Roche


  • Katherine Carpenter

    Medical Education Director, WebMD Global, LLC


    Katherine Carpenter, PhD has the following relevant financial relationship:
    Advisor or consultant for: Eisai, GW Pharmaceuticals

  • Eloise Ballard, PhD

    Scientific Content Manager, WebMD Global, LLC


    Disclosure: Eloise Ballard, PhD, has no relevant financial relationships.

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    Associate Director, Accreditation and Compliance, Medscape, LLC


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The Future of Duchenne Muscular Dystrophy: Understanding the Science Behind Emerging Gene Therapies

Authors: Crystal M. Proud, MD; Eugenio Mercuri, MD, PhD; Laurent Servais, MD, PhDFaculty and Disclosures

CPD Released: 5/18/2022

Valid for credit through: 5/18/2023, 11:59 PM EST


Activity Transcript

Segment 1

Crystal M. Proud, MD: Hello, I'm Dr Crystal Proud, Director of Neurology and Neuromuscular Medicine at the Children's Hospital of The King's Daughters in Norfolk, Virginia. Welcome to this program, “The Future of Duchenne Muscular Dystrophy (DMD): Understanding the Science Behind Emerging Gene Therapies”.

Our goal today is to explain the enthusiasm surrounding gene transfer therapy for DMD and review the scientific foundation, current approaches, and emerging data. Upon reviewing this data, I'm confident that you will identify this approach as having the potential to be transformative for boys diagnosed with DMD and their families. I am joined today by Professor Laurent Servais, who will discuss the science of gene therapy, and Professor Eugenio Mercuri, who will review the evolving therapeutic landscape of DMD.

DMD is a progressive neuromuscular genetic disease affecting approximately 1 in 3,500 to 5,000 males worldwide. It results from deletion, duplication, or point mutation within the DMD gene. The DMD gene is responsible for producing the dystrophin protein, which maintains the integrity of the muscle cell membrane by linking the extracellular matrix to the actin cytoskeleton. Out-of-frame and nonsense mutations in the DMD gene lead to insufficient amounts of dystrophin protein production, and the muscle cell membrane becomes unstable and degrades over time.

Muscle weakness typically becomes evident by elementary school age. And the natural history is such that most boys will achieve their peak in motor function by age 6.3 years, and then they demonstrate a subsequent expected decline in strength thereafter. The weakness impacts the muscles of the extremities, muscles of respiration, and cardiac muscles.

The need for new treatment approaches is clear. The natural history of DMD with current supportive care is relentless, with boys losing the ability to walk between ages 10 to 13, with progressive restrictive lung mechanics leading to the need for supportive ventilation by age 20, with progressive cardiomyopathy leading to heart failure and death typically in the third decade. The standard-of-care includes corticosteroids, which prolong ambulation, but they don't change the inevitabilities of Duchenne. Exon skipping technologies have provided some new optimism for a change from natural history, though they do not apply to a large proportion of boys with DMD. Gene transfer therapy for DMD is gaining enthusiasm for the hope it brings to boys with DMD and their families.

Dr Laurent Servais will explain the science behind this exciting therapeutic strategy, which is gaining traction in neuromuscular medicine.

Segment 2

Laurent Servais, MD, PhD: Hello. My name is Laurent Servais. I'm a Professor of Pediatric Neuromuscular Diseases at the University of Oxford in the UK and the University of Liège in Belgium. Welcome to this section; we're going to talk about the science of gene therapy.

First things first, the genetics of DMD. Dystrophin is a very long gene with 79 exons; it codes for a protein called dystrophin, the shock absorber of the muscle cells. There are 79 exons: some start at the beginning of a codon and finish at the end of a codon. This is the case for exon 32 or 33. But an exon can also start at the beginning of a codon and stop in the middle of another codon, as is the case for exon 45. Then you have the intron and the next exons that will finish with the previous codon and then continue with other codons.

If you're missing exon 45 to 47, you have in-frame mutation, right? You can continue reading the gene from exon 44 to exon 48. It's the most common deletion in Becker Muscular Dystrophy in which patients have a little bit of dystrophin. But if you're missing just exon 45, a smaller deletion, actually exon 44 to 46 will lead to an out-of-frame gene reading, and you won't have any protein produced. This is what happens in DMD. We need to understand that the problem is not the size of the deletion, but to a certain extent, it's if this deletion is out-of-frame or in-frame.

Something important to understand also is that dystrophin is expressed everywhere in the body with different isoforms. The isoforms that are expressed in the brain, for instance, are the isoforms that are mostly expressed after exon 41. According to where the deletion is and the mutations, we could have different phenotypes, especially from the central nervous system perspective. This is another way to illustrate the importance of the different domains of the dystrophin and the fact that actually, you could potentially be in a quite good condition with much shorter dystrophin, which has been demonstrated in some Becker patients.

Something we need to appreciate when we discuss gene therapy for DMD is that it's a very different disease from Spinal Muscular Atrophy. We see amazing results in Spinal Muscular Atrophy with gene therapy, but we need to remember that Spinal Muscular Atrophy is a disease of the motor neurons, which do not divide. But DMD is a disease of the muscle and the muscle mass that we have at birth is much smaller than the muscle mass that we have when we are adults. The importance of the timing of administration will be very different in these 2 conditions. And, of course, the patients are different. The phenotypic spectrum of Spinal Muscular Atrophy is much broader: it can affect babies and adults. Duchenne probably has a less heterogeneous phenotype, at least if you consider Duchenne as a separate disease of Becker Muscular Dystrophy.

About the type of mutations that we can observe in Duchenne: we can observe deletions, we can observe duplications, missense, nonsense mutations, and other more complex mutations. At the end of the day, about 60% of them are potentially eligible for exon skipping, which means skipping the out-of-frame exons flanking the out-of-frame deletion to make it an in-frame deletion. And there are all the possible treatable mutations like, for instance, nonsense mutations that could potentially be treated by drugs that help to go through nonsense mutations.

The correlation between the phenotype and the genotype is quite loose. Actually, some genotypes are associated with milder phenotypes, for instance, deletion of exon 2 to 7 are the deletions that are potentially treatable by exon skipping 44. But alltogether, the differences between the different genotypes are quite small except for the central nervous system involvement.

The principle of gene therapy is actually to use a vector, which is the envelope of a virus, and to put a promoter and a transgene into it. This vector will penetrate the muscle cell, but not only actually. We can try to be specific, but we won't be 100% specific, and most of the vector will actually go in the liver. Then the vector enters the nucleus, and the vector capsid disintegrates. It releases the DNA inside, and the DNA is transcribed into RNA, and then the RNA moves out of the nucleus. This is a general principle.

There are several strategies in DMD. You could, for instance, bring some RNA to perform exon skipping. You could also bring a shorter version of the gene, microdystrophin. You can bring the CRISPR-Cas9 system. You can bring another gene like atropin or GLGT2 in order to modulate other possible pathways like myostatin. Then we could also use potentially other vectors and new generations of vectors like nanoparticles or exosomes.

This is a proof-of-concept of the use of exon skipping in the dogs. As you can see, by injecting dogs with an AAV construct and using an RNA construct to skip the exons that is flanking the out-of-frame deletion in the dogs. We can re-express a very significant amount of dystrophin and increase the strength in the limb of the dogs that have been injected.

This has also been demonstrated using the same U7 construct in mice to skip a duplication of exon 2, mutations that affect 2% of patients with DMD. Keeping with the dog models, we also could inject a large cohort of dogs using AAV8 constructs. And to demonstrate that either if you inject locally or globally, you can obtain a very good re-expression of microdystrophin.

This comes now into humans, and these are 2 constructs that are currently in the clinic or reaching the clinic. We need to appreciate the gene therapy products today. Using microdystrophin is an association of 3 components: the vectors, the type of virus that we use (the transgene), and the type of microdystrophin that we use (and the promoter). These are 2 different constructs: one is using a AAVrh74, which is a completely different capsid than the AAV8 in this other construct. As you can see, the promoter in the microdystrophin construct can differ from one to another.

A very important point to consider when we speak about gene therapy is the dose, because it determines the toxicity.

This comes from a recent FDA workshop, and it illustrates a broad range of serotypes, of vectors, that are used today in gene therapy, not only AAV8 or 9, but also AAV5, AAVrh74 in a broad range of doses. And in Duchenne, we need to inject very high doses, up to 3x1014 vg/kg of patients, which is a huge amount in comparison, for instance, with hemophilia, in which we do not need to give so much transgene because it's a hepatic disease. The construct is very different from one to another microdystrophin, but I will not enter into the detail.

If you want to know more about how it translates in the clinic, I encourage you to stay on for the sessions' next talks. So, it was a pleasure to be with you today, and I hand over to Professor Mercuri. Thank you very much for your attention.

Segment 3

Eugenio Mercuri, MD, PhD: Hello. My name is Eugenio Mercuri. I'm a Professor of Pediatric Neurology at the Catholic University in Rome, Italy. Welcome to this section, “Evolving Therapeutic Landscape of DMD”. Before we talk about therapies, let's discuss for a moment what DMD is?

This is a progressive disorder. As you can see from this slide, there is a progressive involvement of muscle that is shown with a progressive sign of dystrophy on muscle biopsies. When the child is born, at birth or in the first years, there is no obvious clinical manifestation of Duchenne; there is just elevated CK. And between the ages of 3 and 7, the clinical signs become obvious with the delayed global and motor development, it's lower acquisition of skills compared to the peers. And the typical signs are difficulties running and hopping and standing from supine and climbing stairs. After the age of 7, there is a progressive decline with a rapid loss of functions that are important, like standing from the floor, standing, and then loss of ambulation. And after the loss of ambulation, which usually happens around the age when these children are in their late teens, there is a decrease in upper limb function and the progressive involvement of respiratory and cardiac function.

Therapies in DMD are relatively recent. In 2007, steroids were the only available therapy for Duchenne, and now in 2022, we have several possible therapeutic options which are taking account of all the different mechanisms of the disease. Today, we like to divide our therapeutic approaches in 2 main approaches. One corrects the primary protein defect, and the other reduces the progression of the dystrophic processes. The correction of the primary protein defect can be done with different approaches and gene therapy together with exon skipping and nonsense suppressions are the most used. There is also the attempt to reduce the progression of the dystrophic process either by preventing necrosis or fibrosis or by increasing muscle mass.

And a lot of focus in the last few years has been on adeno-associated virus (AAV) gene therapy. The AV-based gene therapy is a new technique. It's designed to address the genetic root cause of Duchenne, because we know children with DMD have a mutation in the dystrophin gene. Dystrophin is a large gene. It is the largest gene that we have. The whole gene cannot be inserted in the vector because it's too large, as is possible for other gene therapies, such as Spinal Muscular Atrophy. So, what has been suggested is to reduce the size of the gene by producing minidystrophin or microdystrophin. The structure of the whole combination of AV and gene is shown in this picture, depicting a part of the transgene, and the AV part.

As I said, dystrophin is a large gene and cannot be inserted fully into the vector because of the vector’s limited capacity. And so, the challenge has been to modify the dystrophin to less than 5 kB to fit in the AV particle. And this has been done in several ways, and different companies are running their programs on AV gene therapy. And as you can see from this slide, the structure is similar because they all consider using an AV, that, however, is not always the same. In the past, we have been using AV-9 in other gene therapies like SMA, but Duchenne, there are also other types of AV that have been considered.

And as you can see, the promoters are different, and some of them have promoters that are more specific for the cardiac muscles and others don't. And the internal part of the transgene is also different among the different approaches, again, targeting or prioritizing aspects of linking with the other proteins, or more specific for specific actions. All these approaches are now in clinical trials and the preliminary results are very promising.

Thank you for your attention. Please continue to watch the next section with Crystal Proud.

Segment 4

Crystal M. Proud, MD: Hello, I'm Dr Crystal Proud, Director of Neurology and Neuromuscular Medicine at the Children's Hospital of The King's Daughters in Norfolk, Virginia. Welcome to this segment, “Clinical Data on Emerging Gene Therapies for DMD”. There are several gene therapies in development for DMD, and we will briefly review the available data from the programs currently in clinical trials. This includes the Pfizer product fordadistrogene movaparvovec and the data released from the phase 1b study. Of note, the phase 3 study was placed on hold in December 2021 by the United States Food and Drug Administration. The Sarepta product SRP-9001, or delandistrogene moxeparvovec, has data from the 101, 102, and 103 clinical trials. The phase 3 study is ongoing and enrolling, referred to as the EMBARK trial. And the Solid Biosciences product SGT-001, with data from the IGNITE DMD trial, will be reviewed as well.

We will start with fordadistrogene movaparvovec. This product has been investigated in the phase 1 study, evaluating 19 ambulatory boys ages 4 to 12 years on a stable corticosteroid regimen. The boys were stratified into a low-dose vs high-dose treatment arm. They underwent a baseline muscle biopsy as well as functional testing at baseline, received their assigned treatment, and then underwent biopsy at 2 months and 12 months, in addition to undergoing functional assessments in monitoring for safety. There was a median follow-up period of 18 months, with 3 patients experiencing serious adverse events, including dehydration due to vomiting, acute kidney injury, and thrombocytopenia.

The phase 3 clinical trial is planning to enroll 99 boys. The population will include ambulatory boys ages 4 to 7 with DMD on a stable corticosteroid regimen. This is a multi-center randomized, double-blind, placebo-controlled study. It is currently on hold in the US, though hopefully will restart in 2022. The hold was placed due to a patient death in the earlier phase 1 study, and Pfizer is still investigating this death.

We'll shift gears now and review SRP-9001, delandistrogene moxeparvovec. SRP-9001 has been investigated in the 101 study, where 4 boys were administered the product intravenously. At baseline, the boys ranged in age between 4 to 6 years old, and 3 years after treatment, they demonstrated an improvement in the North Star Ambulatory Assessment (NSAA) motor function score of an average of 7.5 points. It's important to know that natural history has demonstrated that after age 6.3, boys typically decline by a rate of 3 U/yr on this same test. There were no serious adverse events or discontinuations from the study. The treatment-related AEs were mild or moderate and all resolved. They occurred mostly within the first 90 days. The most common adverse event was vomiting, which usually occurred within the first week after treatment, and there was no clinical evidence of complement activation.

A phase 2 clinical trial evaluating SRP-9001 was conducted using the research-grade material. It enrolled 41 boys with DMD ages 4 to 7 years on stable corticosteroids. They were randomized to receive either investigational product first, or they would receive placebo first, and then would receive SRP-9001 52 weeks later in the crossover portion. Muscle biopsies and functional data were collected.

When pursuing gene transfer studies, one must ask, 'has the transgene been delivered to the cell nuclei effectively?' In this trial, on average 1.6 gene copies per nucleus were observed. The next question is whether that transgene is producing protein effectively. There was an average of 23.8% change from baseline microdystrophin expression by Western blot, identified at the 12-week biopsy. The next question is whether the protein produced is getting to the desired location. The percentage of mean dystrophin positive fibers was 23.9% at the 12-week post-treatment biopsy. Functional data were examined, and at week 48, the change in NSAA score from baseline was 1.7 points higher than baseline in the treated group of 4- to 7-year-olds and 0.9 points higher than baseline in the untreated group, which was not statistically significant.

When the groups were examined more closely, it was revealed that the 4- to the 5-year-old group had an appropriate stratification and randomization, with both the treated and the placebo group demonstrating a similar baseline North Star Ambulatory Assessment score. The boys aged 6 to 7 were not well matched regarding motor function at baseline, demonstrating a statistically significant difference in motor function scores at baseline. There was a mean improvement in NSAA score of 4.3 points from baseline in the 4- to the 5-year-old group who received SRP-9001. These results provided a foundation upon which future studies could be designed, such that appropriate randomization and stratification included not just age as a factor, but also baseline motor functions scores.

Study 103, referred to as ENDEAVOR, is an ongoing, but fully enrolled, study, using commercially processed material to evaluate the safety and efficacy of SRP-9001 with a commercial manufacturing process. This study includes several cohorts, such as boys ages 4 to 7 who are ambulatory, boys ages 8 to 17 years who are ambulatory, and the non-ambulatory cohort. There was a baseline biopsy, treatment infusion, a 12-week follow up biopsy, and an ongoing long-term extension study. The study investigates whether the commercial-grade material has been similar in outcomes to the research-grade material. The interim results from the first 11 patients showed the average vector genomes per nucleus at 3.9, microdystrophin protein expression by western immunoblot at 12 weeks was 55.4% change from baseline, immunofluorescence showed a 57.7% dystrophin-positive fiber change from baseline, and safety assessments showed no new safety signals that were identified. Vomiting was the most common adverse event occurring in 64% of patients.

Overall, the commercial process material appeared similar in safety and efficacy compared to the research-grade material. This prompted ongoing clinical trials, including the EMBARK clinical trial, a double-blind, placebo-controlled clinical trial investigating SRP-9001. This study is currently enrolling.

We'll talk next about SGT-001. In the phase 1/2 clinical trial IGNITE DMD, examining the product at 4 study sites and boys with DMD. Eligible boys were ages 4 to 17 years old with DMD and on a stable dose of corticosteroids. This was an ascending dose study, whereby 3 boys received low-dose, and 3 boys received high-dose treatment. A delayed treatment cohort served as an untreated control cohort.

Biopsies demonstrated the widespread distribution of microdystrophin-positive muscle fibers, with colocalization of neuronal nitric oxide synthase and beta-sarcoglycan in the muscles of these patients. The average microdystrophin protein level and subjects in the high-dose cohort via Western blot at day 90 was about 10% of normal dystrophin, ranging from 6.8% to 17.5%. 12-to-18-month data from biopsies showed 20.3% dystrophin expression at 12 months and 69.8% dystrophin expression at 18 months. Functional data collected 2 years post-dosing show an improvement in a 6-minute walk test distance of 100.6 meters in the treated group compared to the natural history cohort. The NSAA improved by an average of 4.3 points compared to natural history. Of note, a clinical hold was placed on the trial in 2018 and 2019 due to concerns for complement-mediated adverse effects, including decreases in red blood cell and platelet counts, activation of the complement immune system response, acute kidney injury, and cardiopulmonary insufficiency. The clinical trial hold was subsequently lifted in October 2020.

We have reviewed the data from these 3 promising gene transfer programs. Thank you for your attention, and please continue to watch the conclusions.

Segment 5

Crystal M. Proud, MD: We have reviewed the science of gene therapy, the evolving therapeutic landscape, and the clinical data on these emerging gene transfer therapies for DMD. The foundation of gene transfer in DMD is distinguished from other gene transfers in that the DMD gene is too large to incorporate entirely into the vector. This has led to different products produced by different companies that contain varying critical regions of the dystrophin gene packaged into particular viral vectors, along with distinct promoters.

The data demonstrate notable changes in dystrophin protein production within the muscle fibers examined following a one-time intravenous infusion of gene transfer therapies. There have also been observed distinctions in motor function after gene transfer therapy, compared to what is known for natural history. These findings support a cautious optimism. The neuromuscular community has the potential efficacy of gene transfer therapy regarding the treatment of DMD. However, these treatments are not without risk, as demonstrated by clinical holds on 2 of the investigational programs. We move forward with the need for continued investigation, with attention to safety and efficacy for boys impacted by this degenerative disease. It is the neuromuscular community's hope to stabilize or improve the health of our boys impacted by DMD.

It just want to thank our excellent faculty, Professor Laurent Servais and Professor Eugenio Mercuri. And thank you for your attention. Please continue on to answer the questions and complete the evaluation.

This transcript has been edited for style and clarity.

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