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Moving Toward Precision Medicine in Duchenne Muscular Dystrophy: Where We Are and Where We’re Going

  • Authors: Jerry Mendell, MD
  • CME / ABIM MOC Released: 10/26/2022
  • Valid for credit through: 10/26/2023, 11:59 PM EST
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Target Audience and Goal Statement

This activity is intended for neurologists, pediatricians, and primary care physicians.

The goal of this activity is for learners to be better able to increase awareness of how to reduce the time to diagnose DMD, improve the personalized selection of therapy for DMD, and increase knowledge of clinical data for the study of gene therapies for DMD treatment.

Upon completion of this activity, participants will:

  • Have increased knowledge regarding the
    • Specific laboratory tests that are important to the initial assessment of a patient with DMD
    • Differentiation of characteristics of investigational gene therapies for the management of DMD
    • Clinical trial data for gene therapies being studied for the management of DMD
  • Have greater competence related to
    • Selection of an appropriate therapy for the management of DMD


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  • Jerry Mendell, MD

    Professor of Pediatrics and Neurology
    The Ohio State University
    The Dwight E. Peters and Juanita R. Curran Endowed Chair in Pediatric Research
    Abigail Wexner Research Institute
    Nationwide Children’s Hospital
    Columbus, Ohio


    Jerry Mendell, MD, has the following relevant financial relationships:
    Consultant or advisor for: Avexis (Novartis Gene Therapies); Novartis; Sarepta; Vertex
    Research funding from: Sarepta


  • Pakinam Aboulsaoud, PharmD

    Senior Medical Education Director, Medscape, LLC


    Pakinam Aboulsaoud, PharmD, has no relevant financial relationships.

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  • Leigh Schmidt, MSN, RN, CNE, CHCP

    Associate Director, Accreditation and Compliance, Medscape, LLC


    Leigh Schmidt, MSN, RN, CNE, CHCP, has no relevant financial relationships.

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This activity has been peer reviewed and the reviewer has disclosed no relevant financial relationships.

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Moving Toward Precision Medicine in Duchenne Muscular Dystrophy: Where We Are and Where We’re Going

Authors: Jerry Mendell, MDFaculty and Disclosures

CME / ABIM MOC Released: 10/26/2022

Valid for credit through: 10/26/2023, 11:59 PM EST




Dr. Jerry Mendell (00:05): Hi, I want to review today the great progress we've made in treating muscular dystrophy. In this slide deck, [00:13] Moving Forward Precision Medicine in Duchenne Muscular Dystrophy: Where We Are and Where We're Going, we'll address those issues. I'm Dr. Jerry Mendell, Professor of Pediatrics and Neurology at Ohio State University, and a member of the Center for Gene Therapy at Nationwide Children's Hospital. [00:30] Thank you for participating in [Please move yellow highlight to [00:13] above] Moving Forward Precision Medicine in Duchenne Muscular Dystrophy: Where We Are and Where We're Going is discussed in this program. This covers the agenda we'll talk about today. It'll cover the genetics, diagnostic tests, the importance of recognition, and a lot about treatments and future therapeutics. (00:59): Let's start with the genetic basis and the natural history of the disease. On the right, you see an explanation of the disease we'll discuss. It's X-linked Duchenne muscular dystrophy. X-linked means that the disease is transmitted by the mother and the mother also represents a carrier, which might have some relevance to potential symptomatics. [1:25] The result of… The disease is the result of a mutation in the muscular dystrophy gene called DMD gene, by no surprise. When there's a mutation in this gene, there's not sufficient protein for the muscle cell to survive and we see progressive muscle degeneration. (01:49): On the left, you see the incidence of the disease. This is really universal. As you can see from the numbers here, the incidence is one in 5,000 newborns. This is a picture cartoon of [2:10] the gene… the protein that's produced by the gene. If you look, you'll see underneath the membrane or what's called the sarcolemma on that illustration is the dystrophin gene. Its sub-sarcolemma, underneath the membrane. It extends from an interesting part of the center of the muscle fiber and connecting to actin filaments and extends all the way up to membrane proteins that are ligands for dystrophin. By this connection, you can see dystrophin is absent. (02:49): There is really a fragility of the membrane because there's no longer support, and that's how we end up with a form of muscular dystrophy. This is a complex slide, but what it shows here is, one, the size of the gene is very large. It has 79 exons. Exons are coding regions of the gene, and these coding regions then determine what the protein looks like. You'll see on the next slide that certain portions of the codons one or more or a fraction of one can be missing. This is an illustration of a mutation that affects three codons, 45, 46, and 47. The reason that's important is when these three are missing, there is a connection that persists between exon 44 and exon 48. (03:52): Both of them have purely vertical ends and they can meet and satisfactorily portray the function of the gene as it moves through that area. What happens is the product of the gene is smaller. That is, it produces a microform of the dystrophin protein, but it still functions. This is the type of gene defect that causes Becker muscular dystrophy. But another term that's important is it causes an in-frame mutation. This is just the opposite of that. It's smaller mutation, but it's misleading because it's smaller. In this mutation, what happens is that you can see 45 is missing. (04:50): When 44 connects with 46, a square end of their exon meets with a triangular exon in 46, and that will not convey the message through that area. It's called an out-of-frame mutation. This is typical for Duchenne muscular dystrophy. Don't let me mistake you for the fact or dissuade you from the fact that more than one exon can be missing in Duchenne and be out-of-frame, but it's these ends of the exons that meet that determine whether it's in-frame or out-of-frame. This is an important slide because it shows how we measure function in Duchenne dystrophy. We use the North Star Ambulatory Assessment to measure the total score both in clinical trials and in natural history. (05:44): The importance of this slide is it shows natural history. And in that sense, here's over 300 measurements from patients. An important point is that in Duchenne dystrophy, the development increases and improves up to about six years old. And after that, it starts going in the other direction. The reason that's important for clinical trials is if we continue to produce improvement in function after age six, we know that we have an efficient form of treatment that unequivocally works. If you look over on the right side, you'll see that the North Star actually is composed of 17 measures. There are bit of strategy behind that, in that eight of them measure and compare limb function with one limb versus the other. (06:45): Here's an illustration of a person standing on one leg and then the other part of that is standing on the other leg. It can also be climbing on and off the box one step at a time [6:59] or standing on one or hopping on one leg. [7:02] The other measures…. There are nine other measures that measure total body function that incorporate both sides of muscle function. The scoring system here is relatively simple. If you can't do the test, you get a zero. If you can do it, but not fully, you get a one. A two means that you do it completely. This is the natural history of the disease. Here you see that you have in the first three years of life, getting back to birth, you are born with a disease. (07:39): We know that because the muscle enzymes are elevated at birth. But during the first three years, you have delay of milestones, delay in sitting, standing, walking. By three years of old, the disease is fairly well manifest. But by five, it is prominently displayed in that there is muscle weakness, toe walking, difficulty climbing stairs, and unequivocally infected. By 10 to 12, boys are really impaired. They're usually wheelchair dependent and have lost significant function. By 15, many require noninvasive ventilation, especially at bedtime. And by 20, their life is threatened from cardiac and respiratory disease. (08:31): This shows some of the early signs of dystrophy. If you look on the left, you see what I mentioned delayed walking in loss of motor skills. There's a waddling gait, difficulty running, jumping, negotiating stairs, a sway back movement or lordosis, frequent falling in large casts, and then this one sign here, Gowers sign, which is illustrated here. A Gowers sign means that the boys' spread their legs and then walk up their legs and have trouble standing. But when they stand, their legs are spread apart and they usually will hyper extend their back. The other part of the disease often is loss of some kind of cognitive function. (09:23): This may manifest in behavior or language delays. In general, DMD boys have a shift in their IQ by 10 points. Having said that, I want to emphasize, this is not true of every patient with Duchenne, because some it's really a shift in the curve. But if you take a bell shaped curve, many of them can be well within normal limits or even beyond and excel like children with advanced IQs. Let's look at the diagnosis of the disease. The diagnosis depends on DNA testing. There was a time when we used more primitive methods of DNA testing, but now we use the MLPA, which is multiplex ligation-dependent probe amplification. (10:26): Forget about that. Call it MLPA. It enables us to find large deletions and duplications of the gene in about 70% of the cases. But still, some mutations are harder to find and new testing has come into play. And that's called next-generation sequencing. Between MLPA and next-generation sequencing, more than 90% of the mutations are identified. Those are the two most efficient ways that you'll see used in the clinic. The importance of accurate diagnosis can't be overemphasized. Family planning is important. Parents may want to defer having more children. That's one possibility. Also, it helps interpretation of testing. (11:21): Boys with Duchenne dystrophy have what appears to be elevated liver enzymes. When, in fact, these liver enzymes overlap with muscle enzymes, so that if a boy has only the liver enzymes tested, he may end up with a liver biopsy. It's important for early diagnosis to recognize that and avoid doing liver biopsy. The first line of treatment we'll discuss on the next few slides, so I'll defer that. And then of course, the other thing that's important about early diagnosis is referral to clinical trials. What is the future of Duchenne muscular dystrophy in terms of treatment options? These are the four things that we'll talk about and I'll take each one of these one slide at a time. (12:17): I won't list them here. But on this slide, we see what the four are. One is corticosteroids and we'll talk a little bit more about that. This was the first form of treatment that was introduced. Exons skipping was next and we'll talk about the details of that. And gene therapy, which is the most promising method now. The fourth method is called CRISPR-Cas or CRISPR-Cas9. This we won't talk about because it's not in clinical trial, but CRISPR allows for direct editing of the DNA in place. By doing that and if you can correct the gene in place, it represents a powerful tool for treatment. We anticipate that will be coming on board sometime in the next year, two years, or maybe longer. (13:11): It depends on when the FDA approves it. But corticosteroids were the first treatment that was really significant for the disease and introduced back in 1989. It was prednisone. Later on, a more sophisticated corticosteroid called deflazacort was introduced. It has fewer side effects and is generally preferred over prednisone. Either both of these agents delay the loss of ambulation, preserve arm function, delay any onset of scoliosis. What they don't do effectively is change cardiac function. But they also have a series of complications, as all steroids do, cause loss of calcium from the bone. (14:09): Steroids replace corticosteroids that are delivered from the adrenal gland so that they may stop the body from producing its own steroids and cause adrenal insufficiency. They impair glucose tolerance so that they produce sort of a pseudo diabetic state, and they cause increased appetite and lead off into obesity. Cataracts will be produced in a certain percentage more likely with deflazacort than prednisone. And then there may be behavior problems from steroids. This is another treatment other than steroids. This is exon skipping. Exon skipping was the second most effective treatment that was introduced for the disease. (15:03): And now there are four forms of exon skipping: Casimersen, Eteplirsen, Golodirsen, and Vitolarsen. They skip exons 45, 51, and 53. Now, this is very specific treatment, so there must be... By skipping this exon or skipping any one of these exons, it must allow for the gene to come back into frame. And if we look here under B, you see that this patient had an exon 52 mutation. But if you skip exon 53, you get back to that principle I was telling you about where you have 51 and 54 match, they're both square ends and they match perfectly. The gene turns out to be a little bit smaller and a smaller size of dystrophin that works very well. (16:05): The other way is to….These different exon, the one I illustrated, skips 53, but the same principle occurs from skipping these other exons. Ataluren is a different agent. If you look on the top now, if there's a point mutation or a stop code on in one exon, not a loss of the whole exon, but one specific base pair is mutated, then Ataluren allows for what we call read through. It allows [16:39] for that gene….for that point mutation to be ignored essentially and the whole gene is read. It has been tested in clinical trial, but is not yet an approved product. Whereas all of these exon [16:56] duplications, I mean mutations, and these agents are in clinical trial now and can be given to any patient. (17:08): Now let's move on to gene therapy. Gene therapy is more complex overall. I have this illustration here that specifically, I think, shows it well. This is a virus. For gene therapy for Duchenne dystrophy, we use a virus called adeno-associated virus or AAV. In this adenovirus, we take out the AAV associated genes and we put in the gene for muscular dystrophy. Let me emphasize, this is adeno-associated virus, not adenovirus. It has its name adeno-associated virus because it uses adenovirus as a helper virus, but it is adeno-associated virus. A very important distinction. We inject it intravenously. It goes to the muscle fiber. (18:12): It courses through the muscle fiber to the muscle nucleus. It goes through the nucleus. And in the nucleus, the capsid of the virus breaks down, releases the gene to allow the DNA that we put in, represented in red here and now represented in double stranded DNA, more like what we see in the typical DNA. [18:40] It then produces…. It's translated, or I'm sorry, It’s transcribed to produce messenger RNA. Messenger RNA then leaves the nucleus, goes into the cytoplasm to the ribosome. The ribosome then produces the full end protein. It would go back to the membrane and strengthen the membrane in Duchenne dystrophy. [19:05] AAV viruses…. AAV vectors have major advantage over other forms of delivery of the virus. (19:14): It doesn't cause any human disease. There are more than one serotype, more than one variant of AAV that can be used in clinical trial. The one I'm going to show you that has the most favorable outcome now is one we call AAVrh74. The advantage of AAV is that when it gets into the nucleus, it doesn't disrupt any of the other genes that are already in place. It doesn't go into the genome. It stays outside the genome, just like I illustrated on the last figure. There's no mutation by disrupting any other normal genes. It has disadvantages because it's small in packaging capacity. It can be a problem at times. [20:08] for... (20:09): This virus can be found in the environment in general and about somewhere around 10 to 12% of people have been exposed to this virus. And if they have, they can build up an antibody to this virus, which then makes it virtually impossible to use for gene therapy. [20:30] [please insert 312556_11_P2P_Mendell_092022_AddOn] So let’s move on and discuss about the clinical trial results and there were 3 competing clinical trials. They are numbered: SRP-9001, PF-06939926, and SGT-001. Now, these are a summary of the clinical trials that have been done. The most effective is [20:37] by Sarepta Therapeutics and their product is called SRP-9001 that competes with Pfizer and Solid, and we'll look at that data. This is what the gene looks like. The gene that we put in is called the transgene. It is activated by a promoter. (21:02): When this cassette goes into the virus, it would look like this and then would express from that region. Once we inject it into the cell, it would go into the muscle cell, the nucleus, as I showed you, and drop off the gene. The promoter is extremely important because it activates the gene and the gene expression is regulated by different promoters. We use MHCK7 because it expresses the gene in the heart and in muscle. The function of the gene is displayed by what's called SRP-9001. This is a mini or small transgene because the whole gene will not fit into AAV, but it works very effectively. Once it's put into the vector and delivered, it's very safe as you'll see. (22:08): Now, there are really three clinical trials that are underway and I'll just briefly point those out. This is called Study 101, 102, and 103, not surprising numerically, and they all have different benefits. Study 101, which is summarized here, was the first one we ever did. It had only four patients. It was an open trial, and that means there was no control group, but four patients received the gene IV, single IV infusion of SRP-9001. The key outcome measures were safety, the North Star, and then time function tests and a muscle biopsy done 12 weeks after the infusions. Four years later, and this is important because the common question is, how long will the virus persists? (23:07): Right now, the best data we have in Duchenne dystrophy is four years. We expect it to go longer, but in four years, it still seems to be working very well. This is a picture of the North Star. Here they are in the purple, starting out at these functions and everyone went up and stayed pretty persistently high, so that====== the overall improvement of the North Star was seven points even at four years. And that is a lot of improvement in the function of the patient. As far as the safety goes, we have very good safety and administration. The most common side effect following delivery is vomiting that will occur during the first week, but is relatively mild symptoms go and well-handled. (24:05): The other thing is vomiting. In addition to vomiting, there can be inflammation of the liver and that will be relatively mild as well and handled well by the steroids that boys take during the clinical trial. There are no other serious abnormalities that we see in the clinical trial. Some of the other ones were there's compliment activation and other side effects have not occurred in the SRP-9001 clinical trial. [24:44] Now this contrasts…. This is the next phase of the trial, which was the 102 phase. This was now a double blind randomized placebo-controlled trial. Basically what that means is that during the first trial of patients were split into two groups, one got the gene, one got placebo, and the next year they switched over. (25:12): The results of this trial are interesting and important. These are four to five year olds. The younger group had overlapping starting points using the North Star and the improvement was highly statistically significant. In the older group, unfortunately, the starting points were not overlapped and there was no really clinically significant outcome. This points out two things. The control group in the treated group must have the same starting point and that younger boys do better for gene therapy. This was the 103 trial, which is still ongoing, but the importance of this... (26:00): This was back to an open trial and we have data from 20 patients now, and that data showed excellent gene expression with good muscle expression. This is called vector genome copy number, that's how many genes got to each of the muscle cells. This was a very high number. Over three genes got to each muscle cell, and that was more than adequate. The gene expression, if you look here at the red outlined muscle fibers, they were very robust and good gene expression. Now, as we move on to the clinical trial, we're in the final phase of the trial. This is a phase three trial. This phase three trial now is really for approval of the product. (27:00): 120 patients have already enrolled in this trial and it's going very well. [27:05] It's likely that this product will be approved between now and the end of the academic year. In other words, between now and July. Now, this contrast with the Pfizer study using this product. In the Pfizer trial, 19 patients have been enrolled. The dose escalation, one, a small number got a lower dose than the larger number. The second trial was called PF. It was sponsored by another company and had 19 patients enrolled, three at lower dose and 16 at higher dose. Still the same outcome measures looking at the North Star and how much gene expression there was. (27:57): The problem with this trial was if you look at efficacy, they did have good gene expression or relatively good. It wasn't as good as the SRP-9001. But on the other hand, the change in the North Star was also modest, not as good as the SRP-9001. They did have more complications in this trial, one fatality, two with inflammatory change in the heart, and then this one, complicated name, thrombotic microangiopathy, but it's essentially compliment activation with kidney involvement. That is the results. This trial used AAV9 instead of AAVrh74. Different stereotype, not quite as good. The last one is SGT-001, also using microdystrophin. (29:00): A modest number of patients here, only nine patients in this trial, similar outcomes with dystrophin looking at safety. What you see in this trial is that there were a lot more complications with nausea, vomiting, lower platelets with compliment activation, a systemic inflammatory response, and some evidence of hepatitis. This is the current clinical picture. It's looking very good. DMD is a severe disease. [29:35] SRP-9001 has excellent outcomes and will probably be approved by the end of the year. I think this will certainly completely change the disease as it looks now. We're very optimistic as we move forward that we have what looks like to be an effective treatment for the disease. (30:01): I'll stop there and answer any questions. Thank you. That ends the story as we see it. I want to thank you for participating in this event. Thank you for participating in this activity. Please continue to answer the questions that follow and complete the evaluation.

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