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Early signs of gait deviation in Duchenne muscular dystrophy

Discussion in 'Pediatrics' started by NewsBot, Sep 15, 2011.

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  1. NewsBot

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    Press Release:
    UMN Medical School Study Provides New Insight Into the Use of Cell Replacement Therapies to Treat Muscular Dystrophies
    February 13, 2019
    MINNEAPOLIS, MN- February 13, 2019 – The University of Minnesota Medical School continues its legacy of advancing cell replacement therapies with a scientific breakthrough that highlights the promise of cell therapies for muscular dystrophy.

    The research published in Proceedings of the National Academy of Sciences of the United States of America (PNAS) allows authors Tania Incitti, Ph.D., Post-Doctoral Associate, and Rita Perlingeiro, Professor in the Department of Medicine, and member of the Lillehei Heart Institute, Stem Cell Institute, and Wellstone Muscular Dystrophy Center at the University of Minnesota Medical School, and their colleagues, to gain a deeper understanding of the cells generated in vitro for the purpose of muscle regeneration.

    Perlingeiro’s lab, over several years, pioneered the development of muscle stem/progenitor cells from pluripotent stem cells in vitro (i.e. in a culture dish rather than in a human or animal). These cells are able to generate new functional muscle upon transplantation into mice with muscular dystrophy, and critically also populate this new muscle with new muscle stem cells also derived from the pluripotent stem cells, allowing that new muscle to repair itself if it is injured. Now, the researchers have advanced these findings to identify for the first time the molecular signature of muscle stem cells generated in the dish, compared to that of the newly generated muscle stem cells that populate the newly formed muscle. They also compared these profiles to muscle stem cells isolated from mice at different developmental stages (embryonic, fetal, neonatal, and adult). These studies revealed that muscle cells generated in the dish are embryonic in nature, however upon transplantation, the stem cell population they provide to the new muscle change remarkably to a postnatal molecular signature, more resembling neonatal and adult stem cells.

    “While the engrafted muscle stem cells did not look identical to adult muscle cells, they no longer looked like embryonic cells either, which tells us they are changing after they are transplanted into the muscle environment,” said Incitti. The investigators also re-transplanted the engrafted muscle stem cells and found that very small numbers of these cells had tremendous potential for muscle regeneration upon secondary transplantation. “We now are asking- what are the environmental cues that are changing our cells?”

    “We wanted to know more about the cells we have been working on for the last 10 years,” said Perlingeiro. “This study brings us more knowledge about the mechanism behind their tremendous regenerative potential.”

    “We knew that new muscle stem cells were present after transplantation but understanding what role the environment plays, and understanding that the cells are truly reshaped by exposure to muscle environment is an exciting finding,” said Perlingeiro. “Knowledge at the molecular and functional level of what happens to these cells upon transplantation is particularly important to provide the rationale for future therapeutic applications.”
     
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    PUBLIC RELEASE: 21-FEB-2019
    New drug for Duchenne muscular dystrophy clears phase 1 clinical trial testing in boys
    Medication targets NF-κB, a key link between loss of dystrophin and disease progression


    Amsterdam, February 21, 2019 - Patients with Duchenne muscular dystrophy (DMD) have few treatment options. Medications currently available or in development either target only a subset of DMD patients with a particular genetic mutation or cause significant side effects. The investigational drug edasalonexent, an oral NF-κB inhibitor, has the potential to slow the progression of the disease for all patients with DMD. The results of a Phase I clinical trial published in the Journal of Neuromuscular Diseases indicate that the drug was well tolerated with no safety issues in boys with DMD, paving the way for further clinical testing.

    "In addition to being well tolerated in pediatric patients with DMD, our Phase 1 data demonstrated that edasalonexent (CAT-1004) inhibited NF-κB. This is important because NF-κB is a key link between the loss of dystrophin and disease progression in DMD. This would mean that edasalonexent has the potential to limit disease progression for all patients affected by DMD, regardless of their underlying mutation," explains Joanne Donovan, MD, PhD, Chief Medical Officer of Catabasis Pharmaceuticals, Inc. (Cambridge, MA, USA).

    Edasalonexent is an orally administered small molecule that contains two active substances, salicylic acid and the omega-3 fatty acid docosahexaenoic acid (DHA), which are linked together to produce a unique molecule. Both of these molecules are inhibitors of NF-kB, but edasalonexent inhibits NF-kB much more potently than either of the base molecules alone.

    In a previous study, edasalonexent was well tolerated and absorbed in adults and inhibited NF-κB. The goal of the current study, a Phase 1/2 study known as MoveDMD, was to evaluate the effects in children with DMD. In this one-week, open-label, multiple-dose Phase 1 clinical trial, 17 boys (mean age 5.5 years) were administered three sequential ascending doses of edasalonexent (33, 67, and 100 mg/kg/day). All doses were found to be well tolerated with no serious adverse events, dosing interruptions, dose reductions or discontinuations due to adverse events. Most adverse events were mild and gastrointestinal.

    Importantly, for the two higher doses (67 and 100 mg/kg/day), seven days of treatment resulted in decreased levels of NF-κB-regulated genes, as measured by whole-blood mRNA sequencing. The treatment also reduced levels of serum proteins thought to originate from damaged muscles. "This shows that with short-term dosing, edasalonexent can directly reduce the levels of elevated NF-κB in circulating DMD mononuclear cells prior to any changes observable in muscles," notes Dr. Donovan.

    Because of the potential universal benefit of edasalonexent for all types of DMD, Dr. Donovan suggests it could be used either alone or in combination with other medications including gene therapeutic approaches currently under development. Edasalonexent can potentially reduce muscle inflammation and degeneration and enhance muscle regeneration. She also suggests that inhibition of NF-κB may have disease-modifying effects.

    "The data from the Phase 1 MoveDMD clinical trial reinforce the good tolerability and safety profile of edasalonexent that we have now also observed in the Phase 2 trial and open-label extension," adds Erika Finanger, MD, Associate Professor of Pediatrics, Division of Neurology, School of Medicine at Oregon Health & Science University and principal investigator for both the MoveDMD and PolarisDMD trials. "I am pleased to continue to evaluate edasalonexent as a potential novel therapy for those affected by Duchenne, and I am excited to participate in the Phase 3 Polaris DMD study."

    DMD is the most common genetic neuromuscular disease, affecting one in 3,500-6,000 male births. The disease is characterized by progressive muscle weakness and degeneration with loss of contractibility. It is caused by one of several mutations in the DMD gene. No matter what the particular mutation, a key driver of muscle degeneration and suppression of muscle regeneration in DMD is chronic activation of the transcription factor NF-κB, which causes loss of dystrophin, a protein which helps keep muscle cells intact.
     
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    Scoliosis in Duchenne muscular dystrophy children is fully reducible in the initial stage, and becomes structural over time
    Young-Ah Choi et al
    BMC Musculoskeletal Disorders201920:277
     
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    A 4-Year-Old Boy with Progressive Weakness, Difficulty Walking and Running, and Increased Falls
    Diana P. CastroChunyu CaiDustin Jacob Paul
    A Case-Based Guide to Neuromuscular Pathology pp 257-262: 25 October 2019
     
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    The use of the gait profile score and gait variable score in individuals with Duchenne Muscular Dystrophy
    MarianaAngélica de SouzaaAnandaCezaraniaElisangelaAparecida da Silva LizzibGabrielaBarroso de Queiroz DavoliaStelaMárcia MattiellocRichardJonesdAnaCláudia Mattiello-Sverzute
    Journal of Biomechanics; 6 November 2019, 109485
     
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    Variable stiffness orthosis for gait normalization in patients with toe walking
    Huerta, Alyda.
    Thesis: S.B., Massachusetts Institute of Technology, Department of Mechanical Engineering, 2019
     
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    Press Release:
    New gene correction therapy for Duchenne muscular dystrophy
    Gene scissors against incurable muscular disease

    Duchenne type muscular dystrophy (DMD) is the most common hereditary muscular disease among children, leaving them wheelchair-bound before the age of twelve and reducing life expectancy. Researchers at Technical University of Munich (TUM), Ludwig Maximilian University of Munich (LMU) and the German Research Center for Environmental Health (Helmholtz Zentrum München) have developed a gene therapy that may provide permanent relief for those suffering from DMD.

    Muscles need dystrophin in order to regenerate. Persons suffering from Duchenne muscular dystrophy lack this essential muscular protein due to mutations in the gene which is responsible for producing dystrophin. As a result, their existing muscle cells deteriorate over time and are gradually replaced by connective and fatty tissue; muscle strength weakens during the course of the disease. The first symptoms usually appear around the age of five. Children with the disease begin to have difficulties with movements they previously completed with ease, for example climbing stairs or getting up from the floor. At approximately the age of twelve, they are no longer able to walk, later losing movement in their arms and hands. Due to concomitant respiratory and cardiac failure, the majority of patients does not reach the age of 40. DMD affects mainly boys, since the responsible mutations are located in the dystrophin gene on the X chromosome.

    Gene scissors remove defective gene sequence
    An interdisciplinary Munich research team led by scientists from TUM has for the first time succeeded in correcting the mutated dystrophin gene in living pigs. In order to cut the defective gene sequence from the DNA of the animals' muscle and heart cells, the researchers modified the Crispr-Cas9 gene scissors. "These gene scissors are highly efficient and specifically corrected the dystrophin gene," says Prof. Wolfgang Wurst, developmental geneticist at TUM and the German Research Center for Environmental Health. It became then again possible to viably read the gene which had been unreadable because of the genetic defect, thus allowing for a successful protein biosynthesis. Now the shorter but stably formed dystrophin protein was able to improve muscle function. The animals treated were less susceptible to cardiac arrhythmia and had an increased life expectancy compared to animals with the disease that did not receive the therapy.

    A permanent therapy
    "Muscle and heart cells are long-lived cell structures. One half of all myocardial cells remain functional from birth throughout the entire lifecycle of a human being," says Prof. Christian Kupatt, cardiologist at university hospital TUM Klinikum rechts der Isar. "The genome of a cell is used for protein biosynthesis as long as the cell is alive, and once a cell has been affected by the therapy, it remains corrected. So if we change the genome of a myocardial cell, the correction is a long-term success, in contrast to the results of previous methods."

    Therapeutic success with clinically relevant model
    The gene sequence responsible for the dystrophin protein has already been successfully corrected in the past, however in mice and other animal models. "Our results are very promising, since for the first time, we have now been able to demonstrate therapeutic success in a clinically relevant large animal model," says Prof. Maggie Walter, neurologist at the LMU university hospital. In terms of important biochemical, clinical and pathological changes, the pig model mirrors Duchenne muscular dystrophy in humans. "Since the disease proceeds faster in our pig model, we were able to verify the efficacy of the therapeutic approaches within a manageable period of time," says Prof. Eckhard Wolf, LMU specialist in veterinary medicine.

    Publications:
    Moretti, A., et al., Wolf, E.; Wurst, W., Kupatt, C.: Somatic gene editing ameliorates skeletal and cardiac muscle failure in pig and human models of Duchenne muscular dystrophy. In: Nature Medicine, 27 January 2020.
    DOI: 10.1038/s41591-019-0738-2
     
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    Walking and weakness in children: a narrative review of gait and functional ambulation in paediatric neuromuscular disease
    Rachel A. Kennedy, Kate Carroll, Jennifer L. McGinley & Kade L. Paterson
    Journal of Foot and Ankle Research volume 13, Article number: 10
     
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    This clinical trial was just registered:
    Effect of Foot Structure and Foot and Body Posture on Gait and Balance in Duchenne Muscular Dystrophy
     
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    Progression of muscular co-activation and gait variability in children with Duchenne muscular dystrophy: A 2-year follow-up study
    Martina Rinaldi et al
    Clinical Biomechanics: July 03, 2020
     
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    FDA NEWS RELEASE
    FDA Approves Targeted Treatment for Rare Duchenne Muscular Dystrophy Mutation
    August 12, 2020
    Today, the U.S. Food and Drug Administration granted accelerated approval to Viltepso (viltolarsen) injection for the treatment of Duchenne muscular dystrophy (DMD) in patients who have a confirmed mutation of the DMD gene that is amenable to exon 53 skipping. This is the second FDA-approved targeted treatment for patients with this type of mutation. Approximately 8% of patients with DMD have a mutation that is amenable to exon 53 skipping.

    “The FDA is committed to fostering drug development for serious neurological disorders like Duchenne muscular dystrophy,” said Billy Dunn, M.D., director of the Office of Neuroscience in the FDA’s Center for Drug Evaluation and Research. “Today’s approval of Viltepso provides an important treatment option for Duchenne muscular dystrophy patients with this confirmed mutation.”

    DMD is a rare genetic disorder characterized by progressive muscle deterioration and weakness. It is the most common type of muscular dystrophy. DMD is caused by mutations in the DMD gene that results in an absence of dystrophin, a protein that helps keep muscle cells intact. The first symptoms are usually seen between three and five years of age and worsen over time. DMD occurs in approximately one out of every 3,600 male infants worldwide; in rare cases, it can affect females.

    Viltepso was evaluated in two clinical studies with a total of 32 patients, all of whom were male and had genetically confirmed DMD. The increase in dystrophin production was established in one of those two studies, a study that included 16 DMD patients, with 8 patients receiving Viltepso at the recommended dose. In the study, dystrophin levels increased, on average, from 0.6% of normal at baseline to 5.9% of normal at week 25.

    The FDA concluded that the applicant’s data demonstrated an increase in dystrophin production that is reasonably likely to predict clinical benefit in patients with DMD who have a confirmed mutation of the dystrophin gene amenable to exon 53 skipping. A clinical benefit of the drug has not been established. In making this decision, the FDA considered the potential risks associated with the drug, the life-threatening and debilitating nature of the disease, and the lack of available therapies.

    As part of the accelerated approval process, the FDA is requiring the company to conduct a clinical trial to confirm the drug’s clinical benefit. The ongoing study is designed to assess whether Viltepso improves the time to stand for DMD patients with this confirmed mutation. If the trial fails to verify clinical benefit, the FDA may initiate proceedings to withdraw approval of the drug.

    The most common side effects observed in DMD patients (pooled from the two studies) treated with 80 mg/kg once a week were: Upper respiratory tract infection, injection site reaction, cough and fever.

    Although kidney toxicity was not observed in the Viltepso clinical studies, the clinical experience with Viltepso is limited, and kidney toxicity, including potentially fatal glomerulonephritis, has been observed after administration of some antisense oligonucleotides. Kidney function should be monitored in patients taking Viltepso.

    Viltepso was approved under the FDA’s accelerated approval pathway, which provides for the approval of drugs that treat serious or life-threatening diseases and generally offer a meaningful advantage over existing treatments. Approval under this pathway can be based on adequate and well-controlled studies showing the drug has an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit to patients (i.e., how patients feel or function or whether they survive). This pathway provides earlier patient access to promising new drugs while the company conducts clinical trials to verify the predicted clinical benefit.

    The FDA granted this application Priority Review designation.

    The FDA is granting the approval to NS Pharma, Inc.

    The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.
     
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    NEWS RELEASE 27-AUG-2020
    Duchenne: "Crosstalk" between muscle and spleen
    Researchers at the Universities of Maynooth and Bonn discover a new connection in muscular dystrophy


    Duchenne muscular dystrophy (DMD) is the most common muscle disease in children and is passed on by X-linked recessive inheritance. Characteristic is a progressive muscular atrophy. The disease often results in death before the third decade of life. Researchers of the Universities of Maynooth (Ireland) and Bonn have found a connection between dystrophic muscles and the lymphatic system in mice with Duchenne disease. The results have now been published in the journal iScience.

    The muscular atrophy in Duchenne disease is caused by a lack of dystrophin, a protein of the cytoskeleton. In vertebrates, dystrophin is found in the muscle fiber membrane and is important for muscle contraction. Although the disease is principally caused by a defective single gene (DMD gene), as a primarily neuromuscular disease it also has far-reaching and complex health-relevant effects on non-muscular tissues and organ systems.

    In recent years, the research groups associated with Prof. Dr. Dieter Swandulla, Physiological Institute of the University of Bonn, and Prof. Dr. Kay Ohlendieck, National University of Ireland, Maynooth, have used mass spectrometric protein analysis (proteomics) to show that Duchenne muscular dystrophy causes changes in the respective set of proteins (proteome) in a number of organs including heart, brain, kidney and liver as well as in saliva, serum and urine.

    Search for disease-specific marker proteins

    "Proteomics is a reliable and effective analytical method for identifying disease-specific marker proteins that provide information about the course of the disease, possible therapeutic targets and the effectiveness of therapeutic interventions," says senior author Prof. Swandulla.

    In the current study, the researchers used proteomics in mice suffering from Duchenne muscular dystrophy to model how the skeletal muscles and the spleen influence each other in view of the dystrophin deficiency. The spleen plays a key role in the immune response and is located in the abdominal cavity near the stomach. It ensures the proliferation of lymphocytes, which are white blood cells, and also stores monocyte-type immune cells and disposes of worn-out red blood cells.

    The researchers used the Duchenne mice to decode for the first time the set of proteins (proteome) of the spleen in comparison to healthy control animals and created a comprehensive protein archive for this organ. "The mice with Duchenne disease showed numerous changes in the proteomic signature of the spleen compared to the controls," says Prof. Kay Ohlendieck of the National University of Ireland, Maynooth.

    Furthermore, the researchers found for the first time a shorter form of dystrophin (DP71), which is synthesized as a protein in the spleen. "This dystrophin variant is apparently not affected by the disease because it occurs unchanged in Duchenne mice," says Swandulla. The "crosstalk" is expressed especially by the fact that a large number of proteins in the spleen are drastically reduced due to the loss of the long form of dystrophin. "This includes proteins that are involved in lipid transport and metabolism and in the immune response and inflammatory processes."

    Secondary effects in the lymphatic system

    Furthermore, the study provides evidence that the loss of the long form of dystrophin, as observed in Duchenne muscular dystrophy in skeletal muscle, apparently causes secondary effects in the lymphatic system. "It's a real 'crosstalk' between skeletal muscles and the lymphatic system," says lead author Dr. Paul Dowling of Maynooth University.

    The term "crosstalk" is used, for example, when there is a disruptive overlay of another conversation on the phone that can be heard in the background. In the specific case of Duchenne muscular dystrophy, the "crosstalk" was particularly expressed by the fact that the short form of the dystrophin was still produced as normal in the spleen, but there were disruptive changes of the proteomic signature in the other protein species.

    The researchers point out that the results of the study suggest that the mechanisms of the inflammatory processes which occur in the course of Duchenne muscular dystrophy merit special attention. This is because these inflammatory mechanisms are an important feature of muscle fiber degeneration and contribute significantly to the progression of the disease. "The specific interactions of the dystrophin deficiency with the immune system might therefore open up new therapeutic approaches," says Prof. Swandulla.
     
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    Press release:
    Drugging the undruggable: Yale finds treatment path for muscular dystrophy
    September 11, 2020
    Researchers at Yale have identified a possible treatment for Duchenne muscular dystrophy (DMD), a rare genetic disease for which there is currently no cure or treatment, by targeting an enzyme that had been considered “undruggable.” The finding appears in the Aug. 25 edition of Science Signaling.

    DMD is the most common form of muscular dystrophy, a disease that leads to progressive weakness and eventual loss of the skeletal and heart muscles. It occurs in 16 of 100,000 male births in the U.S. People with the disease exhibit clumsiness and weakness in early childhood and typically need wheelchairs by the time they reach their teens. The average life expectancy is 26.

    While earlier research had revealed the crucial role played by an enzyme called MKP5 in the development of DMD, making it a promising target for possible treatment, scientists for decades had been unable to disrupt this family of enzymes, known as protein tyrosine phosphatases, at the enzymes’ “active” site where chemical reactions occur.

    In the new study, Anton Bennett, the Dorys McConnell Duberg Professor of Pharmacology and professor of comparative medicine, and his team screened over 162,000 compounds. They identified one molecular compound that blocked the enzyme’s activity by binding to a previously undiscovered allosteric site — a spot near the enzyme’s active site.

    “There have been many attempts to design inhibitors for this family of enzymes, but those compounds have failed to produce the right properties,” Bennett said. “Until now, the family of enzymes has been considered ‘undruggable.’”

    By targeting the allosteric site of MKP5 instead, he said, “We discovered an excellent starting point for drug development that circumvented the earlier problems.”

    The researchers tested their compound in muscle cells and found that it successfully inhibited MKP5 activity, suggesting a promising new therapeutic strategy for treating DMD.

    The research was supported by a National Institutes of Health grant through the National Institute of Arthritis and Musculoskeletal and Skin Diseases, as well as by the Blavatnik Fund for Innovation at Yale, which annually presents awards to support the most promising life science discoveries from Yale faculty.

    Bennett said that the Blavatnik funding, which is administered by the Yale Office of Cooperative Research, was critical in moving the research forward. “It resulted in a license with a major pharmaceutical company,” he said, “and we hope they will rapidly move forward with the development of the new treatment.”

    The finding has implications well beyond muscular dystrophy, he added. The researchers have demonstrated that the MKP5 enzyme is broadly implicated in fibrosis, or the buildup of scar tissue, a condition that contributes to nearly one-third of natural deaths worldwide.

    “Fibrosis is involved in the end-stage death of many tissues, including liver, lung, and muscle,” Bennett said. “We believe this enzyme could be a target more broadly for fibrotic tissue disease.”

    The research team from Yale included Naftali Kaminski, the Boehringer-Ingelheim Professor of Internal Medicine and chief of pulmonary, critical care and sleep medicine; Jonathan Ellman, the Eugene Higgins Professor of Chemistry and professor of pharmacology; Karen Anderson, professor of pharmacology and of molecular biophysics and biochemistry; Elias Lolis, professor of pharmacology; Zachary Gannam, a graduate student in pharmacology; Kisuk Min, a postdoctoral fellow; Shanelle Shillingford, a graduate student in chemistry; Lei Zhang, a research associate in pharmacology; and the Yale Center for Molecular Discovery.
     
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    NEWS RELEASE 15-SEP-2020
    Scientists uncover a novel approach to treating Duchenne muscular dystrophy
    Scientists at Sanford Burnham Prebys Medical Discovery Institute, Fondazione Santa Lucia IRCCS, and Università Cattolica del Sacro Cuore in Rome have shown that pharmacological (drug) correction of the content of extracellular vesicles released within dystrophic muscles can restore their ability to regenerate muscle and prevent muscle scarring (fibrosis). The study, published in EMBO Reports, reveals a promising new therapeutic approach for Duchenne muscular dystrophy (DMD), an incurable muscle-wasting condition, and has far-reaching implications for the field of regenerative medicine.

    "Our study shows that extracellular vesicles are bioactive mediators that can transfer the benefits of medicine--in this case, HDAC inhibitors (HDACi)--to treat DMD," says Pier Lorenzo Puri, M.D., professor in the Development, Aging and Regeneration Program at Sanford Burnham Prebys and co-corresponding author of the study. "We discovered the promise of this treatment almost 20 years ago and did all of the preclinical work, which led to a current clinical trial for boys with DMD. However, the therapeutic potential of HDACi has been so far limited by its systemic adverse effects."

    In the current clinical trial, boys with DMD are treated with HDACi at suboptimal doses due to the risk of adverse side effects. The scientists are hopeful that extracellular vesicles might provide a cell-free, non-immunogenic, transplantable tool for local delivery of bioactive particles that transfer HDACi to dystrophic muscles, thereby overcoming the undesirable secondary effects caused by chronic use at high doses.

    "We believe this novel approach of using pharmacologically corrected extracellular vesicles may be used to safely deliver drugs such as HDACi directly to dystrophic muscles to obtain the beneficial action that would otherwise only be achieved at higher, toxic doses," says Puri.

    Extracellular vesicles are bioactive particles, meaning they have an effect in the body. They have recently attracted significant attention from the biomedical community because of their therapeutic potential. These particles contain information in the form of DNA, RNA or proteins and are exchanged from one cell to another. Alterations in the content of these particles leads to faulty communication between cells in dystrophic muscles and changes their behavior. In this study, the scientists discovered that these content alterations can be corrected to restore the physiological communication between the cells of dystrophic muscles.

    Communication breakdown

    Prior research from Puri's team showed that as DMD progresses, special muscle-healing cells called fibro-adipogenic progenitors (FAPs) become corrupted and start to promote muscle wasting and fibrosis. The team suspected that altered communication between FAPs and muscle stem cells--perhaps via extracellular vesicles--might be part of the problem.

    To answer this question, Martina Sandonà, Ph.D., first author of the study, and her colleagues conducted a series of experiments using muscle biopsies from boys with DMD who are enrolled in the clinical trial testing experimental HDACi treatment as well as a mouse model of DMD. The scientists were able to show that as DMD progresses, cellular communication via extracellular vesicles is progressively altered over time, which impairs the regeneration potential of DMD muscles. Importantly, the researchers demonstrated that correcting the content of the extracellular vesicles with an HDAC inhibitor activates muscle stem cells and promotes regeneration while reducing fibrosis and inflammation.

    "Our findings can likely be extended to other conditions and diseases, as pharmacologically 'lifted' extracellular vesicles could be exploited as a general therapeutic tool in regenerative medicine," says Valentina Saccone, Ph.D., group leader at Fondazione Santa Lucia IRCCS, tenured assistant professor at Università Cattolica del Sacro Cuore and co-corresponding author of the study. "These particles might also be used as an adjuvant approach for other treatments, such as gene or cell therapies."

    A ray of hope

    Treatment advances can't come soon enough for people with DMD and their loved ones. The genetic condition is caused by a lack of dystrophin, a protein that strengthens muscles, and causes progressive muscle degeneration. DMD primarily affects boys, with symptoms often appearing between the ages of 3 and 5. With recent medical advances, children with DMD now often survive beyond their teenage years into their early 30s, but effective treatments are still needed.

    "For children and adults living with DMD and their families, research provides a ray of hope for a better future," says Filippo Buccella, founder of Parent Project Italy, which has provided continual support to Puri's team for the last 20 years. "This study uncovers a promising new therapeutic approach for DMD and brings us one step closer to treatments that may help children maintain muscle strength for as long as possible and live long, fulfilling lives."

    "The more options we have to treat DMD, the better, as it's likely that drugs with different mechanisms of action could be more effective in combination," says Sharon Hesterlee, Ph.D., executive vice president and chief research officer of the Muscular Dystrophy Association. "Dr. Puri's work represents a unique approach that could prove complementary."

    ###

    A global team

    The co-first authors of the study are Martina Sandonà of Fondazione Santa Lucia and Sapienza University of Rome; and Silvia Consalvi of Fondazione Santa Lucia. Additional study authors include Luca Tucciarone of Fondazione Santa Lucia and Sapienza University of Rome; Marco De Bardi and Daniela Francesca Angelini of Fondazione Santa Lucia; Manuel Scimeca of the University of Rome "Tor Vergata"; Valentina Buffa and Antonella Bongiovanni of the National Research Council of Italy; Adele D'Amico and Enrico Silvio Bertini of the Bambino Gesù Children's Hospital; Sara Cazzaniga of Paolo Bettica of Cinisello Balsamo; and Marina Bouché of Sapienza University of Rome.

    This work is supported by the National Institutes of Health (1R01AR076247-01, R01GM134712-01), Duchenne Parent Project Italy and Netherland, the Muscular Dystrophy Association, Epigen, Association Française contre les Myopathies, and the Italian Ministry of Health (GR2016-02362451). The study's DOI is 10.15252/embr.202050863.
     
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