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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

    NewsBot The Admin that posts the news.

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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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    NewsBot The Admin that posts the news.

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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
     
  7. NewsBot

    NewsBot The Admin that posts the news.

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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
     
  8. NewsBot

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    Articles:
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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
     
  10. NewsBot

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    Articles:
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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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