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14 - (Muscle & Nerve, 2012) EARLY CORTICOSTEROID TREATMENT IN 4 DUCHENNE MUSCULAR DYSTROPHY PATIENTS: 14-YEAR FOLLOW-UP
LUCIANO MERLINI, MONIA GENNARI, ELISABETTA MALASPINA, ILARIA
CECCONI, ANNARITA ARMAROLI,
SAVERIO GNUDI, BERIL TALIM, ALESSANDRA FERLINI, ALESSANDRO CICOGNANI, EMILIO
FRANZONI - Italy
ABSTRACT: Introduction: Corticosteroid treatment is the standard of care in Duchenne muscular dystrophy (DMD), but the optimal age to initiate treatment and dosage pattern remain a matter of discussion. Methods: We performed a long-term study of alternate-day corticosteroids in five 2- to 4-year-old DMD patients. The primary outcome measure was prolongation of the ability to walk. Results: One patient lost ambulation at age 10. Four patients, aged 16 to 18 were fully ambulant, and 3 of them could still climb stairs. Respiratory function was moderately reduced in 2. Left ventricular ejection fraction was > 45%. Short stature and delayed puberty were the most relevant side effects. Although the negative impact of corticosteroid treatment on growth rate remained their major concern, parents and patients stated that they preferred corticosteroid therapy. Conclusions: Long-term corticosteroid treatment is effective in prolonging function but not in recovering lost function, and its early use seems appropriate.
6 - (Cardiovasc Res, May 2012) Bradykinin restores left ventricular function, sarcomeric protein phosphorylation and e/nNOs levels in dogs with Duchenne muscular dystrophy cardiomyopathy
Jin Bo Su, Olivier Cazorla, Stéphane Blot, Nicolas Blanchard-Gutton, Younss Ait Mou, Inčs Barthélémy, Lucien Sambin, Carolina Carlos Sampedrano, Vassiliki Gouni, Yves Unterfinger, Pablo Aguilar, Jean-Laurent Thibaud, Alain Bizé, Jean-Louis Pouchelon, Hubert Dabiré, Bijan Ghaleh, Alain Berdeaux, Valérie Chetboul, Alain Lacampagne, and Luc Hittinger - France
Aims Cardiomyopathy is a lethal result of Duchenne muscular dystrophy (DMD) but its characteristics remain elusive. The golden retriever muscular dystrophy (GRMD) dogs produce DMD pathology and mirror DMD patient’s symptoms including cardiomyopathy. We previously showed that bradykinin slows the development of pacing-induced heart failure. Therefore, the goals of this research were to characterize dystrophin-deficiency cardiomyopathy and to examine cardiac effects of bradykinin in GRMD dogs
Methods and results At baseline, adult GRMD dogs had reduced fractional shortening (28±2% vs 38±2% in control dogs, p<0.001) and left ventricular (LV) subendocardial dysfunction leading to impaired endo-epicardial gradient of radial systolic velocity (1.3±0.1 cm/s vs 3.8±0.2 cm/s in control dogs, p<0.001) measured by echocardiography. These changes were normalized by bradykinin infusion (1 µg/min, 4 weeks). In isolated permeabilized LV subendocardial cells of GRMD dogs, tension-calcium relationships were shifted downward and force-generating capacity and transmural gradient of myofilament length-dependent activation were impaired compared with control dogs. Concomitantly, phosphorylation of sarcomeric regulatory proteins and levels of endothelial and neuronal nitric oxide synthase in LV myocardium were significantly altered in GRMD dogs. All these abnormalities were normalized in bradykinin-treated GRMD dogs
Conclusions Cardiomyopathy in GRMD dogs is characterized by profound LV subendocardial dysfunction, abnormal sarcomeric protein phosphorylation and impaired endothelial and neuronal nitric oxide synthase, which can be normalized by bradykinin treatment. These data provide new insights into pathophysiological mechanisms accounting for DMD cardiomyopathy and open new therapeutic perspectives.
6 - (Cell Stem Cell, Volume 10, Issue 5, 4 May 2012, Pages 610–619) Human ES- and iPS-Derived Myogenic Progenitors Restore DYSTROPHIN and Improve Contractility upon Transplantation in Dystrophic Mice
Radbod Darabi, Robert W. Arpke, Stefan Irion, John T. Dimos, Marica Grskovic, Michael Kyba,Rita C.R. Perlingeiro - USA
A major obstacle in the application of cell-based therapies for the treatment of neuromuscular disorders is obtaining the appropriate number of stem/progenitor cells to produce effective engraftment. The use of embryonic stem (ES) or induced pluripotent stem (iPS) cells could overcome this hurdle. However, to date, derivation of engraftable skeletal muscle precursors that can restore muscle function from human pluripotent cells has not been achieved. Here we applied conditional expression of PAX7 in human ES/iPS cells to successfully derive large quantities of myogenic precursors, which, upon transplantation into dystrophic muscle, are able to engraft efficiently, producing abundant human-derived DYSTROPHIN-positive myofibers that exhibit superior strength. Importantly, transplanted cells also seed the muscle satellite cell compartment, and engraftment is present over 11 months posttransplant. This study provides the proof of principle for the derivation of functional skeletal myogenic progenitors from human ES/iPS cells and highlights their potential for future therapeutic application in muscular dystrophies.
6- (B47 INTENSIVE CARE UNIT PHYSIOTHERAPY AND WEANING: MIND OVER MUSCLE?) Audit Of The Cardiac Management Of Patients With Duchenne Muscular Dystrophy On Ventilatory Support
L. O'Brien , M. Avendano , R. Goldstein , R. A.
Evans - Canada
Introduction. The life expectancy of patients with Duchenne Muscular
Dystrophy (DMD) has increased, from the 2 decade to the 5 decade, in part due to
improved ventilatory support. However, cardiomyopathy is common and is projected
to increase as a cause of death. Current international guidelines recommend an
annual assessment of cardiac function in adult patients with DMD and initiation
of appropriate pharmacological treatment (1). We conducted an audit of the
current cardiac management of patients with DMD with respiratory failure under
the care of West Park Healthcare Centre, Toronto, Canada.
Methods: We reviewed the medical charts of patients with DMD requiring
ventilatory support. Patients were included if they had respiratory follow up
within the last three years and were alive at the time of the audit. Patient
demographics and ventilatory status were recorded. Cardiac management was
recorded including date of the last documented electrocardiogram (ECG),
echocardiogram (ECHO), cardiology review and pharmacological management. The ECG
and ECHO reports were reviewed.
Results: 32 patients with DMD (31 male, mean [SD] age 31 [7] yrs) met the
inclusion criteria and their medical notes were retrieved. 7/32 patients were
living in a chronic assisted ventilation unit and 25/32 were cared for at home.
18/32 required continuous ventilation and 14/32 required nocturnal ventilation
only. 17/32 patients were ventilated via a tracheostomy. 10/32 and 6/32 patients
had a documented ECG and ECHO respectively, within the last year. 26/32, 22/32,
and19/32 patients had previous documentation of an ECG, ECHO, and had been
assessed by a cardiologist, respectively. Out of the available results, 21/25
patients had an abnormal ECG and 15/20 patients had demonstrable left
ventricular dysfunction (Grade II: 6, Grade III: 7, Grade IV: 2). 16/32 were
prescribed either an Angiotensin Converting Enzyme inhibitor or an Angiotensin
Receptor Blocker, 11/32 were prescribed Beta-Blockers, 4/32 were prescribed
digoxin and 1/32 was prescribed spironolactone.
Conclusions: Although cardiac function had been assessed in over two
thirds of patients with DMD, few were undergoing annual cardiac assessments. A
new policy of closer monitoring is suggested with a repeat audit in two years.
This audit highlights the need for respiratory physicians to refer these
patients for annual cardiology review in line with current guidance.
(1) Bushby K et al. Lancet Neurol 2010; 9(1):77-93
APRIL
22 - RESEARCH THAT WILL BE PRESENTED IN ANNUAL MEETING OF AMERICAN SOCIETY OF GENE THERAPY 2012, MAY 2012
14 - EXERCISE AND DUCHENNE
MUSCULAR DYSTROPHY: WHERE WE HAVE BEEN AND WHERE WE NEED TO GO
6 - UPDATE 2-AVI muscular dystrophy results fail to impress
6 - Treatment hope for muscular dystrophy
4 - (Experimental Biology 2012) Acute phosphodiesterase inhibition improves functional muscle ischemia in patients with Becker muscular dystrophy
Elizabeth Anne Martin1, Ashley E Walker1, Bryan L Scott1, Teresa C Malott1, Nirmal Singh1, Swaminatha V Gurudevan1, Jimmy Johannes1, Robert M Elashoff2, Gail D Thomas1 and Ronald G Victor1
1
The Heart Institute, Cedars Sinai Medical Center, Los Angeles, CA
2
Biomathematics, UCLA, Los Angeles, CA
oss of sarcolemmal nitric oxide
synthase (nNOS) engenders ischemia of exercising dystrophin-deficient muscles of
mdx mice and boys with Duchenne muscular dystrophy. We tested if muscle ischemia
also occurs in Becker muscular dystrophy (BMD), a milder disease often caused by
dystrophin mutations involving the nNOS binding site, and is improved by
tadalafil, a phosphodiesterase (PDE5A) inhibitor that enhances cGMP/NO signaling.
We measured reflex vasoconstriction (decreased forearm muscle oxygenation [
Hb02,
near infrared spectroscopy] during lower body negative pressure [LBNP]) at rest
and during rhythmic handgrip (HG) in 5 male controls (Ctrls) and 10 men with BMD
who underwent a placebo-controlled cross-over trial of single-dose (20 mg)
tadalafil. At baseline, HG greatly attenuated vasoconstriction in Ctrls (Hb02:–393±89
vs. –91±40 units, p<.01; rest vs. HG) but caused no attenuation in BMD (–381±45
vs. – 374±46). Tadalafil markedly improved ischemia in BMD (Hb02:–
439±70 vs. –230±54, rest vs. HG; p=0.014) whereas placebo had no effect. These
data provide the first evidence in man that PDE5A inhibition can improve blood
flow regulation in dystrophin-deficient skeletal muscle. Funded by MDA 201149.
4 - (Experimental Biology 2012) Early Anatomical Identification Markers for Duchenne Muscular Dystrophy in a Subadult Subject
Jasmine H. Harris1, Ellen Godwin2 and Samuel Marquez3
1
College of Medicine, SUNY Downstate Medical Center, Brooklyn, NY
2 Department of Orthopaedic Surgery & Rehabilitation Medicine, SUNY
Downstate Medical Center, Brooklyn, NY
3 Department of Cell Biology, SUNY Downstate Medical Center,
Brooklyn, NY
Duchenne Muscular Dystrophy (DMD) readily affects gait and posture in subadult populations afflicted with the disease. This study used instrumented motion analysis (IMA) to identify how gait and posture changes respond to DMD disease. 3-D motion analysis was performed with the Vicon Motion Capture System on a 5-year-old boy suspected with DMD. Thirty-nine reflective markers were placed on specific anatomical landmarks according to the Plug-in-Gait Model used with the Vicon system. The child walked across the 25 feet gait analysis laboratory for 10 trials. A single representative trial was selected for analysis. Kinematic parameters of gait were compared to those of a typically developing child. IMA identified specific changes in joint kinematics in the child with DMD as compared to the typically developing child. Changes include: increase in anterior pelvic tilt and hip flexion in swing, genu recurvatum in stance, plantar flexion on initial contact with ground, and lack of dorsiflexion in swing. These gait deviations are commonly found in boys with DMD. The results show the ability to identify these changes translating in the early diagnosis of DMD as they represent a specific pattern of walking that is related to the progression of weakness observed. Identification of anatomical gait deviations can assist in the development of treatment interventions to assist the child to be ambulant as long as possible.
4 - (Experimental Biology 2012) Resveratrol decreases inflammation and oxidative stress in the mdx mouse model of duchenne muscular dystrophy
Bradley Scott Gordon, Patti Weed, Emily Learner, Drew Schoenling and Matthew C Kostek
Exercise Science, University of South Carolina, Columbia, SC
Duchenne Muscular Dystrophy (DMD) is a genetic disease characterized by muscle damage, oxidative stress, chronic inflammation, and fibrosis. Resveratrol (RES) is an antioxidant and anti-inflammatory. We have shown that RES improves muscle function in the mdx mouse model of DMD, and others have shown resveratrol decreases fibrosis and oxidative stress in older mdx mice. However, its effect on pathology in young mdx mice is unknown. The purpose of this study was to investigate the effect of resveratrol on muscle pathology in young mdx mice. RES (100 mg/kg) or vehicle was administered to 4–5 week old mdx mice everyday for 10 days or every other day for 8 weeks. Muscle fiber integrity, inflammation, and oxidative stress were assessed by H&E staining and 4-HNE content. Total inflammation was reduced 21 ± 6% (p < 0.05) after 10 days of treatment with no change in oxidative stress. After 8 weeks of RES treatment, centrally located nuclei were reduced 12 ± 4% (p < 0.05), oxidative stress measured through 4-HNE content decreased 2 ± 0.13 fold (p < 0.05), and total inflammation and fibrosis did not change. We conclude that RES enhances muscle membrane integrity by reducing inflammation during the peak pathological period and long term oxidative stress. Therefore, resveratrol could be a treatment for boys with DMD. This project was funded by The Center for Alternative Medicine at The University of South Carolina School of Medicine.
4 - (Experimental Biology 2012) Mdx mice have a defect in autophagy that is restored by rapamycin-loaded nanoparticle treatment
Allison Jinquan Li1, Kristin P. Bibee1, Jon N. Marsh1, Conrad C. Weihl2 and Samuel A. Wickline1
1
Department of Medicine, Division of Cardiology, Washington University in St.
Louis, St. Louis, MO
2 Department of Neurology, Washington University in St. Louis, St.
Louis, MO
Duchenne Muscular Dystrophy (DMD) is genetic disorder caused by mutations in dystrophin, a cytoskeletal protein in muscles, leading to progressive muscle wasting and ultimately death in the second or third decade of life. The current standard of care for DMD patients is corticosteroid therapy which slows down the natural progression of the disease but causes unwanted side effects. Our lab’s previous studies of therapeutics in an in vivo DMD model has demonstrated that mdx mice treated with rapamycin-loaded nanoparticles showed an increase in strength that was not observed with oral rapamycin treatment. Because rapamycin is known to induce autophagy, we assayed for autophagy in mdx mice treated with rapamycin-loaded nanoparticles. Western blot analysis of LC3B-II, the processed form of a protein used in autophagy, suggests that there is a previously unknown defect in autophagy in mdx mice, as shown by a lack of LC3 3B-II accumulation after blockade of autophagic flux by colchicine (Fig. 1A). Rapamycin nanoparticle treatment rescues autophagy to levels comparable to the control (Fig. 1B), suggesting that defective autophagy may contribute to the physical manifestations of muscular dystrophy in mdx mice and that restoration to normal levels may lead to the observed strength increase. Supported by NIH grant (R01 AR056223 to S.A.W.)
4 - (Experimental Biology 2012) Acute phosphodiesterase inhibition ameliorates functional muscle ischemia in dystrophin-deficient mdx mice
Liang Li, Ronald G Victor and Gail D Thomas
The Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA
We previously have shown that the loss of sarcolemmal nitric oxide synthase (nNOS) in the dystrophin-deficient muscles of mdx mice and boys with Duchenne muscular dystrophy (DMD) renders the diseased muscles susceptible to ischemia during exercise. We now are extending this finding to men with Becker muscular dystrophy (BMD). We therefore hypothesized that treatment with a phosphodiesterase (PDE) inhibitor to reduce cGMP breakdown and enhance the NO signal from residual nNOS would prevent functional muscle ischemia. To test this, we compared norepinephrine (NE)-mediated vasoconstriction in resting and contracting hindlimbs of mdx mice after acute treatment with vehicle or a PDE inhibitor (tadalafil, 8 mg/kg; zaprinast, 4 mg/kg). In vehicle-treated mice, the usual effect of muscle contraction to attenuate NE-mediated vasoconstriction was impaired as shown by similar decreases in femoral vascular conductance in contracting vs resting hindlimbs (attenuation ratio = 0.87 ± 0.11; n = 10). NE-induced ischemia in the contracting hindlimbs was partially reversed in mice treated with the selective PDE5A inhibitor tadalafil (0.61 ± 0.06; n = 6; P < 0.05 vs vehicle) or the nonselective PDE inhibitor zaprinast (0.46 ± 0.10; n = 7; P < 0.05 vs vehicle). The effect of PDE inhibition to ameliorate functional muscle ischemia in mdx mice suggests a novel potential use for the treatment of DMD/BMD patients. Supported by MDA, 201149.
4 - (Experimental Biology 2012) Dietary quercetin supplementation alleviates disease related muscle injury in dystrophic muscle
Katrin Hollinger1, Elizabeth Snella1, R. Andrew Shanely2 and Joshua T. Selsby1
1
Animal Science, Iowa State University, Ames, IA
2 Human Performance Laboratory; North Carolina Research Campus,
Appalachian State University, Kannapolis, NC
Duchenne muscular dystrophy is the most common, fatal, X-linked muscle disease
and is modeled by the mdx mouse. Dystrophic muscle shows signs of progressive
necrosis and fibrosis leading to a loss of muscle function. Peroxisome
proliferator-activated receptor
coactivator-1α
(PGC-1α)
up-regulation has been shown to alleviate some aspects of dystrophic pathology.
Quercetin (QCN), a natural polyphenolic compound derived from foods such as red
apples and red onions, is a potent sirtuin 1 (SIRT1) activator capable of
entering muscle cells via oral delivery. SIRT1, in turn, activates PGC-1α
by deacetylation. To determine the extent to which a diet containing QCN could
alter the progression of disease related muscle injury 3 mo old mdx mice were
fed a diet containing 0% or 0.2% QCN for 6 mo, sacrificed, and diaphragms
removed. Control and treated mice ate similar amounts of food and grew at a
similar rate during the study period. Dietary QCN reduced the number of
extracellular nuclei/mm2 by 37% (p<0.05). The number of muscle
cells/mm2 was increased by 20% (p<0.05) and muscle cells with
centralized nuclei were reduced by 33% (p<0.05) in diaphragms from treated
animals compared to control. Fibrosis was similar between groups. These data
suggest that dietary QCN is beneficial to dystrophic muscle and warrants greater
exploration as a potential therapeutic agent. Partially supported by the Martin
Fund.
4 - (Experimental Biology 2012) PCG-1 alpha over-expression rescues dystrophic muscle by modifying gene expression
Katrin Hollinger, Drance Rice, Elizabeth Snella and Joshua T Selsby
Animal Science, Iowa State University, Ames, IA
Duchenne muscular dystrophy is caused by the inability to produce a functional
dystrophin protein. Typically, diagnosis is in the preschool years due to
locomotor deficits, indicating muscles have already been damaged by the disease.
Thus, it is critical that treatments be able to rescue muscle from further
deterioration. We have shown that Peroxisome proliferator-activated receptor
coactivator-1α
(PGC-1α)
gene transfer rescues dystrophic muscle from disease related decline. To better
understand the mechanism underlying the benefits of PGC-1α
over expression, 3 wk old mdx mice were injected in one hind limb with null AAV6
(empty capsid) and in the other with an AAV6 driving expression of PGC-1α.
At six weeks of age solei were collected. Utrophin protein expression was
measured by immunohistochemistry and was increased nearly 3-fold (p<0.05) in
PGC-1α
over-expressing limbs compared to control limbs. PCR arrays were performed to
identify genes regulated by PGC-1α
over-expression. In the PGC-1α
treated soleus expression of genes associated with the dystrophinglycoprotein
complex (DGC) were increased by 40–92% (p<0.05), oxidative metabolism by 35–87%
(p<0.05), muscle repair by 56–92% (p<0.05), and structural components by 20–300%
(p<0.05). These data indicate that PGC-1α-mediated
rescue of dystrophic muscle is accomplished through numerous contributing
mechanisms.
Partially supported by CIAG.
4 - (Experimental Biology 2012) The effect of N-acetylcysteine on contractile function and protein-thiol oxidation in skeletal muscles of mdx mice
Gavin Jon Pinniger1, Evanna Binti Assan1, Jessica Terrill2 and Peter Arthur3
1
Physiology, University of Western Australia, Crawley, Australia
2 Anatomy and Human Biology, University of Western Australia,
Crawley, Australia
3 Biochemistry, University of Western Australia, Crawley, Australia
Duchenne Muscular Dystrophy (DMD) is a fatal X-linked recessive disease characterized by severe muscle weakness. We hypothesized that oxidation of skeletal muscle proteins such as myosin contributes to dystrophic muscle weakness seen in DMD boys and dystrophic mdx mice and that this muscle weakness will be attenuated by treatment with the antioxidant N-acetylcysteine (NAC). Six week old mdx mice and non-dystrophic, C57 mice were treated with 2% NAC in drinking water for six weeks and compared to untreated mdx and C57 mice. Grip strength and body weight were measured weekly during the treatment period. After six weeks of treatment, the 12 week old mice were anaesthetized (sodium pentobarbitone; 40 mg/kg; IP) and the extensor digitorum longus (EDL) muscles were excised for analysis of contractile function and protein thiol-oxidation. n mdx mice, NAC treatment significantly increased normalized grip strength and maximum specific force in isolated EDL muscles (NAC = 13.1 ± 1.2 N/cm2; Untreated = 9.8 ± 0.8 N/cm2, p<0.05), and significantly reduced myosin protein-thiol oxidation (NAC = 10.6 ± 0.8 %; Untreated = 13.7 ± 0.8 %, p<0.05). In non-dystrophic C57 mice, NAC treatment significantly increased normalized grip strength by 36%, but had no significant effect on maximum specific force or myosin protein-thiol oxidation in EDL muscles.
4 - (Experimental Biology 2012) Treatment with a nitric oxide-donating NSAID counteracts functional muscle ischemia in dystrophin-deficient mdx mice
Gail D Thomas1, Angela Monopoli2, Claudio De Nardi2, Ennio Ongini2 and Ronald G Victor1
1
The Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA
2 NicOx Research Institute, Bresso, Italy
he dystrophin-deficient muscles of boys with Duchenne muscular dystrophy (DMD) and mdx mice, a model of DMD, are susceptible to ischemia during exercise due to loss of neuronal nitric oxide synthase (nNOS) from the sarcolemma. We hypothesized that treatment with a NO-donating drug would compensate for nNOS deficiency and counteract functional muscle ischemia. We fed mdx mice a standard diet containing 1% soybean oil (vehicle) or a low (15 mg/kg) or high (45 mg/kg) dose of a NO-releasing derivative of the NSAID flurbiprofen (n = 12/group). After 1 month of treatment, we compared vasoconstrictor responses to intra-arterial norepinephrine (NE) in resting and contracting hindlimbs. In vehicle-treated mice, the usual effect of muscle contraction to attenuate NE-mediated vasoconstriction was impaired as shown by similar decreases in femoral vascular conductance in contracting vs resting hindlimbs (attenuation ratio = 0.88 ± 0.03). NE-induced ischemia was also seen in the contracting hindlimbs of mice treated with low dose drug (0.92 ± 0.04; P > 0.05 vs vehicle), but was markedly attenuated in mice treated with high dose drug (0.22 ± 0.03; P < 0.05 vs vehicle or low dose). The beneficial effect of the high dose was maintained with treatment up to 3 months. These data demonstrate a robust anti-ischemic effect of a NO-donating drug in mdx mice and suggest a potential use in the treatment of DMD patients. Supported by NicOx, 801130.
4 - (Experimental Biology 2012) Administration of recombinant adeno-associated virus vector to the diaphragm through direct intramuscular injection
Ashley J Smuder1, Darin J Falk2, W Bradley Nelson1 and Scott K Powers1
1
Department of Applied Physiology and Kinesiology, University of Florida,
Gainesville, FL
2 Department of Pediatrics, University of Florida, Gainesville, FL
Ventilatory insufficiency due to impaired diaphragm function is the leading cause of morbidity and mortality in many conditions (e.g. muscular dystrophy). Currently, pharmacological inhibitors and genetically modified animals are used to study many diseases affecting the diaphragm. However, these methodologies are problematic due to the occurrence of off-target effects and possible consequences of life-long genetic alterations. Further, conventional approaches to gene transfection (i.e., plasmid injection and electroporation) are not possible due to the size and location of the diaphragm and thus alternative methods are needed to alter gene expression. Therefore, we have developed a method for the delivery of recombinant adeno-associated virus vectors (rAAV) to the rat diaphragm via direct intramuscular injection. We hypothesized that by directly injecting rAAV we could selectively target diaphragm muscle fibers and establish a novel animal model for studying signaling pathways and also provide a strategy for effectively using gene therapy to rescue the diaphragm in disease states. Our results demonstrate that the morphology of the rat diaphragm is sufficient to allow direct injection and provide support for the use of rAAV as an intervention to study the diaphragm during conditions that promote diaphragm dysfunction.
MARCH
24 - (Annals of Neurology, 2012) Evidence Based Path to Newborn Screening for Duchenne Muscular Dystrophy
Jerry R Mendell, Chris Shilling, Nancy D. Leslie, Kevin
M Flanigan, Roula al-Dahhak, Julie Gastier-Foster, Kelley
Kneile, Diane M. Dunn, Brett Duval, Alexander Aoyagi, Cindy Hamil, Maha
Mahmoud, Kandice Roush, Lauren Bird,
Chelsea Rankin, Heather Lilly, Natalie Street, MS, Ram Chandrasekar,
Robert B. Weiss - USA
Background: Creatine kinase (CK) levels are increased
on dried blood spots in newborns related to the birthing process. As a marker
for newborn screening, CK in Duchenne muscular dystrophy (DMD) results in
false-positive testing. In this report we introduced a two-tier system using the
dried blood spot to first assess CK with follow up DMD gene testing.
Methods: A fluorometric assay based upon the enzymatic
transphosphorylation of ADP to ATP was used to measure CK activity. Preliminary
studies established a population-based range of CK in newborns using 30,547
de-identified anonymous dried blood spot samples. Mutation analysis used genomic
DNA extracted from the dried blood spot followed by whole genome
amplification with assessment of single/multi-exon deletions/duplications in the
DMD gene using multiplex ligation-dependent probe amplification.
Results: DMD gene mutations (all exonic deletions) were found in six of
37,649 newborn male subjects, all of whom had CK levels > 2000 U/L. In three
newborns with CK >2000 U/L in whom DMD gene abnormalities were not found, we
identified limb-girdle muscular dystrophy gene mutations affecting DYSF, SGCB,
and FKRP.
Conclusions: A two-tier system of analysis for newborn screening for DMD
has been established. This path for newborn screening fits our health care
system, minimizes false%positive testing, and uses predetermined levels of CK on
dried blood spots to predict DMD gene mutations.
24 - Lung Volume Recruitment Slows Pulmonary Function Decline in Duchenne Muscular Dystrophy
18 - (Growth Hormone & IGF Research, 2012) Therapeutic potential of PEGylated insulin-like growth factor I for skeletal muscle disease evaluated in two murine models of muscular dystrophy
Stefan M. Gehrig, Chris van der Poela, Andreas Hoeflich, Timur Naim, Gordon S. Lynch, Friedrich Metzger - Australia
Objective: Duchenne muscular dystrophy (DMD) is a fatal
monogenetic disease with affected males displaying severe and progressive muscle
wasting and weakness eventually leading to premature death. Possible therapeutic
benefits of insulin-like growth factor I (IGF-I) have been studied extensively in
various models of muscle disease and DMD with IGF-I as a mediator of improved
skeletal muscle regeneration by enhancing myoblast proliferation and
differentiation.
Design: We tested the efficacy of a novel IGF-I analogue, a polyethylene glycol
modified IGF-I (PEG-IGF-I), to ameliorate the pathophysiology of muscular
dystrophy in two mouse models of DMD. We used mdx mice which lack dystrophin (as
in DMD) but exhibit only a relatively mild phenotype, and the dko mouse which is
a transgenic model lacking utrophin in addition to dystrophin, and which
exhibits a more severe, lethal phenotype like that in DMD.
Results: In young mdx mice, twice-weekly PEG-IGF-I s.c. injections for 6 weeks
protected the diaphragm muscle against fatigue and the tibialis anterior (TA)
muscle against contraction-induced injury. However, this beneficial effect of
PEG-IGF-I was less pronounced in mdx mice when treatment was initiated later in
adulthood. In severely affected dko mice PEG-IGF-I treatment did not affect
pathophysiological parameters including animal survival.
Conclusions: These data suggest a therapeutic benefit with PEG-IGF-I treatment
only in mild muscle pathologies, since its potential to ameliorate the
pathophysiology in models of severe muscular dystrophies was limited. Treatment
should be initiated only for mild muscle pathologies if functional benefits are
to be realised and therefore may be relevant as a short-term therapy to hasten
the functional repair of otherwise healthy muscles after injury.
10 - (Neuromuscular Disorders, 2012) Normal height and weight in a series of ambulant Duchenne muscular dystrophy patients using the 10 day on/10 day of prednisone regimen
K. ten Dam, I.J.M. de Groot, C. Noordam, N. van Alfen, J.C.M. Hendriks e L.T.L. Sie - The Netherlands
Prednisone treatment delays the progressive course of
Duchenne muscular dystrophy. The aim of this study was to determine the
influence of the 10 day on/10 day of treatment on height and weight. We
retrospectively reviewed the growth and weight charts of Duchenne patients born
between 1988 and 2006 (patients between 4 and 9 years old, being able to walk in
the home situation). Forty-seven patients were eligible for further analysis and
divided into two groups: 33 patients treated with prednisone and 14
non-prednisone treated patients. Results of a median follow-up of 57 months
(range 27–146) are described. By using linear mixed models this study
demonstrates that height and body mass index in prednisone-treated patients with
10/10 regimen are not significantly diferent compared to untreated patients. We
cautiously conclude that the alternating prednisone regimen has no apparent side
effects on weight and height in the ambulatory phase of Duchenne muscular
dystrophy.
10 - (Neurology, 2012) Pentoxifylline as a rescue treatment for DMD. A randomized double-blind clinical trial
D.M. Escolar, A. Zimmerman, T. Bertorini, P.R. Clemens, A.M. Connolly, L. Mesa, K. Gorni, A. Kornberg, H. Kolski, N. Kuntz, Y. Nevo, C. Tesi-Rocha, K. Nagaraju, S. Rayavarapu, L.P. Hache, J.E. Mayhew, J. Florence, F. Hu, A. Arrieta, E. Henricson, R.T. Leshner, and J.K. Mah
Objective: To determine whether pentoxifylline (PTX) slows the decline of muscle strength and function in ambulatory boys with Duchenne muscular dystrophy (DMD).
Methods: This was a multicenter, randomized, double-blinded, controlled trial comparing 12 months of daily treatment with PTX or placebo in corticosteroid-treated boys with DMD using a slow-release PTX formulation (∼20 mg/kg/day). The primary outcome was the change in mean total quantitative muscle testing (QMT) score. Secondary outcomes included changes in QMT subscales, manual muscle strength, pulmonary function, and timed function tests. Outcomes were compared using Student t tests and a linear mixed-effects model. Adverse events (AEs) were compared using the Fisher exact test
Results: A total of 64 boys with DMD with a mean age of 9.9 ± 2.9 years were randomly assigned to PTX or placebo in 11 participating Cooperative International Neuromuscular Research Group centers. There was no significant difference between PTX and the placebo group in total QMT scores (p = 0.14) or in most of the secondary outcomes after a 12-month treatment. The use of PTX was associated with mild to moderate gastrointestinal or hematologic AEs
Conclusion: The addition of PTX to corticosteroid-treated boys with DMD at a moderate to late ambulatory stage of disease did not improve or halt the deterioration of muscle strength and function over a 12-month study period.
Classification of evidence: This study provides Class I evidence that treatment with PTX does not prevent deterioration in muscle function or strength in corticosteroid-treated boys with DMD
3 - Research that will be presented in 2012 Annual Meeting of American Academy of Neurology
3 - (Acta Paediatrica, 2012, 101(4): 424-32) Bone mass development in patients with Duchenne and Becker muscular dystrophies: a 4-year clinical follow-up
Ann-Charlott Söderpalm (ann-charlott.soderpalm@vgregion.se), Per Magnusson,, Anne-Christine Ĺhlander, Jón Karlsson, Anna-Karin Kroksmark,Már Tulinius, Diana Swolin-Eide - Sweden
Aim: To investigate the longitudinal development of
bone mass in patients with Duchenne and Becker muscular dystrophies and to study
the impact of muscle strength and motor function on bone mass in these patients.
Methods: Eighteen patients with Duchenne muscular dystrophy (2.3–19.7
years at baseline) and six patients with the milder Becker muscular dystrophy
(10.8–18.9 years at baseline) were followed during a 4-year period with respect
to areal bone mineral density (BMD), motor function and muscle strength.
Results: Greater bone mineral accretion was observed in the Becker
patient group compared with the age-related Duchenne group above 10 years of
age, and the older patients with Duchenne experienced decreased femoral neck BMD
during the study period. In the study group, significant correlations were found
between BMD in the lower extremities and muscle function parameters.
Conclusions: The differences in BMD between patients with Duchenne and
Becker as well as between different bone measurement sites demonstrated in the
present study point out the importance of preserving muscle strength and motor
function in patients with muscular dystrophy. Moreover; it highlights the value
of performing region-specific analysis of the bone quality in these patients.
FEBRUARY
12 - Restoration of dystrophin expression using the Sleeping Beauty transposon
JANUARY
30 - (Biochemical and Biophysical Research Communications, 2012) Restoration of Muscle Fibers and Satellite Cells after Isogenic MSC Transplantation with Microdystrophin Gene Delivery
Shan-wei Feng, , Fei chen, , Jiqing Cao, Ying-yin Liang, Xin-ming Song, Cheng Zhang - China
Duchenne muscular dystrophy is the most prevalent inheritable muscle disease. Transplantation of autologous stem cells with gene direction is an ideal therapeutic approach for the disease. The current study aimed to investigate the restoration of myofibers in mdx mice after mdx bone marrow-derived mesenchymal stem cell (mMSC) transplantation with human microdystrophin delivery. Possible mechanisms of action were also studied. In our research, mMSCs were successfully transduced by retrovirus carrying a functional human microdystrophin gene. Transplantation of transduced mMSCs enabled persistent dystrophin restoration in the skeletal muscle of mdx mice up to the 12th week after transplantation. Simultaneous coexpression of human microdystrophin and desmin showed that implanted mMSCs are capable of long-term survival as muscle satellite cells.
25 - (Pharmacological Research, January 2012) Nitric oxide donor and non steroidal anti inflammatory drugs as a therapy for muscular dystrophies: evidence from a safety study with pilot efficacy measures in adult dystrophic patients
Maria Grazia D’Angelo, Sandra Gandossini, Filippo Martinelli Boneschi, Clara Sciorati, Sara Bonato, Erika Brighina, Giacomo Pietro Comi, Anna C. Turconi, Francesca Magri, Giuseppe Stefanoni, Silvia Brunelli, Nereo Bresolin, Dario Cattaneo, Emilio Clementi - Italy
This open-label, single centre pilot study was designed to evaluate safety and tolerability of the combination of the drugs isosorbide dinitrate, a nitric oxide donor, and ibuprofen, a non steroid anti-inflammatory drug, in a cohort of adult dystrophic patients (Duchenne, Becker and Limb-girdle muscular dystrophy). Seventy-one patients were recruited: 35, treated with the drug combination for 12 months, and 36 untreated. Safety and adverse events were assessed by reported signs and symptoms, physical examinations, blood tests, cardiac and respiratory function tests. Exploratory outcomes measure, such as the motor function measure scale, were also applied.
Good safety and tolerability profiles of the long-term co-administration of the drugs were demonstrated. Few and transient side effects (i.e. headache and low blood pressure) were reported. Additionally, exploratory outcomes measures were feasible in all the disease population studied and evidenced a trend towards amelioration that reached statistical significance in one dimension of the MFM scale. Systemic administration of ibuprofen and isosorbide dinitrate provides an adequate safety margin for clinical studies aimed at assessing efficacy.
21 - (Journal of Neuroscience Research, 2012) Motor performance of young dystrophic mdx mice treated with long-circulating prednisolone liposomes
Charlotte Weller, Jana Zschüntzsch, Gregor Makosch, Josbert M. Metselaar, Florian Klinker, Lars Klinge, David Liebetanz and Jens Schmidt - Germany
For Duchenne muscular dystrophy (DMD), a common myopathy that leads to severe disability, no causal therapy is available. Glucocorticosteroids improve patients' muscle strength, but their long-term use is limited by negative side effects. Thus, pharmacological modifications of glucocorticosteroids are required to increase the efficacy by drug targeting. Liposomal encapsulation augments systemic half-life and local tissue concentrations of glucocorticosteroids and, at the same time, reduces systemic side effects. In this study, the efficacy of novel, long-circulating, polyethylene-glycol-coated liposomes encapsulating prednisolone was compared with free prednisolone in the treatment of mdx mice, a well-established animal model for DMD. Using an objective and sensitive computerized 24-hr detection system of voluntary wheel-running in single cages, we demonstrate a significant impairment of the running performance in mdx compared with black/10 control mice aged 3–6 weeks. Treatment with liposomal or free prednisolone did not improve running performance compared with saline control or empty liposomes. Histopathological parameters, including the rate of internalized nuclei and fiber size variation, and mRNA and protein expression levels of transforming growth factor (TGF)-β and monocytes chemotactic protein (MCP)-1 also remained unchanged. Bioactivity in skeletal muscle of liposomal and free prednisolone was demonstrated by elevated mRNA expression of muscle ring finger protein 1 (MuRF1), a mediator of muscle atrophy, and its forkhead box transcription factors (Foxo1/3). Our data support the assessment of voluntary running to be a robust and reproducible outcome measure of skeletal muscle performance during the early disease course of mdx mice and suggest that liposomal encapsulation is not superior in treatment efficacy compared with conventional prednisolone. Our study helps to improve the future design of experimental treatment in animal models of neuromuscular diseases