BRAZILIAN RESEARCH CENTER - IMPORTANT INFORMATIONS
DECEMBER - 2005
20 - (IN PRESS: Neuromuscular Disorders, 2005): Temporal and spatial mRNA expression patterns of TGF-b1, 2, 3 and TbRI, II, III in skeletal muscles of mdx mice
Lan Zhou, John D. Porter, Georgiana Cheng, Bendi Gong, Denise A. Hatala, Anita P. Merriam, Xiaohua Zhou, Jill A. Rafael, Henry J. Kaminski - USA
Abstract
To address potential regulatory roles of TGF-beta 1 in muscle inflammation and fibrosis associated with dystrophin deficiency, we performed quantitative RT-PCR and in situ hybridization to characterize the temporal and spatial mRNA expression patterns of TGFbeta 1 and other TGF-beta subfamily members, TGF-beta 2 and TGF-beta3, as well as their receptors, in quadriceps and diaphragm muscles of mdx mice. TGF-beta 1 mRNA was markedly upregulated in the endomysial inflammatory cells and regenerating fibers of mdx quadriceps and diaphragm, with the mRNA levels correlated with the degree of endomysial inflammation. Upregulation of TGF-beta2, beta3, and their receptors was also appreciated but to a much lesser degree. While high levels of TGF-beta1 mRNA remained in the aging mdx quadriceps but not the diaphragm, progressive fibrosis only occurred in the diaphragm. Our data support a regulatory role for TGF-beta 1 in muscle inflammation in mdx mice. It also suggests different susceptibility of quadriceps and diaphragm muscles to fibrosis induced by TGF-beta 1 signaling pathway.
14 - PTC124 Trial Now Open to Boys With Duchenne Muscular Dystrophy Who Have Nonsense Mutations
10 - Regulation of muscle growth by multiple ligands signaling through activin type II receptors
'Mighty Mice': New Muscle-building Agent Beats All Previous Ones
3 - Cardiovascular health supervision for individuals affected by Duchenne or Becker muscular dystrophy
NOVEMBER - 2005
26 - High Pulmonary Risk Scoliosis Surgery: Role of Noninvasive Ventilation and Related Techniques
23 - How to manage osteoporosis in children
15 - (IN PRESS: Am.J.Physiol.Heart.Circ.Physiol 289:H2373-H2378,2005) Utrophin deficiency worsens cardiac contractile dysfunction present in dystrophin-deficient mdx mice
The loss of dystrophin in patients with Duchenne muscular dystrophy (DMD) causes devastating skeletal muscle degeneration and cardiomyopathy. Dystrophin-deficient (mdx) mice have a much milder phenotype, whereas double knockout (DKO) mice lacking both dystrophin and its homolog, utrophin, exhibit the clinical signs observed in DMD patients. We have previously shown that DKO and mdx mice have similar severities of histological features of cardiomyopathy, but no contractile functional measurements of DKO heart have ever been carried out. To investigate whether DKO mice display cardiac dysfunction at the tissue level, contractile response of the myocardium was tested in small, unbranched, ultrathin, right ventricular muscles. Under near physiological conditions, peak isometric active developed tension (Fdev, in mN/mm2) at a stimulation frequency of 4 Hz was depressed in DKO mice (15.3 ± 3.7, n = 8) compared with mdx mice (24.2 ± 5.4, n = 7), which in turn were depressed compared with wild-type (WT) control mice (33.2 ± 4.5, n = 7). This reduced Fdev was also observed at frequencies within the murine physiological range; at 12 Hz, Fdev was (in mN/mm2) 11.4 ± 1.8 in DKO, 14.5 ± 4.2 in mdx, and 28.8 ± 5.4 in WT mice. The depression of Fdev was observed over the entire frequency range of 4–14 Hz and was significant between DKO versus mdx mice, as well as between DKO or mdx mice versus WT mice. Under beta-adrenergic stimulation (1 µmol/l isoproterenol), Fdev in DKO preparations was only (in mN/mm2) 14.7 ± 5.1 compared with 30.9 ± 8.9 in mdx and 41.0 ± 4.9 in WT mice. These data show that cardiac contractile dysfunction of mdx mice is generally worsened in mice also lacking utrophin.
12 - (IN PRESS: Thorax,2005;60:1019-24) Randomised controlled trial of non-invasive ventilation (NIV) for nocturnal hypoventilation in neuromuscular and chest wall disease patients with daytime normocapnia
S Ward, M Chatwin, S Heather, A K Simonds - UK
Background: Long term non-invasive ventilation (NIV) reduces morbidity and mortality in patients with neuromuscular and chest wall disease with hypercapnic ventilatory failure, but preventive use has not produced benefit in normocapnic patients with Duchenne muscular dystrophy. Individuals with nocturnal hypercapnia but daytime normocapnia were randomised to a control group or nocturnal NIV to examine whether nocturnal hypoventilation is a valid indication for NIV. Methods: Forty eight patients with congenital neuromuscular or chest wall disease aged 7–51 years and vital capacity ,50% predicted underwent overnight respiratory monitoring. Twenty six with daytime normocapnia and nocturnal hypercapnia were randomised to either nocturnal NIV or to a control group without ventilatory support. NIV was started in the control group if patients fulfilled preset safety criteria. Results: Peak nocturnal transcutaneous carbon dioxide tension (TcCO2) did not differ between the groups, but the mean (SD) percentage of the night during which TcCO2 was .6.5 kPa decreased in the NIV group (257.7 (26.1)%) but not in controls (211.75 (46.1)%; p = 0.049, 95% CI 291.5 to 20.35). Mean (SD) arterial oxygen saturation increased in the NIV group (+2.97 (2.57)%) but not in controls (21.12 (2.02)%; p = 0.024, 95% CI 0.69 to 7.5). Nine of the 10 controls failed non-intervention by fulfilling criteria to initiate NIV after a mean (SD) of 8.3 (7.3) months. Conclusion: Patients with neuromuscular disease with nocturnal hypoventilation are likely to deteriorate with the development of daytime hypercapnia and/or progressive symptoms within 2 years and may benefit from the introduction of nocturnal NIV before daytime hypercapnia ensues.
07 - (IN PRESS: Respirology 2005;10(Suppl):A108-A208) BOTH REHABILITATION EXERCISE AND STEM CELL TRANSPLANTATION HAVE POSITIVE EFFECTS ON LUNG FUNCTION IN PATIENTS WITH DUCHENNE’S MUSCULAR DYSTROPHY
ZHIPING LI, YUN ZHONG, XIAOLI YAO, YUBIAO GUO, JIANQIANG HUANG, KEJING TANG, CHENG ZHANG - CHINA
Objective To describe the pattern of lung function abnormality and to investigate the effects of rehabilitation exercise and stem cell transplantation on lung function.
Subject and Method Lung function was measured in three Duchenne’s muscular dystrophy (DMD) patients. Patient A insisted on long-term rehabilitation exercise with appropriate intensity. Patient B nearly never had any rehabilitation exercise. Patient C had exercises on sitting position before he received stem cell transplantation (SCT) and his lung function was measured both before and after SCT.
Results The lung function impairment was characterized by restrictive ventilatory disorder. FVC was significantly decreased and forced expiration was shorter than 2 seconds in all the three patients. Patient A that insisted on long-term rehabilitation exercise had better FVC% and FEV1% than patient B that nearly never had any rehabilitation exercise by 13% and 16% respectively. And Patient C who had exercises on sitting position before SCT had better FVC% and FEV1% than patient B by 3% and 6% respectively. After SCT, FVC% and FEV1% of patient C were both increased by 44%.
Conclusion The restrictive ventilatory disorder in DMD patients is caused by respiratory muscle damage. Rehabilitation exercise, especially those aiming at respiratory muscles such as abdominal breathing, inspiration against resistance and balloon blowing can help to delay the deterioration of lung function in DMD patients. Also, SCT can significantly improve the lung function in a DMD patient, suggesting that SCT may be a promising therapy for DMD patients.
02 - Noninvasive monitoring of gene correction in dystrophic muscle
01 - Trends in survival from muscular dystrophy in England and Wales and impact on respiratory services
01 - Expression of connective tissue growth factor in progressive muscular dystrophy
OCTOBER - 2005
29 - Genetic Predictors and Remodeling of Dilated Cardiomyopathy in Muscular Dystrophy
Early cardiac screening necessary for muscular dystrophy patients
28 - (IN PRESS: Neurobiology of Disease 2005;20(1):123-30) L-arginine improves dystrophic phenotype in mdx mice
Vincent Voisin, Catherine Sébrié, Stéfan Matecki, Hua Yu, Brigitte Gillet, Michèle Ramonatxo, Maurice Israel and Sabine De la Porte - France
A possible treatment for Duchenne muscular dystrophies would be to compensate for dystrophin loss by increasing the expression of utrophin, another cytoskeletal protein of the muscle membrane. We previously found that l-arginine, the substrate for nitric oxide synthase, significantly increased utrophin level in muscle and targeted it to the sarcolemma. Here, we have addressed the expected benefit in the mdx mice. Magnetic resonance imaging of lower limbs revealed a 35% reduction of the necrotic zones, confirmed by histological staining of muscles. This regression of the necrosis was also supported by the drastic reduction of Evans blue incorporation, a cell impermeable dye. The creatine kinase level in the serum decreased by 57%. Utrophin level increased 2- to 3-fold in muscles. β-dystroglycan was relocalised with utrophin to the membrane. In the diaphragm, the most affected muscle in mdx mice, the isometric tension increased by 30%, with regression of collagen and of cytoplasmic lipid overloading. Finally, molsidomine, a therapeutic agent that is converted to a NO donor, also attenuated the dystrophic phenotype. Our results suggest that pharmacological activators of the NO pathway may constitute a realistic treatment for Duchenne and Becker muscular dystrophies.
26 - Efficient in vivo gene expression by trans-splicing adeno-associated viral vectors
26 - Myostatin: a modulator of skeletal-muscle stem cells
25 - Critics and Reply: Hyperkalemic Cardiac Arrest After Cardiopulmonary Bypass in a Child with Duchenne Muscular Dystrophy
CRITICS:
We read with interest the article by Nathan et al. (1) concerning a hyperkalemic cardiac arrest in a child with unsuspected Duchenne muscular dystrophy. As the authors state in their discussion, children with undiagnosed Duchenne muscular dystrophy are at an increased risk when exposed to depolarizing muscle relaxants; however, the unexpected rhabdomyolysis associated with general anesthesia drugs is still a problem and no specific disease appears to be related to this phenomenon (2– 4). Because of this, we disagree with the authors’ recommendation of routine preoperative screening of all patients for elevated serum creatine kinase. Although an elevated serum creatine kinase is highly sensitive for myopathies, it lacks specificity (4). Serum creatinine kinase may be elevated after trauma and heavy exercise. Universal screening can result in frequent and unnecessary delays in the operating room schedule and also lead to the “Ulysses Syndrome” of “mental and physical disorders which follow the discovery of a false positive result” (5). Careful and thorough preanesthetic evaluation is essential in helping to identify undiagnosed myopathies, but as with the patient in this report and others (6), this method is not foolproof. We agree with the authors that screening in the neonatal period may be helpful but will need a formal cost analysis before this can be accomplished.
Hetam Al-Takrouri, Little Rock, James F. Mayhew, Jackson - USA
REPLY:
We appreciate the comments of Drs. Al-Takrouri and Mayhew. We agree with them that “universal screening” for elevated creatine kinase during the preoperative evaluation is unnecessary. We had been very careful in preparing our manuscript (1) and had only recommended estimating creatine kinase in children with a history of unexplained motor delay. We also agree with them on the need for a cost analysis for neonatal screening.
25 - Critics and Reply: Can Perindopril Delay the Onset of Heart Failure in Duchenne Muscular Dystrophy?
CRITICS:
With interest we read the study by Duboc et al. (
1) about 57 children with Duchenne muscular dystrophy (DMD) and a left ventricular ejection fraction (LVEF) > 55%. Duboc et al. (1) conclude that early treatment with perindopril over 60 months delays both the onset and progression of systolic dysfunction. The study raises the following concerns: First, how to explain that within the first 36 months only one patient in each group developed systolic dysfunction, whereas within the following 24 months eight patients of group 2 (the group that received placebo during the first 36 months) deteriorated? If the deterioration after 60 months was due to not taking perindopril during the first 36 months, why did this effect not become evident earlier? Assuming that perindopril had an effect in preventing the development of systolic dysfunction in group 1 patients (the group that received perindopril during the first 36 months), it remains unclear whether this was really a drug effect, selection bias, or whether these patients were less severely affected when included. Second, did the eight patients in group 2 with LVEF < 45% after 60 months have a lower baseline LVEF than the remaining patients? How do the investigators know that it was the lack of perindopril that led to a decrease in systolic function in these patients? How could it be excluded that this was not the natural course? To claim a positive effect of perindopril in patients with normal systolic function it is not justified to claim a prophylactic effect of the drug despite a nonsignificant difference in mean values of LVEF after 60 months. How then to explain the improvement of LVEF after 36 months in two group 2 patients? Third, because LVEF decreased under angiotensin-converting enzyme (ACE) inhibitor therapy in eight patients below 45% and the mean remained unchanged, there must have been some patients in whom LVEF has improved. How do the investigators explain that the drug given during 24 months improved LVEF in group 2 patients? Fourth, cardiac function was assessed by resting radionuclide ventriculography. As most of the DMD patients develop thoracospinal deformities from age 10 on, the accuracy of scintigraphy is limited (2). Why was no other method, like echocardiography, applied that would yield additional information about cardiac size and diastolic function? Fifth, what was the rationale to give an ACE inhibitor in patients with normal systolic function? Why was the choice perindopril, an ACE inhibitor not previously tested in muscular dystrophy patients (3,4)? Moreover, information is lacking about the exact neurological severity of the patients, especially how rapidly neurologic symptoms deteriorated, and whether respiratory function changed. How many patients had or developed rhythm abnormalities? Did the heart rate increase during follow-up, and was increased heart rate associated with a decrease of LVEF in any of the patients, suggesting tachycardiomyopathy (5)? How to explain that 17 patients developed side effects during placebo therapy? From which drug? Finally, based on the presented data, it is not justified to propose perindopril as a prophylactic medication in DMD. To assess left ventricular function accurately in DMD patients, the application of at least echocardiography is mandatory (4).Claudia Stöllberger, Josef Finsterer - Austria
REPLY:
We thank Drs. Stöllberger and Finsterer for their comments about our paper (
1). They point out several questions, indicating that they probably do not adhere to our conclusion of a preventive effect of perindopril in children with Duchenne muscular dystrophy. The main limitation may be the apparent delay of 60 months to observe a benefit of therapeutics. In fact, this trial investigated a preventive effect very early in the course of Duchenne disease (mean age of children 10.6 years with normal left ventricular ejection fraction [LVEF]); as a consequence, LVEF was preserved at 36 months. These children probably have cardiac involvement that is not accurately detected by conventional measurements; more sensitive methods might be useful in this setting (2). Conversely, after 60 months’ total follow-up, children were older (mean age 15.6 years) and cardiac deterioration could be demonstrated in the group receiving placebo during phase 1; this is in accordance with the natural course of the disease. Such degradation in LVEF is representative of the ineluctable course of the disease, and it was not accurately prevented by a delayed initiation of perindopril. As 1) groups were comparable for demographics, cardiac status, respiratory and peripheral muscle function, 2) drug allocation (placebo or perindopril) during phase 1 was the only difference, thus the natural conclusion is that five years of perindopril may delay the onset and progression of LV dysfunction when compared to later and shorter initiation. The trend in lower mortality in the perindopril group reinforces our conclusion. All adverse effects mentioned in our study were present during the first phase of the study, with no difference between placebo group or perindopril group. Patients with and without LVEF dysfunction at the end of the protocol had similar baseline values (64.9 + 6.5% vs. 65.0 + 5.4%, respectively, p = NS). No patient had significant increased LVEF during the study. Mean LVEF declined moderately in both groups, and some patients exhibited more severe degradation, which reflects heterogeneity in the course of the disease. In our study, radionuclide ventriculography was chosen to determine LVEF, as it is the “gold standard” method. The measurement of LVEF is a direct count of radionuclide activity. Conversely, LVEF determined by echocardiography needs a mathematical hypothesis that may not be valid in cases of severe thoracic deformation (3). Finally, patients with Duchenne disease very frequently have poor quality of acoustic echocardiographic windows. This study was focused on a possible preventive effect of perindopril on LVEF, which is an important prognosis factor, contrary to electrocardiograms, ventricular arrhythmias, and late potential signal-average (4). In conclusion, this correspondence illustrates the need for simple and adequate methodology to limit misinterpretation of investigative results, integrating the difficulties of such necessary controlled trials conducted in a rare disease.Christophe Meune, Denis Duboc, - France
24 - (IN PRESS: Am J Phys Med Rehabil 2005;84:843–850) Corticosteroid treatment and functional improvement in Duchenne muscular dystrophy: Long-term effect.
Balaban B, Matthews DJ, Clayton GH, Carry T - Turkey
Objective: To determine and compare the long-term effects of prednisone and deflazacort on the functional status of children with Duchenne muscular dystrophy.
Design: A total of 49 boys with Duchenne muscular dystrophy, between the age of 12 and 15 yrs, who were observed over a 7-yr period were reviewed retrospectively. Eighteen had been treated with prednisone, 12 with deflazacort, and 19 had no drug treatment. All boys treated with steroids received medication for > 2 yrs before losing their ambulation. Lower and upper limb motor functions, pulmonary function, prevalence of surgery for scoliosis, and side effects were compared.
Results: Boys in the steroid groups were significantly more functional and performed better on all tests than boys not treated (P < 0.05). There was no significant difference between the deflazacort- and prednisonetreated groups (P> 0.05). The number of boys having scoliosis surgery in treated groups was significantly less than nontreated boys (P < 0.05). The control group’s pulmonary capacity was decreasing and significantly less than both prednisone- and deflazacort-treated boys. Both deflazacort and prednisone had beneficial effect on pulmonary function and scoliosis. Cataracts, hypertension, behavioral changes, excessive weight gain, and vertebral fracture were noted as serious side effects.
Conclusions: Prednisone and deflazacort have a significant beneficial effect on slowing the disease progress. Their usage in Duchenne muscular dystrophy may prolong ambulation and upper limb function with similar potency. Both steroids also improve pulmonary function, in addition to delaying the need for spinal interventions, with similar therapeutic profiles.
19 - SNT-MC17 (idebenone) enters Phase IIa study in Duchenne muscular dystrophy
17 - (IN PRESS: CHEST,2005:128(4) Supplement, p 356S) SIGNIFICANT IMPROVEMENT IN SPIROMETRY AFTER STEM CELL TRANSPLANTATION IN ONE DUCHENNE MUSCULAR DYSTROPHY PATIENT
Poster Presentations, November 2, Chest 2005 - Montreal, Canada
Li, Zhiping; Guo, Yubiao; Yao, Xiaoli; Zhang, Cheng; Xie, Canmao - Department of Pulmonary & Critical Care Medicine, the First Affiliated Hospital, Guangzhou, Peoples Rep of China
PURPOSE: To describe the pattern of lung
function abnormality and to investigate the
changes in spirometry before and after autologus hematopoietic stem cell
transplantation in one duchenne muscular dystrophy (DMD) patient.
METHODS: Lung function was measured by maximum expiratory flow-volume loops and
whole
body plethysmography in one 14-yr old DMD patient before and three months after
stem cell transplantation.
RESULTS: Lung function test was characterized by restrictive pattern manifested
by lung
volume reduction and increased FEV1/FVC due to muscular weakness. Before stem
cell transplantation, the FVC, FEV1 and MVV were 1.4L, 1.4L and 59.5L
respectively.
3 months after stem cell transplantation, the patient's FVC, FEV1 and MVV were
significantly increased to 2.12L, 2.12L and 118.0L respectively.
CONCLUSION: Although genetically modified myoblast transplantation remains
controversial for
DMD, a significant change in spirometry was found in this DMD patient after stem
cell transplantation.
CLINICAL IMPLICATIONS: Spirometric measurement provides a simple and useful
means of assessing disease progression in DMD patients and should be considered
when stem cell transplantation is planning. Furthermore, since DMD characterized
by gradually developing
muscular weakness, pulmonary physical rehabilitation should focus on the
training of respiratory accessory muscles.
16 - Wyeth Seeks People With Becker MD for MYO-029 Study
12 - A minidystrophin-EGFP fusion gene expressed in Cos-7 cells mediated by human source vector
SEPTEMBER - 2005
27 - (IN PRESS: Bioorganic & Medicinal Chemistry Letters, 2005) Novel cell-penetrating a-keto-amide calpain inhibitors as potential treatment for muscular dystrophy
Cyrille Lescop, Holger Herzner, Herve Siendt, Reto Bolliger, Marco Hennebohle, Philipp Weyermann, Alexandre Briguet, Isabelle Courdier-Fruh, Michael Erb Mark Foster, Thomas Meier, Josef P. Magyar and Andreas von Sprecher - Liestal, Switzerland
Abstract—Dipeptide-derived a-keto-amide compounds with potent calpain inhibitory activity have been identified. These reversible covalent inhibitors have IC50 values down to 25 nM and exhibit greatly improved activity in muscle cells compared to the reference compound MDL28170. Several novel calpain inhibitors have shown positive effects on histological parameters in an animal model of Duchenne muscular dystrophy demonstrating their potential as a treatment option for this fatal disease.
17 - Nonmolecular treatment for muscular dystrophies
17 - Respiratory function assessment and intervention in neuromuscular disorders
10 - (IN PRESS: American Journal of Obstetrics and Gynecology (2005) 193 (3 Supplement 1), 1105-9) Targeting the respiratory muscles of fetal sheep for prenatal gene therapy for Duchenne muscular dystrophy
Boaz Weisz, Anna L. David, Lisa G. Gregory, Dany Perocheau, Ali Ruthe BS, Simon N. Waddington, Mike Themis, Terry Cook, Charles Coutelle, Charles H. Rodeck and Donald M. Peebles - UK
Objective: Duchenne muscular dystrophy (DMD) is a lethal degenerative
muscular disease. Fetal gene therapy may correct the primary genetic defect. Our
aim was to achieve expression of a reporter gene in the respiratory muscles of
early gestation fetal sheep. Study design: An adenovirus vector
containing the β-galactosidase reporter gene (AdRSVβgal) was injected into the
thoracic musculature (n = 3) and pleural cavity (n = 6) of fetal sheep (61-67
days' gestation) under ultrasound guidance. Tissues were harvested after 48
hours and site and intensity of β-galactosidase expression were assessed.
Results: Limited transgene expression observed after a single injection was
improved by multiple injections, but remained localized. Ultrasound-guided
creation of a hydrothorax led to an increase in the intensity of β-galactosidase
expression (ELISA). X-gal staining and immunohistochemistry showed that vector
spread was confined to the innermost intercostal musculature. Conclusion:
Ultrasound-guided injection can deliver gene therapy vectors to the fetal
pleural cavity and achieve transduction of the respiratory muscles.
9 - Nutritional therapy improves function and complements corticosteroid intervention in mdx mice
9 - (IN PRESS: J. Paediatr. Child Health (2005) 41, 500–503) Sleep-related breathing disorder in Duchenne muscular dystrophy: Disease spectrum in the paediatric population
Sadasivam Suresh, Patricia Wales, Carolyn Dakin, Margaret-Anne Harris and David (Gus) M Cooper - Australia and UK
Duchenne muscular dystrophy (DMD) is a progressive neuromuscular disease with death usually occurring because of respiratory failure. Signs of early respiratory insufficiency are usually first detectable in sleep. Objective: To study the presentation of sleep-related breathing disorder (SRBD) in patients with DMD. Method: A retrospective review of patients with DMD attending a tertiary paediatric sleep disorder clinic over a 5-year period. Symptoms, lung function and polysomnographic indices were reviewed. Results: A total of 34 patients with DMD were referred for respiratory assessment (1–15 years). Twenty-two (64%) reported sleep-related symptomatology. Forced vital capacity (FVC) was between 12 and 107% predicted (n=29). Thirty-two progressed to have polysomnography of which 15 were normal studies (median age: 10 years) and 10 (31%) were diagnostic of obstructive sleep apnoea (OSA) (median age: 8 years). A total of 11 patients (32%) showed hypoventilation (median age: 13 years) during the 5-year period and non-invasive ventilation (NIV) was offered to them. The median FVC of this group was 27% predicted. There was a significant improvement in the apnoea/hypopnoea index (AHI) (mean difference=11.31, 95% CI=5.91–16.70, P=0.001) following the institution of NIV. Conclusions: The prevalence of SRBD in DMD is significant. There is a bimodal presentation of SRBD, with OSA found in the first decade and hypoventilation more commonly seen at the beginning of the second decade. Polysomnography is recommended in children with symptoms of OSA, or at the stage of becoming wheelchair-bound. In patients with the early stages of respiratory failure, assessment with polysomnography-identified sleep hypoventilation and assisted in initiating NIV.
9 - Spirometry is affected by intelligence and behavior in Duchenne muscular dystrophy
AUGUST - 2005
27 - Coagulation system activated in Duchenne muscular dystrophy patients with cardiac dysfunction
25 - Systemic administration of L-arginine benefits mdx skeletal muscle function
25 - Phosphodiesterase 4 inhibition reduces skeletal muscle atrophy
25 - (IN PRESS: Brain & Development (2005) 27:400–405) A novel approach to identify Duchenne muscular dystrophy patients for aminoglycoside antibiotics therapy
Shigemi Kimura, Kaori Ito, Toshihiko Miyagi, Takashi Hiranuma, Kowasi Yoshioka, Shirou Ozasa, Makoto Matsukura, Makoto Ikezawa, Masafumi Matsuo, Yasuhiro Takeshima, Teruhisa Miike - Japan
Abstract
Aminoglycoside antibiotics have been found to suppress nonsense mutations located in the defective dystophin gene in mdx mice, suggesting a possible treatment for Duchenne muscular dystrophy (DMD). However, it is very difficult to find patients that are applicable for this therapy, because: (1) only 5-13% of DMD patients have nonsense mutations in the dystrophin gene, (2) it is challenging to find nonsense mutations in the gene because dystrophin cDNA is very long (14 kb), and (3) the efficiency of aminoglycoside-induced read-through is dependent on the kind of nonsense mutation. In order to develop a system for identifying candidates that qualify for aminoglycoside therapy, fibroblasts from nine DMD patients with nonsense mutation of dystrophin gene were isolated, induced to differentiate to myogenic lineage by AdMyoD, and exposed with gentamicin. The dystrophin expression in gentamicin-exposed myotubes was monitored by in vitro dystrophin staining and western blotting analysis. The results showed that gentamicin was able to induce dystrophin expression in the differentiated myotubes by the read-through of the nonsense mutation TGA in the gene; a read-through of the nonsense mutations TAA and TAG did not occur and consequently did not lead to dystrophin expression. Therefore, it is speculated that the aminoglycoside treatment is far more effective for DMD patients that have nonsense mutation TGA than for patients that have nonsense mutation TAA and TAG. In this study, we introduce an easy system to identify patients for this therapy and report for the first time, that dystrophin expression was detected in myotubes of DMD patients using gentamicin.
25 - (IN PRESS: Current Pediatrics (2005) 15: 400–405) The multidisciplinary management of Duchenne muscular dystrophy
K. Bushby, J. Bourke, R. Bullock, M. Eagle, M. Gibson, J. Quinby - UK
Summary: Duchenne muscular dystrophy (DMD) is an X-linked disorder for which there is currently no curative treatment. The natural history is such that affected boys need to use a wheelchair at around 9 years, develop respiratory and cardiac complications and die at a mean age of 19 years. While treatments based on gene modification or replacement are eagerly awaited, advances in medical management of DMD have made a significant difference to the natural history of the condition such that most affected individuals can now be expected to live into adulthood. The key interventions relate to the use of corticosteroids to improve muscle strength and function, surgical management of scoliosis and surveillance for and timely management of respiratory and cardiac complications. The predictable nature of the complications of DMD lends itself to the implementation of a planned programme of surveillance and management, which makes a real difference to survival and quality of life.
18 - Overview of Research in DMD II: Experimental Studies. Abstracts from 10th International Congress of World Muscle Society - 28 September to 1 October/ 2005 Foz do Iguassu Brazil
16 - 2005 PPMD Annual Conference Powerpoint Presentations
16 - (IN PRESS: European Journal of Paediatric Neurology, 2005) Functional ability and muscle force in healthy children and ambulant Duchenne muscular dystrophy patients
Ernesto A.C. Beenakker, Natalia M. Maurits, Johanna M. Fock, Oebele F. Brouwer, Johannes H. van der Hoeven - The Neherlands
Summary Neuromuscular disorders are characterised by progressive muscle weakness, which in time causes functional impairment. To quantify the extent of disease progression, muscle force and functional ability can be measured. Which of these parameters changes most depends on the disease stage. In a previous study, we reported normal values for muscle force obtained by handheld dynamometry in healthy children aged 4–16 years. In the present study, we report normal values for timed functional tests in healthy children aged 4–11 years. These normal values were compared with values obtained in 16 ambulant patients with Duchenne muscular dystrophy (DMD) aged 5–8 years to study the extent of functional impairment. In ambulant patients with DMD, we found that muscle function assessed by timed functional tests (running 9 m and rising up from the floor) and muscle force assessed by hand-held dynamometry were severely impaired. However, a small reduction of muscle force was accompanied by a large reduction in functional ability. Therefore, in our group of ambulant patients with DMD, timed functional testing was the mostsensitive parameter to determine the extent of disease progression. Timed functional testing may therefore be considered as an additional outcome measure in drug trials to evaluate the effects of therapy in ambulant patients with DMD and possibly in other neuromuscular disorders.
12 - Early onset of inflammation and later involvement of TGF{beta} in Duchenne muscular dystrophy
9 - Therapy of Duchenne muscular dystrophy with umbilical cord blood stem cell transplantation
9 - Splicing intervention for Duchenne muscular dystrophy
8 - (IN PRESS: Neuromuscular Disorders, 2005) Terminal antisense oligonucleotide modifications can enhance induced exon skipping
Bijanka L. Gebski, Stephen J. Erringtona, Russell D. Johnsen, Susan Fletcher, Stephen D. Wilton - Australia,
Abstract
Induction of specific exon skipping during the processing of the dystrophin gene transcript is being pursued as a potential therapy for Duchenne muscular dystrophy. Antisense oligonucleotides directed at motifs involved in pre-mRNA processing can manipulate dystrophin exon incorporation in the mature gene transcript. We have compared the exon skipping ability of oligodeoxyribonucleotides with compounds of the identical sequence incorporating 20-O-methyl modified bases. Antisense oligonucleotides composed entirely of 20-O-methyl modified bases on a phosphorothioate backbone were consistently more efficient at inducing exon skipping than comparable oligodeoxyribonucleotides. Chimeric antisense oligonucleotides, mixtures of unmodified and 20-O-methyl modified bases, induced intermediate levels of exon skipping. In addition, we describe terminal modifications that may be incorporated into the 20-O-methyl antisense oligonucleotides to further enhance efficiency of exon skipping. Our findings suggest that 20-O-methyl antisense oligonucleotides should be considered for human clinical trials involving targeted exon skipping in dystrophin gene expression in preference to oligodeoxyribonucleotides.
JULY - 2005
Steroids help stabilize cell membranes and decrease inflammation. As such, they have the potential to inhibit myocyte cell death and decrease some of the secondary effects associated with cell death. Although there were a number of early case series investigating steroid use in boys with Duchenne muscular dystrophy, a lack of appropriate control groups made the data generated difficult to interpret. This changed with the report of a prospective randomized trial showing that prednisone use slowed the rate of muscle weakening when instituted in boys who were still walking. Unfortunately, once the drug was stopped, the muscle weakness rapidly returned toward expected baseline. Since the steroid effect disappeared when the drugs was stopped, and the medication is associated with potential side effects, including weight gain, cataracts, osteopenia, and avascular necrosis, steroid use remained controversial. Following the initial randomized trial, studies that examined the use of a variety of steroid medications, dosing regimens, and duration of therapy were reported. Several centers, including ours, investigated long-term steroid use, reasoning that since there was a rapid decline toward baseline muscle function following drug cessation, continuing therapy for a longer duration would result in longer-lasting effects. In these long-term steroid treatment studies, medications were started for boys who were still ambulatory and the medications were continued indefinitely. Although these trials did not use a randomized design, the natural history of progressive muscle weakness in Duchenne muscular dystrophy is quite predictable, and a major deviation from this relentless course is easy to detect. We found that use of a relatively high daily dose of the steroid deflazacort resulted in long-term maintenance of pulmonary function. The age at which boys became full-time wheelchair users increased by several years over boys who did not use deflazacort. Similar findings have been reported from other centers. A recent comparative study examined the results from two centers using different dosing regimens and suggested that higher doses, administered daily, resulted in better maintenance of strength and prevention of skeletal deformity. The implications of steroid treatment on the orthopaedic aspects of Duchenne muscular dystrophy are just beginning to be investigated. The most significant orthopaedic problem is the development of scoliosis. While preserving muscle strength might prevent spinal deformity development, osteopenia associated with steroid use could result in a more rapidly progressive deformity that would be difficult to surgically manage. We investigated a group of boys treated with daily high-dose deflazacort and found a substantially reduced rate of scoliosis compared with boys who elected not to take this medication. Eighty percent of untreated boys developed scoliosis of at least 20 degrees by age 18; fewer than 25% of the boys in the treatment group developed scoliosis.Similar findings were subsequently reported from other centers. Although steroid medications substantially alter the natural history of scoliosis development in these boys as teenagers, the longer-term implications remain unknown. It is possible that these boys will later develop progressive scoliosis requiring surgery at a time when operative intervention might be dangerous from anesthetic and postoperative respiratory standpoints. On the other hand, these boys might behave similar to patients with upper-cervical-level spinal-cord injury who develop a rapidly progressive scoliosis if the injury occurs while skeletally immature, but such deformity is rare after skeletal maturity. Perhaps if spinal deformity is prevented until skeletal maturity, a later progressive curve will not develop. The complications reported with steroid use could result in a poor quality of life for boys with muscular dystrophy. Although weight gain associated with steroid use is a concern, this does not seem to be a significant problem. Surprisingly, late adolescent boys treated with steroids typically weigh less than boys not treated, possibly because they remain more physically active. Boys treated with steroids are slightly shorter than boys who are not treated; this is considered a result of long-term steroid effects on growth plate function. Interestingly, this shorter stature may in part be responsible for the impressive pulmonary function results, as predicted values for pulmonary function are calculated based on height and the shorter stature results in the same raw pulmonary function data giving a higher percentage predicted value. Cataracts occur in a high proportion of boys using steroids, and their development seems dose-related. Despite the number of boys developing cataracts, eye involvement seems to be relatively mild, with no reports of a drop in visual acuity requiring ophthalmologic surgery. Avascular necrosis is reported with steroid use, but this side effect has not been reported in boys with Duchenne muscular dystrophy treated with steroids. Boys using high-dose steroids predictably develop osteoporosis. Various series have reported different implications of this osteoporosis, with some showing a rather high incidence of vertebral stress fractures. In our series, we found symptomatic vertebral stress fractures to be relatively rare. Steroid-induced osteoporosis can be effectively managed using bisphosphonate therapy. Although results of bisphosphonate treatment specifically in Duchenne muscular dystrophy have not been reported, promising results have been presented in randomized trials related to other underlying disorders investigating steroid-induced osteoporosis treatment with bisphosphonates. Successful pharmacologic therapy for Duchenne muscular dystrophy should result in affected boys living longer, higher-quality lives. Long-term steroid use improves pulmonary function, delays boys becoming full-time wheelchair users, and at least delays the development of scoliosis. Longterm effects on quality and length of life are not yet known. As the initial cohort of boys treated with long-term steroids reaches their late 20s, these issues can be addressed. In the meantime, current evidence raises the possibility that longterm use of steroids will result in improvement in quality and length of life in Duchenne muscular dystrophy patients. We believe that all boys with this disorder should be given the opportunity to start such medications early in their disease course, well before they reach the stage of full-time wheelchair use.
17 - Chemical 'band-aid' prevents heart failure in mice with muscular dystrophy
17 - New 'mighty mice' research brings muscle growth closer to reality
2 - Steroid Therapy and Cardiac Function in Duchenne Muscular Dystrophy
JUNE - 2005
DONATIONS TO BRAZILIAN RESEARCH CENTER - CLICK HERE
29 - CINRG randomized controlled trial of creatine and glutamine in Duchenne muscular dystrophy
28 - (IN PRESS: Annales de readaptation et de medicine physique, 2005) Pain, osteopenia and body composition of 22 patients with Duchenne muscular dystrophy: a descriptive study
B. Douvillez, P. Braillon, I. Hodgkinson, C. Berard - France
Objectives. – To study the link between pain, osteopenia and body composition in patients with Duchenne muscular dystrophy and to present a detailed questionnaire to evaluate their pain. Materials and methods. – Twenty-two boys with Duchenne muscular dystrophy, mean age 11.4 ± 4.0 years, were examined between February and March 2003. They were asked to complete a detailed questionnaire and undergo a global assessment of pain on a visual analog scale and muscular testing. They were also asked about a history of fractures. Their bone mineral content at the lumbar spine and femoral neck levels, as well as their body composition in fat and lean mass, were assessed by dual energy absorptiometry. Results. – The mean age for walking incapacity was 8.8 ± 1.7 years. The youngest patients, who were still able to walk, had a higher level of pain than patients who depended on wheelchairs. No significant correlation was established between pain and osteopenia. One in 2 patients had spontaneous pain, and mobilization was painful for 21. The score obtained by detailed questionning about pain correlates with the average pain scores on visual analog scales. The bone mineral content was lower, especially in the lower limbs, had decreased before the inability to walk and was correlated with muscular weakness. Fractures were more frequent in mobile patients and usually occurred after a fall. Conclusion. – Although pain in Duchenne muscular dystrophy has not been extensively studied, it is frequent and significant. Twenty-one patients had moderate to severe pain. The youngest patients had intense pain, especially during mobilisation. To evaluate this pain, we propose to use the mean results of 2 visual analog scales associated with a detailed questionnaire. However, in this study, Duchenne muscular dystrophy, pain and osteopenia were not correlated. Dual X-ray absorptiometry provides interesting information about bone mineral content, fat body mass and lean body mass. The fat body mass was higher than normal in our patients. The bone mineral content and lean body mass were lower than that for normal children, because the dystrophic process advances
25 - (IN PRESS:Biochemical and Byophysical Research Communications, 2005; 333(2):644-649) Generation of skeletal muscle from transplanted embryonic stem cells in dystrophic mice
Satyakam Bhagavati and Weimin Xu - USA
Abstract
Embryonic stem (ES) cells have great therapeutic potential because of their capacity to proliferate extensively and to form any fully differentiated cell of the body, including skeletal muscle cells. Successful generation of skeletal muscle in vivo, however, requires selective induction of the skeletal muscle lineage in cultures of ES cells and following transplantation, integration of appropriately differentiated skeletal muscle cells with recipient muscle. Duchenne muscular dystrophy (DMD), a severe progressive muscle wasting disease due to a mutation in the dystrophin gene and the mdx mouse, an animal model for DMD, are characterized by the absence of the muscle membrane associated protein, dystrophin. Here, we show that co-culturing mouse ES cells with a preparation from mouse muscle enriched for myogenic stem and precursor cells, followed by injection into mdx mice, results occasionally in the formation of normal, vascularized skeletal muscle derived from the transplanted ES cells. Study of this phenomenon should provide valuable insights into skeletal muscle development in vivo from transplanted ES cells
22 - (IN PRESS: Transplantation, 2005;79:1696-1702) Improved Success of Myoblast Transplantation in mdx Mice by Blocking the Myostatin Signal
Basma F. Benabdallah, Manaf Bouchentouf, and Jacques P. Tremblay
Background. Duchenne muscular dystrophy (DMD) is caused by a dystrophin gene mutation. Transplantation of normal myoblasts results in long-term restoration of dystrophin. However, the success of this approach is compromised by the limited time of regeneration following muscle damage. Myostatin is known to be responsible for limiting skeletal muscle regeneration. Our purpose is to verify whether blocking the myostatin signal in mdx host mice or in normal myoblasts transplanted in mdx host mice would increase the extent of muscle repair and thus allow the formation of more dystrophin-positive fibers.
Methods. Transgenic mdx mice carrying a dominant negative form of myostatin receptor (dnActRIIB) were used to test the fiber resistance to damage and to act as a host for normal myoblast transplantation. Myoblasts obtained from nondystrophic transgenic mice carrying the dominant negative myostatin receptor were also transplanted in nontransgenic mdx mice.
Results. Transgenic mdx mice carrying the dnActRIIB gene have bigger muscles than mdx mice with the normal gene of ActRIIB. Their fiber resistance to exercise-induced damage was also greatly improved. Moreover, the success of normal myoblast transplantation was significantly enhanced in mdx/dnActRIIB mice. Finally, nondystrophic dnActRIIB myoblasts formed more abundant and bigger dystrophin positive fibers when transplanted in mdx mice.
Conclusions. Blocking the myostatin signal in mdx mice allowed the size of muscle fibers to increase, the fiber resistance to damage induced by exercise to increase, and the success of normal myoblast transplantation to improve. The transplantation in mdx mice of dnActRIIB myoblasts formed more abundant and larger dystrophin positive fibers.
21 - Quality of Life, Physical Disability, and Respiratory Impairment in Duchenne Muscular Dystrophy
14 - Allogeneic umbilical cord blood stem cell transplantation in Duchenne muscular dystrophy
14 - (IN PRESS: Neurobiology of Disease, 2005) Chronic treatment with agents that stabilize cytosolic IKB-A enhances survival and improves resting membrane potential in MDX muscle fibers subjected to chronic passive stretch
C. George Carlson, Abbas Samadi, and Ashley Siegel - USA
The potential pathogenic role of increased NFKB signaling in passively stretched dystrophic skeletal muscle was examined by treating adult mdx mice with an agent that stabilized cytosolic IKB-A (pyrollidine dithiocarbamate, PDTC)and examining the effects of this treatment on the chronically stretched mdx triangularis sterni (TS) muscle. Daily PDTC treatment significantly increased the number of surviving striated TS fibers regardless of age. TS fibers from untreated mdx mice had significantly lower resting potentials (RPs) than nondystrophic mice. Treatment with GdCl3 to block resting Ca2+ influx had no effect on RP in either nondystrophic or mdx preparations. Daily treatment with PDTC significantly improved the RP regardless of age. These results are consistent with the hypothesis that passive stretch activates an NFKB-mediated pathogenic mechanism in dystrophic muscle and suggest that agents which stabilize cytosolic IKB-A levels may be useful for treating Duchenne and related muscular dystrophies.
11 - Cardiac involvement in muscular dystrophies: Molecular mechanisms
06 - FASEB J. 19, 880–891 (2005) Molecular, cellular, and pharmacological therapies for Duchenne/Becker muscular dystrophies
Joe V. Chakkalakal, Jennifer Thompson, Robin J. Parks,
and Bernard J. Jasmin - CanadaAbstract: Although the molecular defect causing Duchenne/Becker muscular dystrophy (DMD/BMD) was identified nearly 20 years ago, the development of effective therapeutic strategies has nonetheless remained a daunting challenge. Over the years, a variety of different approaches have been explored in an effort to compensate for the lack of the DMD gene product called dystrophin. This review not only presents some of the most promising molecular, cellular, and pharmacological strategies but also highlights some issues that need to be addressed before considering their implementation. Specifically, we describe current strategies being developed to exogenously deliver healthy copies of the dystrophin gene to dystrophic muscles. We present the findings of several studies that have focused on repairing the mutant dystrophin gene using various approaches. We include a discussion of cell-based therapies that capitalize on the use of myoblast or stem cell transfer. Finally, we summarize the results of several studies that may eventually lead to the development of appropriate drug-based therapies. In this context, we review our current knowledge of the mechanisms regulating expression of utrophin, the autosomal homologue of dystrophin. Given the complexity associated with the dystrophic phenotype, it appears likely that a combinatorial approach involving different therapeutic strategies will be necessary for the appropriate management and eventual treatment of this devastating neuromuscular disease
Conclusions and Perspective: Initially it was thought that the characterization of the molecular defects causing DMD and the identification of dystrophin would soon result in a cure for this progressive neuromuscular disorders. Almost 20 years have passed since the discovery of the gene and, unfortunately, we have yet to find an effective therapy that could mitigate the dystrophic process. Although numerous approaches are currently being explored, many suffer from a variety of drawbacks. It is only through additional research that these barriers will be overcome and ultimately lead to the development of therapeutic strategies effective in stemming the progressive and multifactorial nature of DMD. A clear possibility is that the effective management and therapy of DMD may only be achieved through a combination of approaches. Thus, it is imperative to initiate studies assessing the potential beneficial impact of multiple strategies combined into a single preclinical trial.
MAY - 2005
28 - Effects of T-Lymphocyte Depletion on Muscle Fibrosis in the mdx Mouse
28 - In Vivo Fusion of Circulating Fluorescent Cells with Dystrophin-Deficient Myofibers Results in Extensive Sarcoplasmic Fluorescence Expression but Limited Dystrophin Sarcolemmal Expression NEW
28 - Gene therapy could bring hope to thousands
21 - Stem Cell Breakthrough in South Korea
21 - (IN PRESS: Reactions Weekly, 2005) Desflurane: First report of heart arrest in a patient with muscular dystrophy:case report
A 16-year-old boy undergoing surgery for
scoliosis correction developed heart
arrest while receiving desflurane-based anaesthesia. The boy, who had muscular
dystrophy and a history of mild chronic obstructive pulmonary disease,
gastro-oesophageal reflux and symptoms of cardiomyopathy, underwent anaesthesia
induction, receiving alfentanil, propofol and rocuronium bromide; anaesthesia
was maintained with desflurane [dosage not stated] and piritramide in an oxygen/air
mix. After 4 hours of uneventful anaesthesia, he developed ventricular
tachycardia followed by ventricular fibrillation. Following external cardiac
compression, defibrillation and epinephrine [adrenaline] administration, the
boy's HR returned to sinus rhythm within 5 minutes and his BP and cardiac output
improved. Postoperatively, his creatine kinase (CK) level and CK-MB fraction
peaked at 11 056 and 253 U/L, respectively, and his myoglobulin level peaked at
62 ng/mL. He was discharged from the ICU 10 days later. Author Comment"In our
patient other causes for cardiac arrest like hypoxaemia, hypercapnia,
hyperkalaemia and hyperthermia were excluded, so the episode was attributed to
cardiomyopathy and the use of desflurane."
1. Smelt WLH.Cardiac arrest during
desflurane anaesthesia in a patient with
Duchenne's muscular dystrophy. Acta Anaesthesiologica Scandinavica 49: 267-269,
No. 2, Feb 2005
Editorial Comment: A search of AdisBase and Medline did not reveal any previous
case reports of heart arrest associated with desflurane. The WHO Adverse Drug
Reactions database contained 12 reports of cardiac arrest associated with
desflurane.
17 - (IN PRESS: Journal of Pediatric Gastrenterology,2005) MANAGEMENT OF OBESITY IN DUCHENNE MUSCULAR DYSTROPHY: A LONGITUDINAL STUDY
Presented on 38th Annual Meeting of the European Society for Pediatric Gastroentrology, Hepatology and Nutrition Porto, Portugal, June 1–4, 2005
C Morin, JM Cuisset, K Mention, A Carpentier,L Jouannic, F Gottrand -France.
Aim: Obesity occurs early in the course of Duchenne muscular dystrophy (DMD), and is observed in more than 50% of patients after the age of 14 years. The aim of this study was to evaluate efficacy and tolerance of a nutritional program in a population of obese DMD patients.
Methods: From 1996 to 2004, all the children with DMD and obesity (weight . 90% for age according to Edward’s chart) followed in our centre, were included in a nutritional program which associated a 10% diet intake reduction including at least 15% of protein, and a twice-a-year paediatrician and dietician follow-up. We measured anthropometrical and impedancemetry data to evaluate weight gain velocity, fat mass and fat free mass. 24h dietetic recall was used to evaluate food intake. A questionnaire gave information on families characteristics and tolerance of the nutritional program.
Results: 25 children, aged 9 years (range 5 to 16 years), weighted 34 kg (range 19 to 62 kg), were included in the study. Four were lost of follow-up. 62% of patients had at least one relative (without DMD) presenting obesity. After a follow-up of 4 years (range 0.5 to 12 years), weight gain velocity (expressed as Z-score) decreased from 2.8 to 20.5 SD (p = 0.0004). Body composition analysis showed a mild increase of fat mass (from 28 to 33 %) (p = 0.03) but no significant variation of fat free mass (21 versus 26 kg). Food intake decreased from 1727 to 1485 kcal/d (p = 0.03) with a parallel decrease of lipids and carbohydrate intakes (p
# 0.005) while proteins remained to 15% of caloric intake. Sixteen children (64%) were consider as a success (weight gain velocity , 0). No criteria were found significantly associated to success excepted that families seemed to be more implicated in the diet in this group (50 versus 33 %) (ns). We were not able to observe any difference in evolution of DMD among groups. This program was judged as well tolerated by children and families. Conclusion: Nutritional program in obese DMD patients is well tolerated and can limit weight gain without apparent deleterious effect on body composition.09 - (IN PRESS: Molecular Therapy,2005) Phenotypic Improvement of Dystrophic Muscles by rAAV/Microdystrophin Vectors Is Augmented by Igf1 CodeliveryB
Simone Abmayr, Paul Gregorevic, James M. Allen and Jeffrey S. Chamberlain - USA
The absence of dystrophin in Duchenne muscular dystrophy (DMD) leads to sarcolemmal instability and enhances the susceptibility of muscle fibers to contraction-induced injury. Various viral vectors have been used to deliver mini- and microdystrophin expression cassettes to muscles of dystrophin deficient mdx mice, significantly increasing both the morphological and the functional properties of the muscles. However, dystrophin delivery to adult mdx mice has not yielded a complete rescue of the dystrophic phenotype. Here we investigated a novel strategy involving dual gene transfer of recombinant adeno-associated viral vectors expressing either microdystrophin (rAAV-MDys) or a muscle-specific isoform of Igf-1 (rAAV-mIgf-1). Injection of mdx muscles with rAAV-MDys reduced myofiber degeneration and turnover and increased their resistance to mechanical injury, but did not increase muscle mass or force generation. Injection of mdx muscles with rAAV-mIgf-1 led to increased muscle mass, but did not provide protection against mechanical injury or halt myofiber degeneration, leading to loss of the vector over time. In contrast, co-injection of the rAAV-MDys and rAAV-mIgf-1 vectors resulted in increased muscle mass and strength, reduced myofiber degeneration, and increased protection against contraction-induced injury. These results suggest that a dual-gene, combinatorial strategy could enhance the efficacy of gene therapy of DMD.
07 - Red–Green Color Vision and Luminance Contrast Sensitivity Losses in Duchenne Muscular Dystrophy
07 - Identification and Characterization of Stem Cells in Extraocular Muscle (EOM)
07 - Extraocular Muscles Contain More Satellite Cells and More Multipotent Precursor Cells than Limb Muscle
02 - (EARLY VIEW: ONLY HERE) ABSTRACTS THAT WILL BE PRESENTED IN THE 8TH ANNUAL MEETING OF THE AMERICAN SOCIETY OF GENE THERAPY, JUNE 1-5, ST LOUIS, MISSOURI
1) Antisense Therapy for Duchenne Muscular Dystrophy: A Realistic Possibility
2) Ex Vivo Gene Therapy for Duchenne Muscular Dystrophy: Lentiviral and PhiC31 Integrase Approaches
3) Immunity to AAV-Mediated Gene Therapy in a Random-Bred Canine Model of Duchenne Muscular Dystrophy
4) Stable Genome Alteration of the Dystrophin Gene for the Treatment of Duchenne Muscular Dystrophy (DMD) Due to Frame-Shift Mutations Using Oligonucleotide-Mediated Gene Editing
5) Embryonic Stem Cell-Mediated Regenerative Therapy for Duchenne Muscular Dystrophy
6) Development of rAAV-Based Skeletal and Cardiac Muscle Regulatory Cassettes for Gene Therapy of Duchenne Muscular Dystrophy
7) Enhanced Plasmid-Mediated Dystrophin Expression in the mdx Mouse Model for Duchenne Muscular Dystrophy by a PhiC31 Integrase Plasmid System
8) Sustained Whole-Body Functional Rescue by Systemic Delivery of AAV8 Vectors in Heart Failure and Muscular Dystrophy Hamsters
9) Dystrophin in Vascular Smooth Muscle Is Important for Duchenne Muscular Dystrophy Therapy
10) An Ideal Therapeutic Agent for Duchenne
Muscular Dystrophy Involving a Gutted Adenovirus Expressing Full-Length Utrophin
11) A Novel Approach of Gentamicin Therapy for Duchenne Muscular
Dystrophy Using Hybrid Liposome and Establishment of a System To Identify the
Patients Eligible for the Treatment
12) Efficient Expression of the 6 kb Mini-Dystrophin Gene by
Trans-Splicing Adeno-Associated Viral (AAV) Vector Restores the Entire
Dystrophin-Associated Glycoprotein Complex and Reduces Contraction-Induced
Damage in the Mdx Mouse Model of Duchenne Muscular Dystrophy
13) Recombinant Adeno-Associated Viral (rAAV) Microdystrophin
Vectors as Therapeutic Tools for Duchenne Muscular Dystrophy (DMD)
14) Evaluation of Immune Responses to Dystrophin in Humanized mdx
HLA-A*0201 Dystrophic Mice: Application in Duchenne Muscular Dystrophy Gene
Therapy after U7 snRNA-Mediated Exon Skipping
15) Successful Myoblast Transplantation to Duchenne Muscular
Dystrophy Patients
16) Highly Efficient Exon-Skipping and Sustained Correction of
Muscular Dystrophy Using an Adeno-Associated Viral Vector
17) Lentivirus Mediated Dystrophin Expression in mdx
Muscles
18) Plasmid-Mediated Gene Transfer in mdx Mice Using Mini-
and Micro-Dystrophin Constructs
19) Canine Mini-Dystrophin Gene Transfer by AAV1 in mdx
Mice Ameliorates Dystrophic Pathology and Protects Membrane Integrity
20) An AAV Vector-Mediated Gene Transfer into Canine Skeletal
Muscle
21) Overlapping Adeno-Associated Viral (AAV) Vector Mediated Gene
Transfer Is Dependent on Viral Serotype and the Transgene Sequence in Skeletal
Muscle
22) Evaluation of Gene Transfer Efficacy
Mediated by AAV1 and AAV6 Vectors in Skeletal Muscle of Adult Mice Following
Different Routes of Administration
23) Identification of Differentially Expressed Genes in Duchenne
Muscular Dystropy Utilising RNAi Technology: Possible Targets for Gene Therapy
24) Perivascular CD45-:Sca-1+:CD34-
Cells Are Derived from Bone Marrow Cells and Participate in Dystrophic Skeletal
Muscle Regeneration
25) AAV-Mediated Myostatin Propeptide Gene Delivery Results in
Growth and Hypertrophy of Skeletal but Not Cardiac Muscles
26) Real Time Imaging of Myoblast Transplantation Using the Human
Sodium Iodide Symporter (hNIS) as Reporter Gene
27) Overexpression of the Myostatin Antagonist Follistatin in
Normal Myoblasts Genetically Modified with a Lentivirus
28) Development of AAV-Mediated Gene Therapy for Murine Models of
Genetic Diseases Affecting the Heart
29) Decorin Promotes Differentiation of
Myoblasts into Myotubes That Express Slow MyHC In Vitro
APRIL - 2005
30 - Assisted cough and pulmonary compliance in patients with duchenne muscular dystrophy
26 - (IN PRESS: Anesthesiology;102:915-9,2005) Onset and Duration of Rocuronium-induced Neuromuscular Blockade in Patients with Duchenne Muscular Dystrophy
Stefanie Wick, Tino Muenster, Joachim Schmidt, Juergen Forst, Hubert J. Schmitt - Germany
Background: In patients with Duchenne muscular dystrophy (DMD) the response to nondepolarizing muscle relaxants is scarcely documented and conflicting. The current study was conducted to determine the time to peak effect and the time for complete spontaneous recovery after a single dose of 0.6 mg/kg of rocuronium in patients with DMD. Methods: Twenty-four patients (12 with DMD, 12 controls, aged 10–16 yr) were studied. All patients were anesthetized with propofol and fentanyl/remifentanil. Neuromuscular transmission was monitored by acceleromyography. After induction all patients received a single dose of 0.6 mg/kg of rocuronium. The complete time course of onset and spontaneous recovery were recorded Results: Significant (P < 0.01) increase in the onset times to 95% neuromuscular block was observed in DMD patients (median, 203 s; range, 90–420 s) compared with controls (median, 90 s; range, 60–195 s). The time between rocuronium administration and recovery of first twitch of the train-of-four to 90% was significantly (P < 0.01) prolonged in DMD compared with controls (median, 132 min; range, 61–209 min versus 39 min; 22–55 min). The recovery index was also significantly prolonged in the DMD group compared with controls (median, 28 min, range, 15–70 min versus 8 min; 3–14 min). Conclusions: The most striking and surprising result of this study is the delayed onset of blockade in DMD after a standard dose of rocuronium. This effect should be kept in mind in situations when a rapid airway protection is necessary in DMD patients. The documented very long recovery from rocuronium- induced block emphasizes the need for careful assessment of neuromuscular function in DMD patients.
25 - (IN PRESS: Southern Medical Journal 98(4):478-80,2005) Worsening of Heart Failure in Becker Muscular Dystrophy After Nonsteroidal Anti-inflammatory Drugs -Report
Stollberger, Claudia ; Finsterer, Josef - Wien
A 40-year-old male with
Becker muscular dystrophy and cardiac involvement was stable in New York Heart
Association class II for 7 years. He then had arthralgia caused by bilateral
gonarthrosis. He received diclofenac 100 mg/d and 500 mg/d mephenamine acid. Six
weeks later, he was hospitalized because of heart failure (New York Heart
Association class IV). Echocardiography revealed biatrial and biventricular
dilation, a left ventricular end-diastolic diameter of 82 mm, an ejection
fraction of 26%, a severe tricuspid regurgitation, and an elevated pulmonary
artery pressure of 60 mm Hg. Nonsteroidal anti-inflammatory drugs were
discontinued, and physiotherapy and equipment with a corset were initiated. He
improved after treatment with parenteral diuretics, returning to class II.
Nonsteroidal anti-inflammatory drugs should be given with caution in Becker
muscular dystrophy with cardiac involvement.
24 -
Analysis of Dystrophin Gene Deletions Indicates that the Hinge III Region of the
Protein Correlates with Disease Severity
23 - Regeneration of dystrophin-expressing myocytes in the mdx heart by skeletal muscle stem cells
21 - (IN PRESS: Neuromuscular Disorders, 2005) Editorial - Antisense oligonucleotides (AO) in the treatment of Duchenne muscular dystrophy: Where are we now?
Steve D. Wilton and Susan Fletcher
Concluding comments
Finally, it should be noted that this antisense oligonucleotide induced exon skipping strategy should not be considered as a form of gene therapy. While the effects do occur in the nucleus, as the dystrophin gene is being actively transcribed and processed, no permanent genetic changes are induced. In contrast to the introduction of entire transgenes in plasmid or viral vectors, AOs should be regarded as ‘informational drugs’
[24], which do not encode a complete product. The site of action for AO induced exon skipping is the primary gene transcript, not the gene. Once the AO has been degraded, metabolised or cleared from the nucleus and cell, its biological activity will dissipate. In many respects, it would be difficult to ‘reverse engineer’ a system with a gene transcript better suited for targeted exon skipping than the dystrophin pre-mRNA. Major regions of the dystrophin protein-coding region can be omitted with minor losses in function, as demonstrated by mildly affected or asymptomatic Becker MD patients. The half-life of the protein is several weeks and there should be a slow turn-over of the muscle fibres if the induced protein does restore strength and stability to the muscle. Induced exon skipping would not be readily applicable to small gene transcripts where all exons are essential for function, or if the gene transcript has a short biological halflife. Similarly, the AOs would not be very effective in cells that divide rapidly, thereby diluting any AO taken up into the nucleus to sub-therapeutic levels. In the event that AOs induce very efficient exon skipping in the early trials, the issue of systemic AO delivery must be addressed and it may conceivably take years to demonstrate clinical benefits to the patients. It will be a frustratingly slow process and this will cause major concerns to parents, patients, clinicians, and the researchers. It is essential that the trials be undertaken transparently and meticulously to ensure no harm to the participants and that any reported benefits are reproducible. Exon skipping will not provide a cure for DMD and will only be effective in a subset of patients. Treatment and care has improved the quality and life expectancy of DMD patients. It may be anticipated that the restoration of some dystrophin by targeted exon skipping will provide additional benefit, the extent of which remains to be determined.21 - PTC Therapeutics Receives $1.5 Million Grant from Muscular Dystrophy Association
21 - Brazil funds human stem cell research
11- (IN PRESS: Neuroscience Letters 2005) Muscle regeneration in dystrophic mdx mice is enhanced by isosorbide dinitrate
Maria Julia Marques, Marcus Alexandre Mendes Luz, Elaine Minatel, Humberto Santo Neto - Brazil
Abstract
Activation of muscle satellite cells, a fundamental step in the success of muscle regeneration is mediated by nitric oxide (NO). In this study, we investigated whether isosorbide dinitrate (ISD), an NO donor, could improve muscle regeneration in dystrophic mdx mice. The right tibialis anterior muscle of mdx and C57Bl/10 mice was injected with bupivacaine (0.3 ml, 33 mg/kg), a myotoxic agent, to induce muscle fiber regeneration. After bupivacaine injection, mice were treated with ISD (30 mg/kg; i.p.), verapamil (a non-NO donor vasodilator, 15 mg/kg, i.p.) or saline solution (vehicle, 0.3 ml, i.p.) for 20 days. Some bupivacaine-injected mice received no pharmacological treatment (control group). Muscle regeneration was evaluated by counting the total number of muscle fibers and measuring myofiber cross-sectional area. ISD significantly improved bupivacaine-induced muscle regeneration in mdx by increasing by 20% the total number of muscle fibers compared to the other groups. Spontaneous muscle regeneration, evaluated in the contralateral non-injected muscle, was not affected. ISD treatment did not affect myofiber cross-sectional area. Verapamil and saline had no effect on muscle regeneration. These results suggested that NO derived from ISD stimulated and/or recruited satellite cells. Pharmacological treatment with ISD could be clinically useful for improving muscle regeneration in Duchenne muscular dystrophy.
8 - (IN PRESS: Arch.Phys.Med.Rehabil 2005;86:802-8) Use of Step Activity Monitoring for Continuous Physical Activity Assessment in Boys With Duchenne Muscular Dystrophy
Craig M. McDonald,Lana M. Widman, Denise D. Walsh, Sandra A. Walsh, R. Ted Abresch - USA
Objectives: To evaluate the StepWatch Activity Monitor (SAM) as a quantitative measure of community ambulation, to investigate activity patterns and heart rate of ambulatory boys with Duchenne muscular dystrophy (DMD), and to correlate the step activity with measures of body composition and strength. Design: Case-control study. Setting: General community and laboratory. Participants: Sixteen ambulatory boys with DMD and 20 male controls (age range, 5–13y). Interventions: Not applicable. Main Outcome Measures: Laboratory determinations of body composition, knee extension strength, and minute-by-minute step rate and heart rate during 3 days of community activity. Results: During the 3 days of activity, DMD subjects, when compared with controls, (1) had significantly more inactive minutes (1096+90min/d vs 1028+85min/d), (2) took significantly fewer steps and spent fewer minutes at moderate (66+31min/d vs 94+30min/d) and high step rates (43+30min/d vs 72+38min/d), (3) had higher resting heart rate (110+12 beats/min vs 94+7 beats/min) and lower increase in heart rate with increased step rate, and (4) had lower maximum heart rates (164+24 beats/min vs 208+16 beats/min). Percentage of body fat and knee extension strength correlated with total step activity in the DMD group but not in the control group. Conclusions: Step-rate monitoring with the SAM provides useful outcome measures with which to evaluate the activity of ambulatory boys with DMD. Their heart rate did not increase with activity to the same degree as observed in the control group.
2 - Resting energy expenditure in Duchenne patients using home mechanical ventilation
2 - When Science Is Not Enough: Fighting Genetic Disease in Brazil
MARCH - 2005
31 - (IN PRESS: Brain e Development, 2005) Intraperitoneal administration of phosphorothioate antisense oligodeoxynucleotide against splicing enhancer sequence induced exon skipping in dystrophin mRNA expressed in mdx skeletal muscle
Yasuhiro Takeshima, Mariko Yagi, Hiroko Wada, Masafumi Matsuo - Japan
Abstract
Antisense oligodeoxynucleotide against the splicing enhancer sequence (SES) in exon 19 of the dystrophin gene have been shown to induce exon 19 skipping and promote the expression of internally deleted dystrophin by correcting the translational reading frame in the cultured Duchenne muscular dystrophy (DMD) myocytes with the deletion of exon 20. Transfection of the antisense oligodeoxynucleotide, therefore, has been proposed as a promising means for therapeutic modification of dystrophin mRNA of DMD, a fatal disorder caused by defects in the dystrophin gene. A systemic delivery method targeting the large number of diseased muscles remains to be established for clinical application of antisense oligodeoxynucleotide. In this study, we investigated capability of oligodeoxynucleotide transfer into the skeletal muscles of mdx mouse, a mouse model of DMD. Thirty-one mer phosphorothioate oligodeoxynucleotide complementary to the SES of dystrophin exon 19 was intraperitoneally administered to mdx mice without any carrier. Histochemical study disclosed that fluorescencelabeled oligodeoxynucleotide appeared in the nuclei of femoral skeletal muscle cell at the second day after injection of 20 mg/kg BW oligodeoxynucleotide, and still visible at 14th day. Reverse transcription (RT)-PCR analysis of dystrophin transcript in these cells disclosed that a proportion of it showed skipping of exon 19 from second to seventh day after injection. These results showed that the intraperitoneally administered oligodeoxynucleotide could be transfected to nucleus of mdx skeletal muscle without any carrier and was able to induce exon skipping in vivo.
31 - (IN PRESS: Muscle and Nerve, 2005) Topiramate for weight reduction in Duchenne muscular dystrophy - Letter to the editor
Gregory T. Carter, Michelle P. Yudkowsky, Jay J. Han, Megan A. McCrory - USA
Obesity may be a significant clinical problem in Duchenne muscular dystrophy (DMD) and difficult to treat due to low resting energy expenditure. The incidence of obesity in DMD is not known. However, studies of body composition in DMD have shown a high ratio of fat to lean mass and bone. Obesity often occurs in adolescents with DMD, after loss of independent ambulation. Despite the known effects of topiramate, an antiepileptic agent, on weight loss and treating obesity, there have been no studies examining its effects on weight reduction in patients with neuromuscular disease. We report two boys with DMD who lost significant weight after initiating therapy with topiramate. These cases provide anecdotal evidence that topiramate is well tolerated and may help patients with DMD to lose weight. Weight loss did not improve functional independence but did improve ease of transfers, skin care, and positioning. Neither boy had significant untoward side effects. The most frequently reported adverse effects in other studies were somnolence, difficulty with mentation, and paresthesias, although the overall incidence was low. The two boys reported here lost 26% and 41% of initial body weight, respectively, which is greater than the reported average weight loss in the prior studies (approximately 15%).
25 - (IN PRESS: The FASEB Journal. 2005;19:543-549) Myostatin propeptide-mediated amelioration of dystrophic pathophysiology
Mutations in myostatin (GDF8) cause marked increases in muscle mass, suggesting that this transforming growth factor-ß (TGF-ß) superfamily member negatively regulates muscle growth. Myostatin blockade therefore offers a strategy for reversing muscle wasting in Duchenne’s muscular dystrophy (DMD) without resorting to genetic manipulation. Here, we demonstrate that pharmacological blockade using a myostatin propeptide stabilized by fusion to IgG-Fc improved pathophysiology of the mdx mouse model of DMD. Functional benefits evidenced by specific force improvement, exceeded those reported previously using myostatin antibody-mediated blockade. More importantly, use of a propeptide blockade strategy obviates possibilities of anti-idiotypic responses that could potentially limit the effectiveness of antibody-mediated myostatin blockade strategies over time. This study provides a novel pharmacological strategy for treatment of diseases associated with muscle wasting such as DMD and since it uses an endogenous inhibitor of myostatin should help circumvent technical hurdles and toxicity associated with conventional gene or cell based therapies.
22 - Nutritional inadequacy in adults with muscular dystrophy
16 - Relationship between peak cough flow and spirometry in Duchenne muscular dystrophy
12 - Stable transduction of myogenic cells with lentiviral vectors expressing a minidystrophin
10 - (IN PRESS: J.Am.Cardiol 2005;45:855-7) Effect of Perindopril on the Onset and Progression of Left Ventricular Dysfunction in Duchenne Muscular Dystrophy
Denis Duboc, ,Christophe Meune, Guy Lerebours, Jean-Yves Devaux, Guy Vaksmann,Henri-Marc Bécane, Paris, France
OBJECTIVES The aim of this research was to examine the effects of perindopril on cardiac function in patients with Duchenne muscular dystrophy (DMD).
BACKGROUND Duchenne muscular dystrophy, an inherited X-linked disease, is characterized by progressive muscle weakness and myocardial involvement.
METHODS In phase I, 57 children with DMD and a left ventricular ejection fraction (LVEF) >55% (mean 65.0 + 5.4%), 9.5 to 13 years of age (mean 10.7+ 1.2 years), were enrolled in a three-year multicenter, randomized, double-blind trial of perindopril, 2 to 4 mg/day (group 1), versus placebo (group 2). In phase II, all patients received open-label perindopril for 24 more months; LVEF was measured at 0, 36, and 60 months.
RESULTS Phase I was completed by 56 (27 in group 1 and 29 in group 2) and phase II by 51 patients (24 in group 1 and 27 in group 2). There was no difference in baseline characteristics between the treatment groups. At the end of phase I, mean LVEF was 60.7 +7.6% in group 1 versus 64.4 + 9.8% in group 2, and was < 45% in a single patient in each group (p = NS). At 60 months, LVEF was 58.6 + 8.1% in group 1 versus 56.0 + 15.5% in group 2 (p = NS). A single patient had an LVEF < 45% in group 1 versus eight patients in group 2 (p = 0.02).
CONCLUSIONS Early treatment with perindopril delayed the onset and progression of prominent left ventricle dysfunction in children with DMD.
05 - Mice deficient in plasminogen activator inhibitor-1 have improved skeletal muscle regeneration
02 - Prednisolone-induced changes in dystrophic skeletal muscle
02 - Adeno-associated virus serotype 8 efficiently delivers genes to muscle and heart
FEBRUARY - 2005
1) Characterization of PTC124 Activity, Specificity, and Mechanism of Action for Nonsense Mutation Suppression
2) PTC124 Nonsense Mutation Suppression Therapy of Duchenne Muscular Dystrophy (DMD)
3) Phase 1 Multiple-Dose Safety and PK Study of PTC124 for Nonsense Mutation Suppression Therapy of Duchenne Musuclar Dystrophy (DMD)
4) Deflazacort Treatment in DMD Symptomatic Carriers
5) Improved DEXA Methodology for Bone Mass Assessment in Boys with Duchenne Muscular Dystrophy
6) Full Length-Utrophin-Expressing Gutted Adenovirus as an Ideal Therapeutic Agent for Duchenne Muscular Dystrophy
7) Temporal and Spatial Expression Patterns of TGF-B1, 2, 3 and TGFBRI, II, III in Skeletal Muscles of Mdx Mice
8) Somatic Mosaicism in a DMD Carrier Detected by Use of Direct Sequence (SCAIP) Analysis
9) “Becker-Type” Dysferlinopathy
10) Regulation of the Utrophin Gene through the Use of Artificial Zinc Finger Proteins
12 - (IN PRESS: Journal of Virology, March 2005, p. 3146-3162, Vol. 79, No. 5 ):Transfer of the Full-Length Dystrophin-Coding Sequence into Muscle Cells by a Dual High-Capacity Hybrid Viral Vector with Site-Specific Integration Ability
Manuel A. F. V. Gonçalves, Gijsbert P. van Nierop,Marloes R. Tijssen, Pierre Lefesvre,Shoshan Knaän-Shanzer, Ietje van der Velde, Dirk W. van Bekkum,Dinko Valerio, and Antoine A. F. de Vries - The Netherlands
Duchenne muscular dystrophy (DMD) is caused by mutations in the DMD gene, making it a potential target for gene therapy. There is, however, a scarcity of vectors that can accommodate the 14-kb DMD cDNA and permanently genetically correct muscle tissue in vivo or proliferating myogenic progenitors in vitro for use in autologous transplantation. Here, a dual high-capacity adenovirus-adeno-associated virus (hcAd/AAV) vector with two full-length human dystrophin-coding sequences flanked by AAV integration-enhancing elements is presented. These vectors are generated from input linear monomeric DNA molecules consisting of the Ad origin of replication and packaging signal followed by the recently identified AAV DNA integration efficiency element (p5IEE), the transgene(s) of interest, and the AAV inverted terminal repeat (ITR). After infection of producer cells with a helper Ad vector, the Ad DNA replication machinery, in concert with the AAV ITR-dependent dimerization, leads to the assembly of vector genomes with a tail-to-tail configuration that are efficiently amplified and packaged into Ad capsids. These dual hcAd/AAV hybrid vectors were used to express the dystrophin-coding sequence in rat cardiomyocytes in vitro and to restore dystrophin synthesis in the muscle tissues of mdx mice in vivo. Introduction into human cells of chimeric genomes, which contain a structure reminiscent of AAV proviral DNA, resulted in AAV Rep-dependent targeted DNA integration into the AAVS1 locus on chromosome 19. Dual hcAd/AAV hybrid vectors may thus be particularly useful to develop safe treatment modalities for diseases such as DMD that rely on efficient transfer and stable expression of large genes.
09 - Muscle regeneration in the prolonged absence of myostatin
02- Wyeth Ayerst clinical trial (phase I) with MYO-029 (myostatin inhibitor) in FSHD, LGDM and BMD
02 - (IN PRESS: Neuromuscular Disorders, 2005): Autologous transplantation of porcine myogenic precursor cells in skeletal muscle
Nicolas Holzer, Simone Hogendoorn, Line Zu¨rcher, Guido Garavaglia, Sheng Yang, Stephane Konig, Thomas Laumonier, Jacques Menetrey - Switzerland
Abstract
Myoblast transplantation is a potential therapy for severe muscle trauma, myopathies and heart infarct. Success with this therapy relies on the ability to obtain cell preparations enriched in myogenic precursor cells and on their survival after transplantation. To define myoblast transplantation strategies applicable to patients, we used a large animal model, the pig. Muscle dissociation procedures adapted to porcine tissue gave high yields of cells containing at least 80% myogenic precursor cells. Autologous transplantation of 3[H]-thymidine labeled porcine myogenic precursor cells indicated 60% survival at day 1 followed by a decay to 10% at day 5 post-injection. Nuclei of myogenic precursor cells transduced with a lentivirus encoding the nls-lacZ reporter gene were present in host myotubes 8 days post-transplantation, indicating that injected myogenic precursor cells contribute to muscle regeneration. This work suggests that pig is an adequate large animal model for exploring myogenic precursor cells transplantation strategies applicable in patients.
JANUARY - 2005
29 - A Multidisciplinary Evaluation of the Effectiveness of Cyclosporine A in Dystrophic Mdx Mice
29 - (IN PRESS: Neuromuscular Disorders, 2005): Complications of anaesthesia in neuromuscular disorders
Werner Klingler, Frank Lehmann-Horn and Karin Jurkat-Rott - Germany
The purpose of this review is to alert non-anaesthesiologists to the various complications from which patients with neuromuscular disorders and those susceptible to malignant hyperthermia can suffer during anaesthesia. The patient's outcome correlates with the quality of consultation between anaesthesiologists, surgeons, neurologists and cardiologists. Special precautions must be taken, since many anaesthetics and muscle relaxants can aggravate the clinical features or trigger life-threatening reactions. Complications frequently occur in these patients, although anaesthetic procedures have become safer by the reduced administration of suxamethonium and the use of total intravenous anaesthesia, new volatile anaesthetics and non-depolarising relaxants. This review provides a synopsis of pre-operative anaesthetic considerations and adverse drug effects on skeletal, cardiac and smooth muscle tissue. It describes the pathogenetic aspects of typical complications and introduces anaesthetic procedures for the various neuromuscular disorders, including regional anaesthesia for patients in whom a restriction of respiratory and/or cardiac function is predicted.
29 - (IN PRESS: Am J Phys Med Rehabil 2005;84:83–88): Mechanical insufflation–exsufflation improves outcomes for neuromuscular disease patients with respiratory tract infections NEW
Abstract:
26 - (IN PRESS: FEBS Letters, 2005): α7B integrin changes in mdx mouse muscles after L-arginine administration NEW
Delphine Chazalette, Karim Hnia, François Rivier, Gérald Hugon and Dominique Mornet - France
Muscle fibers attach to laminin in the basal lamina using two mechanisms, i.e., dystrophin with its associated proteins and α7β1 integrin. In humans, gene-mutation defects in one member of these complexes result in muscular dystrophies. This study revealed changes after L-arginine treatment of utrophin-associated proteins and the α7B integrin subunit in mdx mouse, a dystrophin-deficient animal model. In the two studied muscles (cardiac muscle and diaphragm), the α7B integrin subunit was increased in 5-week-old treated mice. Interestingly, the diaphragm histopathological appearance was significantly improved by L-arginine administration. These results highlight a possible way to compensate for dystrophin deficiency via α7β1 integrin.
18 - Cardiac and Sternocleidomastoid Muscle Involvement in Duchenne Muscular Dystrophy: An MRI Study
15 - (IN PRESS: Neuromuscular Disorders, 2005): The function of Myostatin and strategies of Myostatin blockade—new hope for therapies aimed at promoting growth of skeletal muscle - REVIEW
Ketan Patel, Helge Amthor - UK
Abstract
Genetic deletion of Myostatin, a member of the Transforming Growth Factor-beta family of signalling molecules, resulted in excessive growth of skeletal muscle. It demonstrated the remarkable intrinsic growth potential of skeletal muscle and led to the proposal that growth stimulation could amend diseased muscle without having to correct the primary cause of the disease. Furthermore, the presence of Myostatin in skeletal muscle in a number of muscle diseases and disease models suggested that it aggravated the primary pathology. Inhibition of Myostatin activity in mdx mouse, the animal model for Duchenne muscular dystrophy, resulted in increased force production and better tissue architecture which implicated Myostatin as a target for new therapeutic strategies. In this review we will discuss the phenotypes of animal models in which Myostatin function is altered. We will highlight the particularities of the Myostatin signalling pathway and describe molecular strategies that have been developed to inhibit the function of Myostatin on muscle. Finally, we will summarise the role of Myostatin in diseased muscle and discuss blockade of Myostatin as a potential therapy for muscular dystrophies.
15 - Full article: Corticosteroid treatment of Duchenne dystrophy
15 - Altered long chain fatty acids composition in Duchenne muscular dystrophy erythrocytes
11 - (IN PRESS: Arch.Neurol.2005;62:128-32) Intermittent Prednisone Therapy in Duchenne Muscular Dystrophy - A Randomized Controlled Trial
Background Prednisone treatment is used to prolong ambulation in patients with Duchenne muscular dystrophy (DMD). However, since severe adverse effects often accompany prednisone treatment, it is debatable whether the benefits of prednisone treatment outweigh its adverse effects.
Objectives To study the effects of prednisone on muscle function and to determine the extent of steroid-related adverse effects and their influence on the quality of life of ambulant patients with DMD.
Design A randomized, placebo-controlled, crossover trial with 6 months of treatment: prednisone or placebo (0.75 mg/kg daily) during the first 10 days of each month. After a washout period of 2 months, patients received the other regimen for an additional 6 months.
Setting University hospital and rehabilitation center in the Netherlands.
Patients Seventeen ambulant patients with DMD aged 5 to 8 years.
Main Outcome Measure Change in muscle function assessed by timed functional testing: running 9 m, climbing 4 standard-sized stairs, and rising from the floor to a standing position.
Results The increase in time needed to run 9 m (P = .005) and to climb 4 standard-sized stairs (P = .02) was significantly lower during the prednisone period.
Conclusions Prednisone slowed deterioration of muscle function and muscle force in ambulant patients with DMD. Although adverse effects were present, patient quality of life was not affected. Therefore, short-term prednisone treatment can be recommended to preserve motor functions in ambulant patients with DMD.
10 - Practice Parameter: Corticosteroid treatment of Duchenne dystrophy - Report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society
CORTICOSTEROIDS FOR DUCHENNE MUSCULAR DYSTROPHY
10 - (IN PRESS: Neuromuscular Disorders 15 (2005) 80–85): Bone health in Duchenne muscular dystrophy: a workshop report from the meeting in Cincinnati, Ohio, July 8, 2004
W.D. Biggar, L.K. Bachrach, R.C. Henderson, H. Kalkwarf, H. Plotkin, B.L. Wong - Canada and USA
Summary and next steps
From the workshop discussions, there is general agreement that:
DMD is associated with reduced mobility.
Boys with DMD have an increased risk of fractures, particularly long bones.
DMD patients have reduced bone mineral density.
Corticosteroids may be associated with a further reduction in bone mineral density.
The bone mineral density Z- cannot be used to predict fracture risk, and it should not be used alone to make treatment decisions.
Corticosteroids may increase the risk of a vertebral compression fracture, many of which are asymptomatic.
Vitamin D and calcium contribute to bone health but have not been proven to reduce the risk of low-impact fractures.
The best sources of calcium and vitamin D are a balanced diet and sunshine.
It is recommended that boys with DMD have a serum vitamin D determined annually; supplementation is appropriate if the concentration is <20 ng/ml.
But, we need to determine:
How best to assess and monitor bone health.
The natural history of bone health in DMD.
Risk factors that predict the likelihood of a low-impact fracture.
The contribution of Vitamin D and calcium to bone health in DMD.
Potential interventions involving weight-bearing activities to maintain bone strength.
What strategies are effective in preventing and treating reduced bone mineral density.
How to develop multicenter, collaborative study groups in order to.
Collect standardized, clinical and laboratory data on boys with DMD, and
to collect clinical trials to improve bone health and quality of life for boys with DMD.
The previous article of this researchers and video of this previous study