News in Muscular Dystrophy

 

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DECEMBER/2003

 

BRAZILIAN RESEARCH CENTER - IMPORTANT INFORMATIONS

25/12/03: Christmas gift: Youngest artificial patient survives  

24/12/03: Negamycin Restores Dystrophin Expression in Skeletal and Cardiac Muscles of mdx Mice  

22/12/03: News Conference - Teen-age Patient at UMC is Youngest in World to be Placed on Total Artificial Heart  

20/12/03: NZ scientists looking at potential to 'repair' heart muscles  

19/12/03: Stimulation of calcineurin signaling attenuates the dystrophic pathology in mdx mice

19/12/03: Antisense-Induced Multiexon Skipping for Duchenne Muscular Dystrophy Makes More Sense

19/12/03: Stem cell therapy for muscular dystrophy

16/12/03: Therapeutics for Duchenne muscular dystrophy: current approaches and future directions

16/12/03: Muscle-derived stem cells: potential for muscle regeneration.

06/12/03: NaPro Awarded Phase I SBIR Grant for Research on Muscular Dystrophy

03/12/03: Doctor claims DNA treatment for Duchenne muscular dystrophy

NOVEMBER/2003

26/11/03: Blood loss during posterior spinal fusion surgery in patients with neuromuscular disease: is there an increased risk?.

EDLER, ALICE MD, MA (EDUC) ; MURRAY, DAVID J. MD ; FORBES, ROBERT B. MD 

 Paediatric Anaesthesia. 13(9):818-822, November 2003. 

Abstract Background: Scoliosis surgery in paediatric patients can carry significant morbidity associated with intraoperative blood loss and the resultant transfusion therapy. Patients with neuromuscular disease may be at an increased risk for this intraoperative blood loss, but it is unclear if this is because of direct vascular pathophysiological changes or the fact that neuromuscular patients typically have more extensive orthopaedic disease and more vertebral segments involved. This study examined the risk of extensive blood loss (>50% of total blood volume) in patients with neuromuscular disease compared with patients who did not have neuromuscular disease when the extent of the surgery (number of segments fused), age and preoperative coagulation profile where taken into consideration.

Methods: Retrospective chart review of 163 paediatric patients was preformed. Patients who carried a diagnosis of preexisting neuromuscular disease were classified as such. Idiopathic, traumatic and iatrogenic scoliosis were classified as nonneuromuscular. Extensive blood loss was defined as >50% of estimated total blood volume. Logistic regression was used to predict the risk of extensive blood loss between the two groups when age, weight, extent of surgery was controlled for and anaesthetic and surgical techniques remained similar.

Results: Patients with neuromuscular disease did not vary significantly in age, weight, or preoperative haematocrit and platelet count from patients without neuromuscular disease. Neuromuscular patients did have significantly more vertebral segments fused. When this difference was controlled for statistically, neuromuscular patients had an almost seven times higher risk (adjusted odds ration 6.9, P < 0.05) of losing >50% of their estimated total blood volume during scoliosis surgery.

Conclusions: Patients with neuromuscular disease can present various anaesthetic challenges during scoliosis surgery, among these is the inherent risk of extensive blood loss. Recognizing this may help anaesthesiologists and surgeons more accurately prepare for and treat intraoperative blood loss during scoliosis surgery in patients with neuromuscular disease.

26/11/03: Myocardial cell damage in Duchenne muscular dystrophy

23/11/03: There's No Muscle in Some Supplements

22/11/03 (IN PRESS: Neuromuscular Disorders): A-utrophin up-regulation in mdx skeletal muscle is independent of regeneration

Andrew P. Weir, Jennifer E. Morgan, Kay E. Davies

Abstract

Duchenne muscular dystrophy is a fatal childhood disease caused by mutations that abolish the expression of dystrophin in muscle. Utrophin is a paralogue of dystrophin and can functionally replace it in skeletal muscle. A method to induce utrophin up-regulation in muscle should therefore be therapeutically useful in Duchenne muscular dystrophy. The search for such a method needs to be informed by an understanding of the mechanisms controlling utrophin expression in muscle. Two full length utrophin isoforms are expressed: A and B. A-utrophin is up-regulated in dystrophin deficient skeletal muscle and we sought to test the hypothesis that this up-regulation occurs as a consequence of ongoing regeneration. We measured utrophin expression by immunohistochemistry and immunoblotting in the oesophageal outer muscular layer and in g-irradiated limb muscle from mdx mice. Skeletal muscle in these tissues is dystrophin deficient but not regenerating; we found that A-utrophin up-regulation still occurred. We conclude that utrophin up-regulation in skeletal muscle does not depend on regeneration. An alternative hypothesis involving competition for binding sites between utrophin and dystrophin is discussed. These results have important implications for future studies aiming to effect therapeutic utrophin up-regulation in Duchenne muscular dystrophy patients.

22/11/03: UBC researcher makes heart repair breakthrough - Adult stem cells could heal damaged muscle in heart attack victims

"Given that, it is possible, Rossi says, that they also could be used to artificially regenerate damaged muscle tissue in heart attack patients and people with diabetes or muscular dystrophy"

"Even if we were lucky and our first strategy to make them work well worked, by the time all the controls and clinical trials were done, it would take 10 years," Rossi, a member of UBC's Biomedical Research Centre

19/11/03: Stem Cells Can Regenerate Muscle  

Single hematopoietic stem cells generate skeletal muscle through myeloid intermediates

Contribution of hematopoietic stem cells to skeletal muscle

19/11/03: Measurement of skeletal muscle mass in Duchenne muscular dystrophy: use of 24-h creatinine excretion  

12/11/03: Abstracts from American Heart Association Scientific Sessions 2003, Orlando, 9-12 november 2003  

Perindopril Prevents the Onset and Progression of Left Ventricular Dysfunction in Children with Duchenne Muscular Dystrophy

Henri-Marc Becana, Pitie-Salpetriere Hospital, Paris, France; Christophe Meune, Cochin Hospital, Paris, France; Guy Lerebours, Pitie-Salpetriere Hospital, Paris, France; Jean-Yves Devaux, Denis Duboc, Cochin Hospital, Paris, France; The French Working Group on Heart Involvement in Myopathies

Background: Duchenne Muscular disease (DMD) is an inherited X-linked disease due to the absence of dystrophin and clinically characterized by progressive muscle weakness and constant myocardial involvement responsible for sudden death or end-stage heart failure in 40% of patients between the age of 15 and 30. The aim of this study was to evaluate the preventive effect of early ACEI treatment on left ventricular (LV) dysfunction in young patients with DMD and normal LVEF at inclusion. Methods: In phase I, children with genetically proven DMD and radionuclide ejection fraction (EF) superior than 55% were enrolled in a multicentric, controlled, randomized, double blind trial of perindopril 2-4 mg/day versus placebo for 3 years. In phase II, all patients then received open-label perindopril for 24 more months. Radionuclide LVEF was performed at 0, 36 and 60 months. Student's t-tests and chi-square analysis were used for comparisons. Results: 60 children asymptomatic for heart disease were included in the phase I study (10.6±1.2 years, EF 65.0±5.4%)(31 in the perindropil group and 29 in the placebo group) and 46 in the phase II study (n=23 in both groups). No adverse effect related to treatment was documented. At the end of phase I, LVEF remained stable in both groups (from 64.8±5.3% to 59.6±8.5% in the perindopril group and 65.5±5.4% to 64.5±9.9% in the placebo group, p=0.114). However, at 60 months, 6 patients in the control group (26%) had a LVEF of less than 45, versus one in the perindopril group (4%)(p=0.0319). Conclusions: Early treatment with ACEI perindopril is well tolerated in these young patients and delay onset of LVEF deterioration. This preventive efficacy of ACEI has to be evaluated in other groups of patients genetically exposed to develop LV dysfunction.

Impaired Strain Rate Measurements in Patients With Duchenne Muscular Dystrophy

Nickolaos Giatrakos, Cardiology dept, Hammersmith Hospital, NHLI, ICSM, London, United Kingdom; Maria Kinali, Dubowitz Neuromuscular Centre, Department of Paediatrics, Hammersmith Hospital, ICSM, London, UK, London, United Kingdom; George Koutroulis, Cardiology dept, Hammersmith Hospital, NHLI, ICSM, London, United Kingdom; Francesco Muntoni, Dubowitz Neuromuscular Centre, Department of Paediatrics, Hammersmith Hospital, ICSM, London, UK, London, United Kingdom; Petros Nihoyannopoulos; Cardiology dept, Hammersmith Hospital, NHLI, ICSM, London, United Kingdom

Background: Patients with Duchenne muscular dystrophy (DMD) develop dilated cardiomyopathy at the later stages of the disease. Strain rate (SR) has been used to study myocardial function in ischeamia and cardiomyopathies. The aim of this study was to investigate the usefulness of SR for the early detection of cardiac involvement in young, asymptomatic patients with DMD.
Methods: We studied 53 patients with genetically confirmed diagnosis of DMD (mean age 8.7±2.8 years) without clinical symptoms from the cardiovascular system and normal conventional echocardiographic studies, and compared with 22 normal controls matched for age (mean age 8.5±2.5 years). We used the HDI 5000 (Philips Medical Systems) to acquire from the parasternal long axis the colour M-mode tissue Doppler (TDI) of the posterior wall of the LV. Images were digitally stored for offline analysis with dedicated software HDI-lab (Philips Medical Systems). We calculated the SR using the formula SR=Ua-Ub/d where U the velocities of the endocardium a and epicardium b, and d the distance of a and b at each time point.
Results: There was no significant difference for the parameters from conventional echocardiographic studies between the two groups. The velocities derived from the TDI, mean velocity at systole (26,99±7,12mm/sec vs. 33,4±7,3mm/sec, p<0,000), at early diastole (-45,79±13,93mm/sec vs.-60,46±7,58mm/sec, p<0,000) and late diastole (-10,93±3,41mm/sec vs.-13,32±6,4mm/sec, p<0,02) were significantly different in patients with DMD when compared with controls. SR was found to be significantly lower at systole (1,78±0,75s-1 vs. 2,82±0,5s-1, p<0,000) and early diastole (-5,17±1,98s-1 vs.-9,02±1,25s-1, p<0,000) but not at late diastole (-1,52±0,84s-1vs.-1.6±0,46s-1, p<0,568) in patients with DMD.
Conclusions: Estimation of SR of the posterior wall of the LV showed systolic and diastolic dysfunction at early stages in asymptomatic patients with DMD and when the conventional echocardiography is still normal. Estimation of SR could be a sensitive method to investigate the pathophysiology of the disease and identify early impairment of the cardiac function.

09/11/03: Abstracts from 43rd Annual Meeting The American Society for Cell Biology  - California,  13-17 december, 2003 NEW 

Negamycin restores dystrophin expression in skeletal and cardiac muscles of mdx mice
M. SHIOZUKA,1 M. ARAKAWA,1 Y. NAKAYAMA,2 T. HARA,2 M. HAMADA,3 D. IKEDA,3 Y. TAKAHASHI,3 R. SAWA,3 Y. NONOMURA,3 K. SHEYKHOLESLAMI,4 K. KONDO,4 K. KAGA,4 S. TAKEDA,5 R. MATSUDA1 ; 1 Dept. of Life Sciences, The University of Tokyo, Tokyo, Japan, 2 Dept. of Tumor Biochemistry, Tokyo Metropolitan Institute of Medical Sciences, Tokyo, Japan, 3 The Institute of Microbial Chemistry, Tokyo, Japan, 4 Dept. of Otolaryngology, The University of Tokyo, Tokyo, Japan, 5 Dept. of Molecular Therapy, National Institute of Neuroscience, Tokyo, Japan

 The ability of aminoglycoside antibiotics to promote read-through of nonsense mutations has attracted interests in these drugs as potential therapeutic agents in genetic diseases. However, strong toxicity of aminoglycoside antibiotics may cause severe side effects during long-term treatment. In this study, we report that negamycin, a dipeptide antibiotic, also restores dystrophin expression in skeletal and cardiac muscles of mdx mouse; an animal model of Duchenne muscular dystrophy (DMD) with a nonsense mutation in dystrophin gene, and in cultured mdx myotubes. Dystrophin expression was confirmed by immunohistochemistry and immunoblotting. We also compared the toxicity of negamycin and gentamicin, and found negamycin to be less toxic. Furthermore, we demonstrated that negamycin bound to a partial sequence decording the eukaryotic rRNA A-site. We conclude that negamycin is a promising new candidate for chemotherapy for DMD and other genetic diseases caused by nonsense mutations.

 Calcineurin-Induced Upregulation of Utrophin Attenuates the Dystrophic Pathology in mdx Mouse Muscle
J. V. Chakkalakal,1 M. Harrison,2 E. R. Chin,3 R. N. Michel,2 B. J. Jasmin1 ; 1 Cellular & Molecular Medicine, University of Ottawa, Ottawa, ON, Canada, 2 Neuromuscular Lab, Laurentian University, Sudbury, ON, Canada, 3 Cardiovascular and Metabolic Diseases, Pfizer Global Research and Development, Groton, CT

 We recently showed that mice expressing a constitutively active form of calcineurin (CnA*) have elevated levels of utrophin A in their muscles (Proc. Natl. Acad. Sci. USA, 100: 7791-7796, 2003). In the present study, we crossed these transgenic animals with mdx mice to determine whether mdx/CnA* mice would be less affected by the dystrophic process. Since expression of CnA* has been shown previously to stimulate the slow/oxidative myofiber program, we examined the expression of myosin heavy chain isoforms in mdx/CnA* and mdx mice. By immunofluorecence and RT-PCR assays, we observed in mdx/CnA* a shift in myosin heavy chain profile towards a slower, more oxidative phenotype compared to mdx muscles. In addition, we determined that expression of utrophin A and its transcript were increased by ~ 2 fold in mdx/CnA* mouse muscles. Immunodetection of IgM inside myofibers, used in this case as an index of sarcolemmal disruption, showed that the number of IgM-positive fibers was significantly reduced in muscles from mdx/CnA* mice. Consistent with these findings, we also observed that muscles from mdx/CnA* mice showed less variability in fiber size and contained fewer central nuclei. Together, these results demonstrate that enhanced calcineurin activity can have important beneficial effects on the dystrophic phenotype by stimulating the expression of utrophin A. Furthermore, these findings provide specific targets for which pharmacological strategies may be designed to enhance utrophin levels in muscles from patients with Duchenne muscular dystrophy. Funded by the MDA and CIHR.

08/11/03: Mini-dystrophin restores l-type calcium currents in skeletal muscle of transgenic mdx mice

08/11/03: Sulfated polysaccharides of brown seaweed Cystoseira canariensis bind to serum myostatin protein

08/11/03: Effect of dietary protein on calpastatin in canine skeletal muscle

01/11/03: Lentivector-mediated transfer of bmi-1 and telomerase in muscle satellite cells yields a duchenne myoblast cell line with long-term genotypic and phenotypic stability

01/11/03: Dystrophin Delivery in Dystrophin-Deficient DMD(mdx) Skeletal Muscle by Isogenic Muscle-Derived Stem Cell Transplantation

01/11/03: Correction of the dystrophic phenotype by in vivo targeting of muscle progenitor cells

01/11/03: Long-term noninvasive ventilation in children and adolescents with neuromuscular disorders

01/11/03: Creatine Supplements May Improve Muscle Strength in Young Children With DMD NEW - from http://www.medscape.com/viewarticle/463365

Young children with Duchenne muscular dystrophy (DMD) show improved muscle strength and functional status and evidence of a slowing of disease progression with creatine supplements, researchers reported at the 128th annual meeting of the American Neurological Association.

A study of 60 children with DMD between the ages of five and nine years was conducted, based on studies of animal models of DMD that showed that glutamine and creatine supplementation prevented loss of muscle strength compared with prednisone.

Lead investigator Diana M. Escolar, MD, from the Children's National Medical Center at George Washington University in Washington, D.C., and the Cooperative International Neuromuscular Research Group, randomized the children to one of three arms: creatine 5 g daily plus placebo twice daily, glutamine 0.3 mg/kg daily plus placebo twice daily, or placebo twice daily alone. Dr. Escolar noted that the investigators were comparing creatine versus placebo and glutamine versus placebo, but not creatine versus glutamine.

The primary outcome measure was manual muscle strength (MMT, 34 muscle groups) and the secondary outcome measure was quantitative muscle strength (QMT, seven muscle groups), which measured functional status using various physical activities.

"We found very different outcomes in the 30 children in the younger age group [between the ages of five and seven years] and the 30 children in the older group [between the ages of seven and nine years] on the primary outcome measure," Dr. Escolar told Medscape.

In the six-month study, MMT scores did not significantly differ between the three groups of the study, Dr. Escolar reported. But on QMT scores, children in the placebo group showed more deterioration in muscle strength compared with children in the two treatment groups. Children randomized to creatine showed a lesser degree of deterioration than children receiving glutamine. Children in the younger age group scored higher on measures of functionality such as standing, climbing, and running than the older children receiving creatine.

"I have a theory to explain this," Dr. Escolar said. "These compounds improve muscle energy. Younger kids have muscles that respond more to an increase in energy than older kids.... They don't need more strength, they just need more energy. For the older kids, an increase in strength translates to an increase in functionality." Dr. Escolar said it is possible that the energy supplements may even slow the progression of DMD.

While she stressed that there was only a trend toward increased functionality in the younger children rather than a statistically strong outcome, she pointed out that creatine and glutamine have very minimal adverse effects. "If parents want to go out and buy these supplements, I wouldn't care if they do," Dr. Escolar asserted.

ANA 128th Annual Meeting: Poster WIP7. Presented Oct. 21, 2003.

OCTOBER/2003

20/10/03: Possible Gene Therapy for Muscular Dystrophy - Researchers report success using novel technique to deliver missing gene  


18/10/03: Abstracts from Neuroscience 2003, the Society for Neuroscience 33rd Annual Meeting, New Orleans, November 8 - 12, 2003

1) C. Zhang, S. Chen, Y. Xie, W. Huang, S. Li, W. Zhang, Q. Li, X. Liu. THERAPEUTIC EFFECT OF DUCHENNE MUSCULAR DYSTROPHY MICE WITH BONE MARROW STEM CELLS TRANSPLANTATION. Program No. 413.9. 2003

Objective: To investigate the locomotive function, electronic physiology changes, and expression of dystrophin in Duchenne muscular dystrophy mice(mdx and dko) with bone marrow stem cells transplantation.
Methods: The bone marrow stem cells of C57BL/6
4-to-5 weeks agewere isolated and cultured in vitro for 3 days, then the stem cells about 5.0X106 injected intravenously into the mdx mice and dko mic7-to-8 weeks age, respectively. Before injecting, 10 mdx mice and 10 dko mice were preconditioned with 7 Gy gamma ray to decrease the immune reaction. The clinical features of the graft verse host disease (GVHD). in the transplanted mice were assessed and investigated after bone marrow stem cell transplatation..12 weeks after being transplanted, the locomotion function, muscle electrophysiologic features(EMG) and dystrophin expression of the mdx mice and dko mice were investigated..
Results: Three month after bone marrow stem cells transplanting, we find that (1) there were more than 10% of muscle cells expression dystrophin protein in each transplanted mice(mdx and dko); (2) the electromyography showed almost normal waves in the transplantation mdx mice and dko mice; (3)the locomotive function improved obviously in transplantation dko mice; (4)the life span of the transplantation dko mice were more than 200 days( the life span of control of dko mice were less than 140 days).
Conclusions: Allogenic bone marrow stem cells transplantation can improve the electromyographic items, dystrophin expression in muscles of mdx and dko mice. Further more, the stem cell transplantation can improve the locomotive function and prolong the life span of dko mice.

2) Y. Zhu, B. Chen, H. Gong, J. Pan, W. Zhang. EXPRESSION OF TRANSFERRIN RECEPTOR IN DUCHENNE MUSCULAR DYSTROPHY TISSUES. Program No. 80.2. 2003

Duchenne muscular dystrophy (DMD) is an X-linked, fatal disease caused by mutations of the gene encoding the cytoskeletal protein dystrophin. Skeletal muscle of DMD patients is characterized by an ongoing process of degeneration and regeneration. Transferrin receptor (TfR, CD71), an integral membrane glycoprotein, mediates cellular uptake of iron. In most tissues, TfR expression is correlated positively with proliferation and regulated at the post-transcriptional level. To determine if TfR is involved in muscular regeneration in DMD patients, we examined the expression of TfR in muscle samples of 42 patients with DMD, and 10 from normal volunteers. Immunohistochemical staining of TfR was positive with variable intensity in normal control and DMD patients. In normal control, TfR was faintly expressed on the surface of muscle fibers. In DMD patients, strong TfR reaction was detected. In some muscular fibers from DMD patients, TfR was found strongly expressed inside the fibers. Further detection with Enzyme histochemistry and acridine orange (AO) fluorescence techniques showed that these fibers with strong TfR expression were regenerative IIc type fibers. The increase of TfR expression in regenerative fibers suggests that the high uptake of iron may promote the capacity of muscle regeneration and thus may delay the deterioration of DMD patients.

3) C.G. Carlson. STEADY STATE CALCIUM AND RESTING CALCIUM INFLUX IN NONDYSTROPHIC AND MDX MYOTUBES EXPOSED TO PREDNISONE OR PREDNISOLONE. Program No. 413.10. 2003

Certain glucorticoids, such as prednisone, prednisolone and deflazacort, increase muscle strength and slow the progress of Duchenne muscular dystrophy (Fenichel et al., Neurology, 41, 1874, 1991) by one or more mechanisms that have not yet been fully characterized. Evidence from 45calcium uptake studies in the C2C12 muscle cell line suggests that one mechanism may involve decreases in calcium influx following one or more days of exposure to these agents beginning at the period of myoblast fusion (Passaquin et al., Brit. J. of Pharmacol., 1998). Recent evidence from this laboratory obtained in FURA-loaded cultured lens epithelial cells indicates that some steroids, however, may induce very rapid (seconds to minutes) effects on resting calcium influx measured by the manganese quench technique (Samadi et al., Pfluegers Arch. Europ. J. Physiol.,444, 700-709, 2002). To determine whether glucorticoids exert a unique action on resting calcium influx in dystrophic muscle, studies have begun to characterize any acute, nongenomic effects of prednisone or prednisolone on steady state calcium levels and resting calcium influx in cultured nondystrophic and mdx myotubes. Initial results indicate that neither prednisone (10 microM, 100 microM) nor prednisolone (100 microM) has immediate effects on steady state calcium levels in nondystrophic myotubes, but that prednisolone may induce a slight decrease in manganese quench rate in mdx myotubes at relatively early stages in culture (culture day 12-14). These results further demonstrate the utility of the manganese quench technique in assessing whether short or long term exposure to glucorticoids induces a beneficial reduction in resting calcium influx in dystrophic skeletal muscle.

18/10/03: Study: 'Bubble boy' gene therapy caused cancer

15/10/03: Patients with severe muscle wasting are prone to develop hypoglycemia during fasting  

14/10/03: NIH, MDA ANNOUNCE THREE TOP MUSCULAR DYSTROPHY RESEARCH CENTERS

11/10/03: Xenotransplantation of embryonic precursors of human myogenesis for the correction of dystrophinopathy in mice with hereditary muscular dystrophy

10/10/03:CONFERENCE REPORT: CARDIOMYOPATHY IN MUSCULAR DYSTROPHY

04/10/03: Adeno-associated virus vector carrying human minidystrophin gene SMCKA3999 effectively ameliorates dystrophic pathology in mdx model mice  

04/10/03: ADVANCES IN DUCHENNE MUSCULAR DYSTROPHY GENE THERAPY

full text

04/10/03: Genetics and nutrition

04/10/03: Effect of intrapulmonary percussive ventilation on mucus clearance in duchenne muscular dystrophy patients: a preliminary report  

 

SEPTEMBER/2003

26/09/03: Proteasome Inhibitor (MG-132) Treatment of mdx Mice Rescues the Expression and Membrane Localization of Dystrophin and Dystrophin-Associated Proteins

23/09/03: Cardiomyopathy in muscular dystrophies

20/09/03: Exercise in Neuromuscular Disease

Lisa S. Krivickas, MD (Spaulding Rehabilitation Hospital, Boston, Massachusetts)

J Clin Neuromusc Dis 2003;5:29–39

Abstract

In the past, patients with neuromuscular diseases were advised not to exercise because of the fear that too much exercise might produce "overuse weakness." No controlled studies have demonstrated that the phenomenon of overuse weakness actually exists. Most studies of exercise training in patients with neuromuscular disease, despite methodologic limitations, suggest that strength and aerobic capacity gains can occur in patients with slowly progressive disorders. Four forms of exercise training are relevant to patients with neuromuscular disorders: flexibility, strengthening, aerobic, and balance exercises. The literature regarding these forms of exercise in patients with neuromuscular disorders is summarized in this article, and recommendations are made regarding the direction future research on exercise in this population should take.

20/09/03: Irradiation of dystrophic host tissue prior to myoblast transfer therapy enhances initial (but not long-term) survival of donor myoblasts

20/09/03: Adult stem cell specification by wnt signaling in muscle regeneration

15/09/03: Use of Alendronate to treat osteoporosis in boys with muscular dystrophy: a report of 3 cases.

Susan D. Apkon, MD (Children's Hospital and University of Colorado Health Sciences Center, Denver, CO), e-mail: [email protected]

Archives of Physical Medicine and Rehabilitation - 2003 Academy annual assembly abstracts

Setting: Tertiary care pediatric hospital. Patients: 2 boys with Duchenne’s muscular dystrophy (DMD), ages 11 and 12 years, and 1 boy with Becker’s muscular dystrophy (BMD), age 11 years. All boys are ambulatory for a portion of the day. Case Descriptions: Baseline bone mineral density of the lumbar spine and femoral neck were assessed using dual-energy x-ray absorptiometry (DXA). Results revealed significant osteoporosis at the femoral neck, with a mean z score (SD using ageand sex-matched peers) of –3.73 (range, –3.16 to –4.42). Results at lumbar spine revealed mean z score of –1.14 (range, –1.6 to 0.82). Because all subjects were having frequent falls, parents and physicians felt aggressive treatment was necessary to prevent fractures. Oral alendronate was initiated at 45mg weekly for 6 months. Assessment/Results: All 3 subjects tolerated the medication without side effects. There were no gastrointestinal complaints. Follow-up DXAs performed after 6 months of treatment revealed improvements at the femoral neck in all 3 subjects, with a mean improvement in z score of 0.94 (range, 0.3–1.33) representing an improvement of almost 1 SD. There was improvement at the lumbar spine, with a mean change of 0.28 (range, –0.45 to 1.11). Discussion: Osteoporosis is problematic in boys with DMD and becomes more severe as the disease progresses. The high incidence of fractures in this group of boys is likely due to osteoporosis. This is the first known report on the use of alendronate in children with DMD or BMD in the treatment of osteoporosis. Conclusion: In this small case series, weekly oral alendronate over 6 months was effective in improving bone mineral density in boys with DMD and BMD. A prospective, randomized, double-blinded study is underway.

11/09/03: Gentamicin administration in Duchenne patients with premature stop codon. Preliminary results  

11/09/03: Parental stress in mothers of boys with duchenne muscular dystrophy

10/09/03:(Article in Press: Neuromuscular Disorders - 2003) Detection of glucocorticoid-like activity in traditional Chinese medicine used for the treatment of Duchenne muscular dystrophy

Isabelle Courdier-Fruh, Lee Barman, Philipp Wettstein, Thomas Meier

Abstract

Anecdotal reports of positive influence of certain traditional Chinese medicines on the progression of neuromuscular diseases in general and Duchenne muscular dystrophy (DMD) in particular has raised interest in patient support groups and clinical experts alike. However, clinical signs of steroid-specific side effects in patients treated with a particular form of Chinese medicine raised the concern that they may contain glucocorticoids, which in turn could also explain the mild beneficial effects seen in some of the patients. We have extracted and fractionated capsules containing pulverized Chinese medicine that had been used for the treatment of DMD patients and analyzed their content for glucocorticoid-like activity using promoter–reporter assays. We demonstrate that extracts from this Chinese medicine activate a prototype glucocorticoid-response element, increase the level of utrophin protein in human muscle cells and activate the utrophin promoter A. Based on our bioassays we conclude that this particular Chinese medicine used for the treatment of muscular dystrophy patients contains glucocorticoids as one of its active ingredients.

10/09/03: Efficient and long-term intracardiac gene transfer in delta-sarcoglycan-deficiency hamster by adeno-associated virus-2 vectors

08/09/03: (Article in Press: Neuromuscular Disorders - 2003) Looking under every rock: Duchenne muscular dystrophy and traditional Chinese medicine

J. Andoni Urtizbereaa, Qi-Shi Fan, Elizabeth Vroom, Dominique Recan, Jean-Claude Kaplan

Abstract

Traditional Chinese medicine has been advocated to alleviate symptoms in Duchenne muscular dystrophy. To investigate this hypothesis, a pilot study was carried out in Beijing on 10 DMD boys treated with various regimens, including pills, decoctions, massages and acupuncture at various stages of their disease course. Despite the limited scientific impact of such a study, it seems as if the benefit, if any, is minimal. Moreover, some indirect clinical clues such as the cushingoid appearance found in a few patients suggest these drugs may also contain corticosteroids to some extent.

08/09/03: (Article in Press: Neuromuscular Disorders - 2003) The Duchenne muscular dystrophy population in Denmark, 1977–2001: prevalence, incidence and survival in relation to the introduction of ventilator use

J. Jeppesen, A. Green, B.F. Steffensen, J. Rahbek

Abstract

Mechanical ventilation of patients with Duchenne muscular dystrophy continues to be a subject of study. The purpose was to estimate prevalence, incidence, mortality and use of mechanical ventilation in the total Duchenne muscular dystrophy population in Denmark between 1977 and 2001 and further, to reconstruct the introduction of mechanical ventilation to assess the role of the patient organization. Study objects were collected from five sources and verifiable cases identified. Negotiations between health authorities and the patient organization constituted main empirical data for the reconstruction. While overall incidence remained stable at 2.0 per 105, prevalence rose from 3.1 to 5.5 per 105, mortality fell from 4.7 to 2.6 per 100 years at risk and prevalence of Duchenne muscular dystrophy ventilator users rose from 0.9 to 43.4 per 100. We conclude that survival of Duchenne muscular dystrophy patients has increased and ventilator use is probably a main reason. The patient organization exercised a key role but acted upon preconditions created by other players.

08/09/03: (Article in Press: Molecular Brain Research - 2003 Dystrophin antisense oligonucleotides decrease expression of nNOS in human neurons 

Valeria Sogos, Camilla Reali, Veronica Fanni, Monica Curto, Fulvia Gremo

Department of Cytomorphology, School of Medicine, Cittadella Universitaria, SS 554 Bivio Sestu, 09042, Monserrato (CA), Italy

Abstract

Nitric oxide (NO) plays an important role in the pathogenesis of neurodegenerative disease. It has been shown that neuronal NO synthase (nNOS), the enzyme that constitutively produces NO in brain, is a component of the dystrophin-associated protein complex. The absence of dystrophin causes Duchenne muscular dystrophy. Thus, we attempted to study whether or not a decrease of dystrophin expression would induce a modification in nNOS expression in cultured human neurons. Human fetal neuronal cultures were treated with antisense oligonucleotides against different isoforms of dystrophin and the expression of nNOS tested by RT-PCR and immunocytochemistry. Results showed that nNOS mRNAwas significantly decreased by about 35% in neurons treated with brain-specific dystrophin (brain Dp427) antisense, whereas iNOS expression was not affected. Accordingly, a decrease in immunostaining for nNOS was observed in antisense treated neurons compared to controls. Expression of neuronal markers, such as bFGF or synaptophysin, was not affected by the same antisense treatment. Astrocytes were not affected by treatment, as shown by utrophin expression, a dystrophin-like protein that was not modified in pure astrocytic cultures. Thus, we conclude that a decrease of dystrophin in human neurons is associated with a decrease of nNOS expression.

06/09/03: The new frontier in muscular dystrophy research: booster genes

02/09/03: Microdystrophin Gene Therapy of Cardiomyopathy Restores Dystrophin-Glycoprotein Complex and Improves Sarcolemma Integrity in the Mdx Mouse Heart

Shrunken Gene Package Corrects Muscular Dystrophy

02/09/2003: Platelet-derived growth factor and its receptors are related to the progression of human muscular dystrophy: an immunohistochemical study

AUGUST/2003

27/08/03 (Article in Press): Enhanced in vivo delivery of antisense oligonucleotides to restore dystrophin expression in adult mdx mouse muscle.

K.E. Wells;, S. Fletcher, C.J. Mann, S.D. Wilton, D.J. Wells - Australia

FEBS Letters 27592 (2003):1-5

Abstract: The use of antisense oligonucleotides (AOs) to induce  exon skipping leading to generation of an in-frame dystrophin protein product could be of benefit in around 70% of Duchenne muscular dystrophy patients. We describe the use of hyaluronidase enhanced electrotransfer to deliver uncomplexed 2P-O- methyl modified phosphorothioate AO to adult dystrophic mouse muscle, resulting in dystrophin expression in 20-30% of fibres in tibialis anterior muscle after a single injection. Although expression was transient, many of the corrected fibres initially showed levels of dystrophin expression well above the 20% of endogenous previously shown to be necessary for phenotypic correction of the dystrophic phenotype.

26/08/03: Improvement of muscle healing through enhancement of muscle regeneration and prevention of fibrosis

26/08/03: Skeletal muscle disorders associated with selenium deficiency in humans

26/08/03: Antioxidant dietary deficiency induces caspase activation in chick skeletal muscle cells

21/08/03: Ventilatory dysfunction in mdx mice: Impact of tumor necrosis factor-alpha deletion

18/08/03: Body composition and energy expenditure in Duchenne muscular dystrophy

European Journal of Clinical Nutrition. 57(2):273-278, February 2003

Abstract
Objective: To investigate the relationship between resting energy expenditure (REE) and body composition in Duchenne Muscular Dystrophy (DMD).
Design: An observational study.
Setting: University Research Centre.
Subjects: Nine Duchenne children (age range 6-12 y), mean relative weight 128%, agreed to undergo the investigation and all of them completed the study;
Interventions: Assessment of body composition (total body fat and skeletal muscle mass) by magnetic resonance imaging and resting energy expenditure by indirect calorimetry.
Main outcome measures: Fat mass (FM; kg and percentage weight), fat-free mass (FFM; kg and percentage weight), muscle mass (kg and percentage weight), resting energy expenditure (kJ/kg body weight and kJ/kg fat-free mass).
Results: In Duchenne children fat mass averages 32% and total skeletal muscle mass 20% of body weight. Resting energy expenditure per kg of body weight falls within the normal range for children of the same age range, while when expressed per kg of FFM is significantly higher than reference values. No relationship was found between REE and total skeletal muscle mass.
Conclusions: Our results do not demonstrate a low REE in DMD boys; on the contrary REE per kg of FFM is higher than normal, probably due to the altered FFM composition. We suggest that the development of obesity in DMD children is not primarily due to a low REE but to other causes such as a reduction in physical activity and or overfeeding.

13/08/03: The inflammatory response: friend or enemy for muscle injury?

Muscle injury can occur through diverse mechanisms such as mechanical injury, muscular dystrophies, infectious diseases, and biochemical toxicities. Several types of skeletal muscle injury fall into the broad category of sport and exercise induced muscle injury. When exercise involves eccentric muscular contractions, it is associated with overloading of the contractile elements and connective tissues—that is, the force requirement of the muscle exceeds the habitual requirements—and can result in injury to skeletal muscle. It has traditionally been felt that the events following the initial injury, including inflammation, are necessary for optimal repair. Conclusion: Neutrophils and macrophages play a role in muscle damage after repeated eccentric exercise and acute stretch injury. However, contrary to conventional thinking, it is possible that certain aspects of neutrophil function cause damage to healing muscle or delay its regenerative capabilities. Because neutrophils can release oxygen free radicals during phagocytosis, it is possible that neutrophil derived oxidants exacerbate pre-existing muscle injury in vivo by damaging previously uninjured muscle. These findings suggest the possibility that innovative treatment strategies directed at specific functions of the neutrophil are theoretically possible to improve recovery from muscle injury. Pharmacological intervention may be better targeted against specific aspects of neutrophil function such as free radical production, while maintaining the steps necessary for phagocytosis and removal of cellular debris. This possibility is being investigated.

13/08/03: Compensation for dystrophin-deficiency: ADAM12 overexpression in skeletal muscle results in increased alfa 7 integrin, utrophin, and associated glycoproteins

13/08/03: ViaCell obtains license to preserve unfertilized human eggs

13/08/03: Scientists Create Britain's First Stem Cell Line

10/08/03: Identification of an HLA-A*0201-restricted epitopic peptide from human dystrophin: application in duchenne muscular dystrophy gene therapy

07/08/03: Psychopathological assessment in children affected by Duchenne de Boulogne muscular dystrophy

05/08/03: Bone mineral density and bone metabolism in Duchenne muscular dystrophy

05/08/03: Gadolinium reduces short-term stretch-induced muscle damage in isolated mdx mouse muscle fibres

01/08/03: Skeletal muscle engraftment potential of adult mouse skin side population cells

JULY/2003

30/07/03: Identification of a putative pathway for the muscle homing of stem cells in a muscular dystrophy model

30/07/03: H. Lee Sweeney, Ph.D. Joins PTC Therapeutics' Scientific Advisory Board

28/07/03: The 2003 Parent Project Muscular Dystrophy Annual Conference - the powerpoint presentations

26/07/03: Spain Approves Stem Cell Research, with Conditions

26/07/03: Rocuronium in Children with Duchenne's Muscular Dystrophy (from the Annual Meeting of Anestesiology - october 2003)

26/07/03: Gene therapy for muscular dystrophy - a review of promising progress

23/07/03: Morpholino antisense oligonucleotide induced dystrophin exon 23 skipping in mdx mouse muscle

15/07/03:IMPORTANT - Ultrasound Tissue Characterization Detects Preclinical Myocardial Structural Changes in Children Affected by Duchenne Muscular Dystrophy

J Am Coll Cardiol 2003;42:309 –16 

Vincenzo Giglio,  Vincenzo Pasceri, Loredana Messano, Fortunato Mangiola,  Luciano Pasquini,  Antonio Dello Russo, Antonello Damiani, Massimiliano Mirabella, Giuliana Galluzzi, Pietro Tonali,  Enzo Ricci

OBJECTIVES Our goal was to identify early changes in myocardial physical properties in children with Duchenne muscular dystrophy (DMD).

BACKGROUND Duchenne muscular dystrophy (DMD) is caused by the absence of dystrophin, which triggers complex molecular and biological events in skeletal and cardiac muscle tissues. Although about 30% of patients display overt signs of cardiomyopathy in the late stage of the disease, it is unknown whether changes in myocardial physical properties can be detected in the early (preclinical) stages of the disease.

METHODS We performed an ultrasonic tissue characterization (UTC) analysis of myocardium in DMD with normal systolic myocardial function and no signs of cardiomyopathy. Both the cyclic variation of integrated backscatter (cvIBS) and the calibrated integrated backscatter (cIBS) were assessed in 8 myocardial regions of 20 DMD, age 7 + 2 years (range 4 to 10 years), and in 20 age-matched healthy controls.

RESULTS We found large differences in the UTC data between DMD and controls; the mean valueof cvIBS was 4.4 + 1.5 dB versus 8.8 + 0.8 dB, whereas the mean value of cIBS was 36.4 + 7.1 dB versus 26.9 + 2.0 dB (p 10+6 for both). In DMD, all eight sampled segments showed cIBS mean values to be significantly higher and cvIBS mean values to be significantly lower than those in the controls. Finally, interindividual differences were greater in DMD than in controls for both parameters.

CONCLUSIONS The myocardium in DMD displays UTC features different from those in healthy controls. These results show that lack of dystrophin is commonly associated with changes in myocardial features well before the onset of changes of systolic function and overt cardiomyopathy. 

PARTS OF THE EDITORIAL OF THIS ARTICLE: (Jeffrey A. Towbin, Houston, Texas)

In most centers, individuals affected with DMD obtain echocardiograms after symptoms of heart failure begin. Unfortunately, this approach may lead to irreversibly progressive disease, ending in death. Hence, the concept of early referral and a noninvasive imaging approach that identifies early disease could be a more useful methodology with better long-term outcomes. Clearly, new approaches that enable early, presymptomatic diagnostic capability would be useful. Giglio et al. (10) took this one step further, seeking early detection of myocardial physical property changes in children with no signs or symptoms of cardiac involvement, including normal electrocardiograms and normal LV size and systolic function indexes. Patients and controls displayed significantly different UTC parameters, and interindividual differences were larger in DMD patients than in controls as well. Based on their results, the investigators (10) suggest that this method demonstrates subtle involvement of the myocardium early in DMD and could be potentially useful and reliable in assessing myocardial changes over time. We have been studying children through the use of echocardiography and cardiac magnetic resonance imaging; the children are evaluated starting at 10 years of age and are evaluated longitudinally on a yearly basis, with therapeutic intervention using angiotensin-converting enzyme inhibitors and beta-blockers at the earliest signs of myocardial disease. In a high percentage of cases, both reverse remodeling and normalization of LV size and systolic function rapidly occur using this approach. It is possible that earlier use of these agents would be beneficial as these patients are "destined" to develop cardiac disease. Perhaps UTC analysis will answer this question. The potential improvement in the care of DMD patients attributable to the development of UTC analysis is exciting.

15/07/03: Antifibrotic effects of suramin in injured skeletal muscle after laceration NEW

 J Appl Physiol 95: 771–780, 2003. 

Yi-Sheng Chan,1,2,3 Yong Li,1,2 William Foster,1 Takashi Horaguchi,1,2 George Somogyi,4 Freddie H. Fu,2 and Johnny Huard1,2,5

Muscle injuries are very common in traumatology and sports medicine. Although muscle tissue can regenerate postinjury, the healing process is slow and often incomplete; complete recovery after skeletal muscle injury is hindered by fibrosis. Our studies have shown that decreased fibrosis could improve muscle healing. Suramin has been found to inhibit transforming growth factor (TGF)- beta1 expression by competitively binding to the growth factor receptor. We conducted a series of tests to determine the antifibrotic effects of suramin on muscle laceration injuries. Our results demonstrate that suramin (50 g/ml) can effectively decrease fibroblast proliferation and fibrotic-protein expression (alfa-smooth muscle actin) in vitro. In vivo, direct injection of suramin (2.5 mg) into injured murine muscle resulted in effective inhibition of muscle fibrosis and enhanced muscle regeneration, which led to efficient functional muscle recovery. These results support our hypothesis that prevention of fibrosis could enhance muscle regeneration, thereby facilitating more efficient muscle healing. This study could significantly contribute to the development of strategies to promote efficient muscle healing and functional recovery.

 

15/07/03: IGF-I gene transfer by electroporation promotes regeneration in a muscle injury model  

Gene Therapy. 10(8):612-620, April 2003.

Takahashi, T 1; Ishida, K 1; Itoh, K 1; Konishi, Y 2; Yagyu, K-I 2; Tominaga, A 2,3; Miyazaki, J-I 4; Yamamoto, H 1

The goal of this study was to determine whether insulin-like growth factor-I (IGF-I) gene delivery by electroporation promotes repair after muscle injury. An injury-repair model was created using mice in which a hamstring muscle was cut and sutured. A total of 50 [mu]g of IGF-I DNA or green fluorescent protein (GFP) DNA (both in pCAGGS) was injected into the lesion and introduced into muscle cells by electrostimulation using an electric pulse generator. The number of regenerating muscle fibers in the IGF-I DNA group was significantly more than that in the GFP DNA group at 2 weeks after injection. The diameter of regenerating muscle fibers from the IGF-I DNA group was larger than that of the GFP DNA group at 4 weeks after injection. There was no significant difference in the serum IGF-I concentration between the IGF-I DNA group and the GFP DNA group at 1, 2, and 4 weeks after injection. However, muscle IGF-I concentration in the IGF-I DNA injection group was significantly greater than that in the GFP DNA injection group at 2 weeks after injection. These results demonstrated that the effects of enhanced IGF-I production were local and limited to the injected area. The ratio (injected/uninjected; intact) of the amplitude of compound muscle action potentials (CMAP) in the IGF-I DNA injection group was greater than that in the GFP DNA injection group at 4 weeks after injection and of the control group. In conclusion, IGF-I gene transfer by electroporation proved to be a simple, safe, inexpensive, and effective method to promote the regeneration of injured muscles in our injury model.

 

12/07/03: Evaluation of cardiac disease in adult female carriers in familial dystrophinopathies (abstract presented on The International Congress of Genetics, July 6-11, Melbourne, Australia) 

ROBYN OTWAY1, Jian Janet Liu1, Guanglan Guo1, Jasmine Hessell1, Peter Macdonald2, Anne Keogh2, Christopher Hayward2, Diane Fatkin1

1Sr Bernice Research Programme in Inherited Heart Diseases, Victor Chang Cardiac Research Institute, Darlinghurst, NSW Australia; 2 Cardiac Transplant Unit, St Vincent’s Hospital, Darlinghurst, NSW Australia

Dystrophinopathies are a group of X-linked myopathies, including Duchenne Muscular Dystrophy (DMD), Becker Muscular Dystrophy (BMD) and X-linked Dilated Cardiomyopathy (XLDCM) caused by mutations in the DMD gene, that encodes the large cytoskeletal protein, dystrophin. In males, dystrophinopathies exhibit variable skeletal muscle and cardiac involvement. Clinically evident DCM has been reported to occur in 0-26% of female carriers of DMD and BMD. There is a paucity of data regarding cardiac disease in female carriers with XLDCM. Traditionally, cardiac disease in female carriers has been presumed to be relatively mild and occur in later adult life. We performed clinical and genetic evaluation of 10 adult members of a 4-generation kindred with an atypical BMD/XLDCM phenotype. Sequence analysis of the DMD gene showed a 5’ splice site mutation, exon 1+1G>T. Five females (71%), aged 21 to 64, were carriers for this mutation. Cardiac investigations (ECG, echocardiogram) were performed in all female carriers. One individual, aged 63 years, presented with symptomatic DCM. Two individuals, aged 60 and 42 years, respectively, had structurally normal hearts. In 2 female carriers, aged 39 and 21 years,  asymptomatic echocardiographic abnormalities (mild left ventricular dilation with normal or borderline contractile function) were identified. These data indicate that the severity and age of onset of cardiac disease in female carriers with DMD mutations is variable. Regular cardiac screening of all female carriers is warranted from late adolescence. Elucidation of the pathophysiological basis for variable phenotypic expression in female carriers may facilitate rationalisation of cardiac screening strategies.

10/07/03: New prospects for treating muscular dystrophy: Stem cells restore muscle in MD mice

Stem Cells Offer Hope for Muscular Dystrophy

Modified Blood Vessel Stem Cells Might Treat Muscular Dystrophy  

STEM CELLS WORK AGAINST MUSCULAR DYSTROPHY IN MICE,
MDA SCIENTISTS FIND

New link: Cell Therapy of {alpha}-Sarcoglycan Null Dystrophic Mice Through Intra-Arterial Delivery of Mesoangioblasts.


07/07/2003: RNA injections boost muscle strength  

Gene breakthrough in muscular dystrophy fight

More links to this article:

RESEARCHERS REMOVE GENE DEFECT IN COMMON FORM OF MUSCULAR DYSTROPHY

Functional amounts of dystrophin produced by skipping the mutated exon in the mdx dystrophic mouse NEW

05/07/2003: Therapeutic Effect of Camostat Mesilate on Duchenne Muscular Dystrophy in mdx Mice

JUNE/2003

29/06/03: Wnt Signaling Induces the Myogenic Specification of Resident CD45+ Adult Stem Cells during Muscle Regeneration

Ottawa team uncovers how stem cells form muscle

MDA FINDS KEY PROTEIN FOR REBUILDING MUSCLE

Ottawa team discovers 'switch' that tells muscles to repair selves

29/06/03: Expression of Dystrophin Driven by the 1.35-kb MCK Promoter Ameliorates Muscular Dystrophy in Fast, but Not in Slow Muscles of Transgenic Mdx Mice

MOLECULAR THERAPY Vol. 8, No. 1, July 2003

Patrick Dunant,1 Nancy Larochelle,1,2 Christian Thirion,1 Rolf Stucka,1 Daniel Ursu,3 Basil J. Petrof,4 Eckhard Wolf,1 and Hanns Lochmu¨ller1,*

 E-mail: [email protected]

Successful gene therapy of Duchenne muscular dystrophy may require the lifelong expression of a therapeutic gene in all affected muscles. The most promising gene delivery vehicles, viral vectors, suffer from several limitations, including immunogenicity, loss of therapeutic gene expression, and a limited packaging capacity. Therefore, various efforts were previously undertaken to use small therapeutic genes and to place them under the control of a strong and muscle-specific promoter. Here we report the effects of a minidystrophin (6.3 kb) under the control of a short muscle-specific promoter (MCK 1.35 kb) over most of the lifetime (4–20 months) of a transgenic mouse model. Dystrophin expression remained stable and musclespecific at all ages. The dystrophic phenotype was greatly ameliorated and, most importantly, muscle function in limb muscles was significantly improved not only in young adult but also in aged mice compared to nontransgenic littermates. Dystrophin expression was strong in fasttwitch skeletal muscles such as tibialis anterior and extensor digitorum longus, but weak or absent in heart, diaphragm, and slow-twitch muscles. Additionally, expression was strong in glycolytic but weak in oxidative fibers of fast-twitch muscles. This study may have important implications for the design of future gene therapy trials for muscular dystrophy.

29/06/03: Successful heart transplantation in patients with inherited myopathies associated with end-stage cardiomyopathy


29/06/03: Circular letter from WANDA (World Alliance of Neuromuscular Disorder Association) about myoblast transfer treatment

Fake treatment for Duchenne turns into a police affair

21/06/03: US doctors support 'therapeutic' cloning  

21/06/03: The price of life  

Genetically matched baby sparks ethical debate

21/06/03: Pharmacokinetics of the Dietary Supplement Creatine [Review Article]   

Clinical Pharmacokinetics, 2003, 42(6):557-574

Persky, Adam M; Brazeau, Gayle A;Hochhaus, Günther

Creatine is a nonessential dietary component that, when supplemented in the diet, has shown physiological benefits in athletes, in animal-based models of disease and in patients with various muscle, neurological and neuromuscular disease. The clinical relevance of creatine supplementation is based primarily on its role in ATP generation, and cells may be able to better handle rapidly changing energy demands with supplementation.

Although the pharmacological outcome measures of creatine have been investigated, the behaviour of creatine in the blood and muscle is still not fully understood. Creatine is most probably actively absorbed from the gastrointestinal tract in a similar way to amino acids and peptides. The distribution of creatine throughout the body is largely determined by the presence of creatine transporters. These transporters not only serve to distribute creatine but serve as a clearance mechanism because of creatine ‘trapping’ by skeletal muscle. Besides the pseudo-irreversible uptake by skeletal muscle, creatine clearance also depends on renal elimination and degradation to creatinine.

Evidence suggests that creatine pharmacokinetics are nonlinear with respect to dose size and frequency. Skeletal muscle, the largest depot of creatine, has a finite capacity to store creatine. As such, when these stores are saturated, both volume of distribution and clearance can decrease, thus leading to complex pharmacokinetic situations. Additionally, other dietary components such as caffeine and carbohydrate can potentially affect pharmacokinetics by their influence on the creatine transporter. Disease and age may also affect the pharmacokinetics, but more information is needed.

Overall, there are very limited pharmacokinetic data available for creatine, and further studies are needed to define absorption characteristics, clearance kinetics and the effect of multiple doses. Additionally, the relationship between plasma creatine and muscle creatine needs to be elucidated to optimise administration regimens.

14/06/03: Muscular dystrophies: influence of physical conditioning on the disease evolution

14/06/03: A cytokine that packs a punch

The Journal of Cell Biology, Volume 161, Number 5, 835-a-835

Muscle cells undergo an unusual developmental program in which several partially differentiated cells called myoblasts fuse to form a multinucleated myotube. This nascent myotube undergoes further maturation and growth, which requires the addition of nuclei by fusion of more mononucleated myoblasts with myotubes. Valerie Horsley, Grace Pavlath, and colleagues (Emory University, Atlanta, Georgia) have found that nascent myotubes promote fusion, and thus their own growth, by secreting a cytokine normally associated with immune cells.The cross-system cytokine is IL-4, which is required in immune cells for macrophage fusion. Not one to throw away a good thing, Nature evidently coopted the system for muscle cells. As in immune cells, IL-4 expression in nascent myotubes is driven by a member of the NFAT transcription factor family. Myotubes lacking either IL-4 or the NFAT factor were smaller and had fewer nuclei than wild-type cells. Recovery from muscle injury was also diminished by the lack of IL-4 or the IL4alfa receptor.Myoblasts are the targets of IL-4 action, which may promote fusion by inducing myoblast expression of adhesion molecules such as integrins (as in macrophages) or VCAM. Alternatively, IL-4 may act as a chemokine, as it does for osteoblasts, to stimulate migration of myoblasts toward myotubes. Whatever the mechanism, stem cell therapies for disorders such as muscular dystrophies may be improved by expression of IL-4 to increase the fusion capacity of the muscle stem cells. 

Reference: Horsley, V., et al. 2003. Cell. 113:483–494

Nicole LeBrasseur [email protected]

14/06/03: A novel mechanism of myocyte degeneration involving the Ca2+-permeable growth factor-regulated channel

14/06/03:Photo from manifestation of  brazilian  DMD parents and boys on a Hospital Equipment Fair: we fight to receive the noninvasive ventilator (BIPAP) and pulmonary assistance  free; the Brazilian Health Minister saw and heard this manifestation.

07/06/03: Press release from Transgene and AFM (French Association against Muscular Dystrophies) (see the news in 5/05/2003) 

07/06/03: Enhancement of whole body glucose uptake during and after human skeletal muscle low-frequency electrical stimulation

Comments from Terence Partridge (Muscle Cell Biology Group, MRC Clinical Sciences Centre, ICSM, Hammersmith Hospital Site,London) about this article:

Electrical stimulation has been proposed for DMD for a number of reasons. Slow stimulation patterns – 10Hz – is supposed to convert muscle to the ‘slow’ type which is said to be less susceptible to necrosis than fast muscle (though the evidence for the latter point is rather dicey) has been proposed but I do not know if it has been tested in DMD boys.  In the genethon, one of the people I am working with believes that denervated segments of muscle fibre in DMD muscle causes the fibres to convert directly to fat.  He has some evidence that this may be so. It does not yet overcome my scepticism but we have discussed it and there are ways in which he could test it more stringently. His point is that electrical stimulation might prevent or even reverse the conversion.
My overall feeling is that any non-traumatic way of keeping muscle in physical shape would probably be good – moreover, it would be possible to assess this benefit if there is any by non-invasive methods.

MAY/2003

31/05/03: Acute heart failure during spinal surgery in a boy with Duchenne muscular dystrophy

31/05/03: PTC THERAPEUTICS AWARDED FAST TRACK SBIR GRANT TO DEVELOP NOVEL THERAPEUTICS TO TREAT GENETIC DISEASES

31/05/03: Skeletal muscle disorders associated with selenium deficiency in humans.

31/05/03: Carnitine Metabolism and Deficit - When Supplementation is Necessary? 

31/05/03:1st stem cells generated in Japan

24/05/03: Prolonged dystrophin expression and functional correction of mdx mouse muscle following gene transfer with a helper-dependent (gutted) adenovirus-encoding murine dystrophin

21/05/03: (IN PRESS: Drug & Market Development) Muscular Dystrophies: Recent Milestones

• This article was been written by G. Thor, PhD and J. Terryberry, BS, who are associated with NeuroConsultants based in San Diego, [email protected]

• Gene therapy human clinical trials have been reactivated after a 2-year freeze. Several gene therapeutic approaches to study Muscular Dystrophies (MD) – a set of neuromuscular diseases wherein muscle atrophies - are being resumed in clinical and preclinical stages.

• About one in 3,000 boys, independent of ethnic background, is born with this disease, which is caused by a mutation or damage of the Duchenne or Dystrophin gene carried on the X chromosome.

• More than 90% of MD genetic defects have been identified and have led to several components of the Dystrophin Glycoprotein complex that are in turn being used as targets for disease manipulation.

• Genetic tests for detecting alterations in the Dystrophin gene or Creatine Kinase detection by a blood test are available for prenatal screening.

• Prevention of MD by gene transfer in a mouse model and the creation of dog models that mimic Muscular Dystrophies phenotypes are enabling researchers to design effective strategies to study and conquer this set of musculature related diseases.

• Stem cell research has gained ground as mice models prove to be rewarding testing grounds for therapeutic manipulation of Dystrophin and other related polypeptides of the Dystrophin Glycoprotein Complex (DGC).

IMPORTANT IN THIS ARTICLE IS THIS CONCLUSION: Although gene therapeutic approaches offer the most promise for an ultimate cure for DMD, gene therapeutics are not expected to be available for several years or longer, meaning that many patients diagnosed at the present time are not likely to benefit from gene therapy. Since the incidence of DMD in the US is about 100,000 new cases per year, DMD is not an orphan disease. Pharmaceutical companies should therefore be interested in developing drugs for DMD; since Orphan Drug status is not applicable. Furthermore, developing drugs for DMD could be made more attractive to pharmaceutical companies as part of an idea to discover drugs for muscle weakness. Synthetic Dystrophin will not pass through the muscle cell membrane and must be produced or introduced inside the membrane by the muscle cell to be effective. WE NEED SAFE TREATMENTS TO DELAY/STOP THE EVOLUTION OF THE DISEASE.

21/05/03: Vertebral Fractures in Boys with Duchenne Muscular Dystrophy

Bothwell, J. E. MB BCh MRCP(UK), MRCPCH1; Gordon, K. E. MD, FRCP(C)2; Dooley, J. M. MB, FRCP(C)2; MacSween, J. RN2; Cummings, E. A. MD, FRCP(C)3; Salisbury, S. MD, MRCP(C)3

1Royal Belfast Hospital for Sick Children, Northern Ireland; Divisions of 2Pediatric Neurology and 3Pediatric Endocrinology, IWK Health Centre, Nova Scotia, Canada.

Summary: Osteoporosis causes significant morbidity for boys with Duchenne muscular dystrophy. Corticosteroid therapy given to prolong mobility may increase the rate of osteoporosis and risk of fracture. This study of 33 boys with Duchenne muscular dystrophy determined retrospectively the incidence of vertebral fractures particularly after initiation of corticosteroids. A latency period of 40 months after commencement of steroids occurred before the first vertebral fracture appeared. However, by 100 months of treatment approximately 75% had sustained a vertebral fracture. Clin Pediatr. 2003;42:353-356

17/05/03: Spinal fusion in patients with Duchenne's muscular dystrophy and a low forced vital capacity.  

10/05/03: U7 snRNAs induce correction of mutated dystrophin pre-mRNA by exon skipping

10/05/03: Defective membrane repair in dysferlin-deficient muscular dystrophy

Protein Tied to Muscular Dystrophy, Muscle Repair

10/05/03: Analysis of dystrophin mRNA from skeletal muscle but not from lymphocytes led to identification of a novel nonsense mutation in a carrier of Duchenne muscular dystrophy

05/05/03: IMPORTANT AND INEDITED: Results of Phase I Clinical Trial of Plasmid-Dystrophin Intramuscular Administration into Duchenne and Becker Dystrophy Patients - that will be presented on the 6th Annual Meeting of American Society of Gene Therapy in June 4-8,2003, in Washington.

Norma B. Romero,1 Olivier Benveniste,2 Aurore Choquel,2 Christine Payan,1 Glenn E. Morris,3 Jean-Gerard Guillet,4 Jean-Claude Kaplan,4 France Leturcq,4 Serge Braun,5 Brigitte Mourot,5 Christine Thioudellet,5 Patrick Squiban,5 Serge Herson,2 Michel Fardeau.1

1Institut de Myologie, Groupe Hospitalier Pitié-Salpętričre, Paris, France; 2Clinical Medicine, Groupe Hospitalier Pitié-Salpętričre,Paris, France; 3North East Wales Institute, Wrexham, UnitedKingdom; 4ICGM - INSERM U445, and Groupe Hospitalier Cochin Port-Royal, Paris, France; 5Transgene S.A., Strasbourg, France.

Duchenne dystrophy is a recessive X-linked inherited disorder with deletions or mutations in the dystrophin gene. Clinical onset occurs usually before the age of four years and is fatal (death during the third decade of life). A milder form (Becker dystrophy) is of more variable phenotype, but with abnormalities in the same dystrophin gene. After extensive pre-clinical studies in mdx mice and GRMD dogs we have carried out the first gene therapy phase I clinical trial in both Duchenne and Becker patients. The goal of this study was to provide indications on safety of a full-length human dystrophin-plasmid administration and exogenous dystrophin expression in DMD/BMD patients. Many ethical aspects were considered, including age and sequential inclusion of the patients, and low plasmid dosage. Complete data of each patient was carefully analysed by a steering committee composed of investigators, promoters and external, independent experts, before enrolment of the following patient. Three cohorts of 3 patients, presenting with large deletions, were injected in the radial muscle with either a single injection of 200 µg (cohort 1) and 600 µg (cohort 2) of plasmid, or 2 injections 2 weeks apart with 600 µg plasmid (cohort 3). In all patients, a muscle biopsy was performed in the injected site 3 weeks after the first injection. Each biopsy was serially sectioned and studied for the presence of plasmid (PCR) and for dystrophin expression (nested RT-PCR + immunohistochemistry). The histological aspect of the muscle biopsy and local inflammatory processes were analysed. Besides the usual biochemical / cytological blood parameters (including muscle enzymes), patients were also followed for specific immunological endpoints (anti-DNA and antidystrophin cellular and immunological responses) for 3 months after plasmid injection. Normal dystrophin expression was found in few muscle fibers of 2/3 patients of the first cohort and in 1/3 patients of the second cohort. All the 3 patients of the 3rd cohort displayed significant amounts of weakly dystrophin-stained muscle fibers. Plasmid was detected in the injected muscle sample in all patients. All patients showed perfect tolerance to the plasmid administration. Neither anti-DNA nor anti-dystrophin immune response was found. As demonstrated by MRI, EMG and muscle strength analysis, the procedure did not impair the injected muscle function. These results show for the first time that exogenous dystrophin expression can be obtained in DMD/BMD skeletal muscle in vivo following gene transfer, and without adverse effects. This very cautious approach paves the way for further developments. We are currently working extensively (in collaboration with JA Wolff and Mirus Corp.), on a more ambitious, intra-arterial delivery administration of human full-length dystrophin plasmid, that we intend to evaluate in a next human clinical trial.

05/05/03:IMPORTANT AND INEDITED: Abstracts that will be presented on the 6th Annual Meeting of American Society of Gene Therapy in June 4-8,2003, in Washington. (27 selected abstracts)

03/05/03: Severe muscle dysfunction precedes collagen tissue proliferation in mdx mouse diaphragm

03/05/03: Cultured Eggs Could Defuse Stem Cell Politics

01/05/03: Restoration of dystrophin expression in mdx muscle cells by chimeraplast-mediated exon skipping  

01/05/03:IN PRESS  (Neuromuscular Disorders) Correlated NOS-Iµ  and myf5 expression by satellite cells in mdx mouse muscle regeneration during NOS manipulation and deflazacort treatment

Judy E. Anderson, Cinthya Vargas
Department of Human Anatomy and Cell Science, Faculty of Medicine, University of Manitoba, 730 William Avenue, Winnipeg, MB, Canada 

Abstract

Satellite cells, muscle precursor cells in skeletal muscle, are normally quiescent and become activated by disease or injury. A lack of dystrophin and changes in the expression or activity of neuronal nitric oxide synthase (NOS-I) affect the timing of activation in vivo. Nitric oxide synthase inhibition delays muscle repair in normal mice, and worsens muscular dystrophy in the mdx mouse, a genetic homologue of Duchenne muscular dystrophy. However, the potential role of activation and repair events mediated by nitric oxide in determining the outcome of steroid or other treatments for muscular dystrophy is not clear. We tested the hypothesis that the extent of repair in dystrophic muscles of mdx mice is partly dependent on NOS-Iµ  expression and activity. Myotube formation in regenerating muscle was promoted by deflazacort treatment of mdx dystrophic mice (P<0.05), and improved by combination with the nitric oxide synthase substrate, L-arginine, especially in the diaphragm. NOS-Iµ  mRNA expression and activity were present in satellite cells and very new myotubes of regenerating and dystrophic muscle. Deflazacort treatment resulted in increased NOS-Iµ  expression in regenerating muscles in a strong and specific correlation with myf5 expression (r=0.95, P<0.01), a marker for muscle repair. Nitric oxide synthase inhibition prevented the deflazacort-induced rise in NOS-Iµ and myf5 expression in the diaphragm without affecting the diameter of non-regenerating fibres. These in vivo studies suggest that gains in NOS-Iµ  expression and nitric oxide synthase activity in satellite cells can increase the extent and speed of repair, even in the absence of dystrophin in muscle fibres. NOS-Iµ may be a useful therapeutic target to augment the effects of steroidal or other treatments of muscular dystrophy.

01/05/03: IMPACT OF TNF-ALPHA ELIMINATION ON VENTILATION AND DIAPHRAGM CONTRACTILITY IN DYSTROPHIC MICE

Barkley, J1; Spencer, M2; Farkas, G A.1; McCormick, K M. FACSM1; Gosselin, L E. FACSM1

1University at Buffalo, Buffalo, NY; 2UCLA, Los Angeles, CA

The American College of Sports Medicine Volume 34(5) Supplement 1,May 2002, p S155

Duchenne muscular dystrophy is associated with extensive diaphragm muscle injury and a persistent inflammatory response that leads to muscle degeneration. Ultimately, patients die of respiratory failure by their early twenties. The purpose of this study was to determine if eliminating the inflammatory cytokine tumor necrosis factor-alpha (TNF[alpha]) would improve ventilatory reserve and diaphragm muscle contractility in mdx (dystrophic) mice. For this study mdx mice were crossbred with transgenic. TNF[alpha]-deficient mice to generate TNF[alpha]-deficient mdx (TNF[alpha]-/mdx) mice. At 11–12 months of age, ventilation was measured in awake mice during room air breathing and in response to 7% CO2 using the barometric technique. During room air breathing, neither tidal volume, respiratory rate nor minute ventilation (Ve) differed between TNF[alpha]-/mdx and TNF[alpha]+/mdx mice. In response to 7% CO2, TNF[alpha]-/mdx mice significantly increased Ve whereas Ve did not change in the TNF[alpha]+/mdx group (P < 0.05). In vitro isometric contractile properties of the diaphragm were also measured. Maximal isometric force of the diaphragm muscle was significantly higher in the TNF[alpha]-/mdx group when compared to TNF[alpha]+/mdx group (7.57 N/cm2 vs. 5.56 N/cm2, respectively, P < .05). These data suggest that TNF[alpha] plays a role in ventilatory and diaphragm muscle dysfunction in dystrophic mice.

APRIL/2003

23/04/03:Beneficial effects of creatine supplementation in dystrophic patients

23/04/03:Gentamicin fails to increase dystrophin expression in dystrophin-deficient muscle

22/04/03:IMPORTANT Dystrophic phenotype of canine X-linked muscular dystrophy is mitigated by adenovirus-mediated utrophin gene transfer

21/04/03: Drugs firms 'cure the rich' claim  

19/04/03: Three Wishes and Psychological Functioning in Boys with Duchenne Muscular Dystrophy  

19/04/03: Toxic molecule may provide key for developing vaccine against degenerative diseases

17/04/03: IN PRESS (Lancet Neurology, 2003, vol. 2, may ) Novel therapies for Duchenne muscular dystrophy: Review

The development of therapeutic strategies that overcome the unique problems posed by Duchenne muscular dystrophy (DMD) has lead to the development of many contemporary approaches to human disease in general. Various treatment approaches have been explored—such as pharmacological therapies and cell-based, cytokine, and genetic therapies—that are all targeted to specific features of dystrophic DMD muscle pathology. In genetic therapies, the large size of the dystrophin gene has necessitated the development and use of novel functional minidystrophin and microdystrophin genes, muscle-specific promoter systems, and gutted adenoviral systems. In addition to these well defined viral strategies, plasmid vectors and the upregulation of utrophin (a dystrophin homologue) have potential. Various novel genetic approaches—such as antisense-mediated exon skipping, gene correction, and new cytokine approaches—are also being developed. Together these exciting developments bring an effective treatment for DMD closer than ever before.

-16/04/03: Threats to "informed" advance directives for the severely physically challenged?

12/04/03: Transformation of adult mesenchymal stem cells isolated from the fatty tissue into cardiomyocytes

07/04/03:IN PRESS ( Free Radical Biology & Medicine, Vol. 34, 2003) PATIENTS WITH DYSTROPHINOPATHY SHOW EVIDENCE OF INCREASED OXIDATIVE STRESS

M. CHRISTINE RODRIGUEZ* and MARK A. TARNOPOLSKY*†

Departments of *Kinesiology and †Medicine (Neurology and Rehabilitation), McMaster University, Hamilton, Ontario, Canada

Abstract—Duchenne muscular dystrophy (DMD) is associated with an increase in oxidative stress. We measured 24 h 8-hydroxy-2'-deoxyguanosine (8-OHdG) excretion in 24 patients with MD (DMD + Becker’s MD), 23 with myotonic dystrophy, and 34 healthy controls. The 8-OHdG/creatinine ratio was higher in patients with dystrophinopathy (increase 48%, p < .01) but not myotonic dystrophy, as compared to healthy controls. These results indicate that 8-OHdG excretion can be used as a marker of oxidative stress in clinical trials with dystrophinopathy. 

IMPORTANT:  BLOCKADE THE OXIDATIVE STRESS IS A POSSIBLE WAY TO DELAY THE PROGRESSION OF DMD.

07/04/03: IN PRESS (Neuromuscular Disorders, 2003): Cardiomyopathic features associated with muscular dystrophy are independent of dystrophin absence in cardiovasculature

T.A. Hainsey, S. Senapati, D.E. Kuhn, J.A. Rafael*

Department of Molecular and Cellular Biochemistry, College of Medicine, The Ohio State University, 410 Hamilton Hall, 1645 Neil Avenue,Columbus, OH 43210, USA

Abstract

The loss of dystrophin results in skeletal muscle degeneration and cardiomyopathy in patients with Duchenne muscular dystrophy. In skeletal muscle, dystrophin strengthens the myofiber membrane by linking the submembranous cytoskeleton and extracellular matrix through its direct interaction with the dystroglycan/sarcoglycan complex. In limb-girdle muscular dystrophy, the loss of the sarcoglycans in cardiovasculature leads to cardiomyopathy. It is unknown whether the absence of dystrophin in cardiomyocytes or cardiovasculature leads to the cardiomyopathy associated with primary dystrophin deficiency. We show here that the cardiomyopathic features of the utrophin/dystrophin-deficient mouse can be prevented by the presence of dystrophin in cardiomyocytes but not in cardiovasculature. Furthermore, restoration of the dystroglycans and sarcoglycans to the cardiomyocyte membrane is not sufficient to prevent cardiomyopathy. These data provide the first evidence that dystrophin plays a mechanical role in cardiomyocytes similar to its role in skeletal muscle. These results indicate that treatment of cardiomyocytes but not cardiovasculature is essential in dystrophinopathies.

05/04/03: A role for natural killer cells in the rapid death of cultured donor myoblasts after transplantation

03/04/03: Therapeutic antisense-induced exon skipping in cultured muscle cells from six different DMD patients

03/04/03: Scientist studies cell repair

01/04/03: Researchers use nano-particles to deliver gene therapy

01/04/03: Vitamin C transforms mouse stem cells into heart muscle cells

MARCH/2003

29/03/03: Postoperative malnutrition in Duchenne muscular dystrophy

25/03/03: IMPORTANT: Effects of Deflazacort on Left Ventricular Function in Patients With Duchenne Muscular Dystrophy 

Cardiac involvement in Duchenne muscular dystrophy (DMD) is well described. Although the effect of deflazacort, an oxazolone derivative of prednisone, on skeletal and pulmonary muscle function has been described, there is no information on the effects of deflazacort on myocardial function. The purpose of this report is to examine the effect of deflazacort on cardiac function in patients with DMD. This is a retrospective cohort study of patients seen at the Bloorview MacMillan Children’s Center, Toronto, Canada. Patients with DMD between the ages of 10 and 18 years were included in the study. Administration with deflazacort was begun at a mean age of 8.4 + 2 years. The initial dose of deflazacort was 0.9 mg/kg/day along with daily oral supplements of vitamin D and calcium. As per standard protocol, the dose of deflazacort decreased with the duration of treatment (at 10 years, the mean dose of deflazacort was 0.76 + 0.19 mg/kg/day; at 15 years 0.61+ 0.20 mg/kg/day; and at 18 years 0.59 + 0.15mg/kg/day). All patients took deflazacort for at least 3years.This is the first published study examining the effects of deflazacort treatment on cardiac function in patients with DMD. We found that patients who had been receiving deflazacort for > 3 years were more likely to have preserved cardiac function than those who had not received the medication. Preservation of cardiac muscle function was associated with better pulmonary and skeletal muscle function. Cardiac dysfunction did not correlate with patient age, blood pressure, or weight. Significant adverse effects from the medication were uncommon apart from growth limitation and asymptomatic cataracts. Long-term studies are important to determine the duration of benefit on gross motor, pulmonary, and cardiac function.

22/03/03: Bladder dysfunction in Duchenne muscular dystrophy

20/03/03 (IN PRESS - European Heart Journal (2003) ): A preliminary randomized study of growth hormone administration in Becker and Duchenne muscular dystrophies 

Antonio Cittadinia, Lucia Ines Comi, Salvatore Longobardi, Vito Rocco Petretta, Cosma Casaburia, Luigia Passamano, Bartolomeo Merola, Emanuele Durante-Mangoni, Luigi Saccŕ, Luisa Politano

Naples, Italy

Aim Since growth hormone (GH) has proven beneficial in experimental heart failure, and the natural history of Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) is frequently complicated by the development of dilated cardiomyopathy, we administered GH to six patients with DMD and 10 with BMD, with the evidence of cardiac involvement.

Methods and results Patients were randomized to receive for 3 months either placebo or recombinant human GH, in a double-blind fashion. In GH-treated patients, left ventricular (LV) mass increased by 16% in BMD and by 29% in DMD (both p<0.01), with a significant increase of relative wall thickness (+19%). Systemic blood pressure remained unchanged, while LV end-systolic stress fell significantly by 13% in BMD and by 33% in DMD, with a slight increase of systolic function indexes. No changes were observed related to cardiac arrhythmias and skeletal muscle function in the patient groups during the treatment period, nor any side effects were observed. Brain natriuretic peptide, interleukin-6, and tumor necrosis factor-alfa circulating levels were elevated at baseline. While brain natriuretic peptide decreased by 40%, cytokine levels did not exhibit significant variations during the treatment period.

Conclusions The 3-month GH therapy in patients with DMD and BMD induces a hypertrophic response associated with a significant reduction of brain natriuretic peptide plasma levels and a slight improvement of systolic function, no changes in skeletal muscle function, and no side effects.

18/03/03: Nerve growth factor expression in human dystrophic muscles

15/03/03: Scientists discover possible new treatment for genetic diseases

15/03/03: Skeletal muscle repair by adult human mesenchymal stem cells from synovial membrane

15/03/03: A novel form of manually assisted ventilation

15/03/03: IN PRESSActivation of nuclear factor- kB in inflammatory myopathies and Duchenne muscular dystrophy 

M.C. Monici, MD; M. Aguennouz, PhD; A. Mazzeo, MD; C. Messina, MD; and G. Vita, MD

Abstract—Objective: To investigate the immunolocalization and activation of nuclear factor-kB (NF-kB) in polymyositis, dermatomyositis, and Duchenne muscular dystrophy (DMD). Background: NF-kB is a major transcription factor modulating the cellular immune, inflammatory, and proliferative responses. In skeletal muscle it was demonstrated to play a role in the expression of inducible genes in response to oxidative stress and ischemia/reperfusion injury, and also in myonuclear apoptosis and muscle catabolism. Some data suggest that NF-kB may play a role in the pathogenesis of inclusion body myositis. Methods: Muscle samples from five patients each with polymyositis, dermatomyositis, and DMD and 10 normal controls were studied by immunocytochemistry and Western blot of nuclear extracts for the activated form of NF-kB. NF-kB DNA binding activity was studied by electrophoretic mobility shift assay (EMSA). Results: Immunoreactivity for NF-kB was found in the cytoplasm of all regenerating fibers and in 20 to 40% of necrotic fibers. Western blot analysis of nuclear extracts showed a single band corresponding to 65 kd in all patients. EMSA analysis confirmed activation of NF-kB pathway in inflammatory myopathies and, to a lesser extent, also in DMD. Conclusions: These data indicate that nuclear factor-kB pathway is activated in polymyositis, dermatomyositis, and Duchenne muscular dystrophy. It may play a role in modulating the immune response and in regulating myogenesis and muscle repair.

NEUROLOGY 2003;60:993–997

08/03/03: High-efficiency plasmid gene transfer into dystrophic muscle

08/03/03: Relationship between Utrophin and Regenerating Muscle Fibers in Duchenne Muscular Dystrophy

08/03/03:Dental characteristics of patients with Duchenne muscular dystrophy

08/03/03: FDA proposes standards for dietary supplements

08/03/03:Teen is first to get stem cell treatment

http://www.beaumonthospitals.com/pls/portal30/cportal30.story_page1?l_recent=265 (with video)

http://www.cnn.com/2003/HEALTH/conditions/03/06/teen.heart.ap/

http://www.heartcenteronline.com/myheartdr/home/research-detail.cfm?reutersid=3432

http://story.news.yahoo.com/news?tmpl=story2&cid=571&ncid=751&e=3&u=/nm/20030305/hl_nm/stemcell_transplant_dc

05/03/03: University of Utah researchers develop test to detect muscular dystrophy

04/03/03: Novel muscle-derived stem cells deliver dystrophin into a dystrophin-deficient murine heart

01/03/03: e-mail from Dr. Tremblay about her research with mioblasts obtained by our friend Uli Gehrt

Dear Mr Gehrt:  the project is not stopped by the leukemia cases in France because we are transplanting cells (myoblasts) which are not genetically modified. The myoblasts that we transplant contain the normal dystrophin gene because they come from the father. Yes the transplantation of the patients own myoblasts genetically  modified with a viral (as the Herpes virus in that article) or non viral vector could avoid the neeed for a sustained immunosupprerssion however the genetic modification of the cells could produce tumorigenic modification as was the cases for these patients with leukemia in France. So there are advantages and problems associated with the genetic correction of the patients own cells. We are however working on s safer way to correct the patient cells . Myoblast transplanation has been done to only one patient so far. It  will take a few months before I have results that I can report.

01/03/03: e-mail from Dr. Serge Braun (Transgene) about the first study of gene therapy obtained by our friend Berit Sofie:

Dear Berit,
news about our program: our phase I has been completed (final pilot cimmette meeting in march). Data will be published after revewal by the scientific community. The results are as expected (very good safety). We are already working on future developments, including a further clinical trial using intra-arterial delivery of an improved dystrophin gene vector. This is time consuming; we hope it can take place in 2004.
Gene therapy of DMD is a very difficult task. To my knowledge, Transgene is the only company being at the clinical stage in this field.
Research in DMD in general:
I know Jeff Chamberlain (US) is working on another vector, namely AAV-microdystrophin. The vector is different, known to be rather efficient in skeletal muscle. The gene is a smaller version (the full dystrophin gene does not fit in AAV vectors), hoped to to the same job as the full gene. They announced they would like to start a phase I clinical trial in 2004.
I know also of a French company (Faust Pharmaceuticals) doing research on conventional molecules. They identified a familly of conventional drugs that could increase utrophin _expression to compensate for the absence of dystrophin. This is at the preclinical stage.
On a similar basis, but with a much larger budget Eric Hoffman is actively pursuing a screening program using gene array technology. I am not aware of any significant breakthrough, but they may eventually end up with potentially therapeutic molecules. I am convinced it is only a matter of time.
All the best to you and Magnus
Serge
 
Serge Braun, PharmD, PhD
Vice-President Research
Transgene S.A.
11 rue de Molsheim
67082 STRASBOURG Cedex (France)

01/03/03: Bush praises House for human cloning ban

01/03/03: Myotonic dystrophy type 2 -Molecular, diagnostic and clinical spectrum

01/03/03: Different Ability of Clenbuterol and Salbutamol to Block Sodium Channels Predicts Their Therapeutic Use in Muscle Excitability Disorders

FEBRUARY/2003

24/02/03: Breakthrough in gene therapy - Scientists have developed a more effective way to carry out gene therapy without the risks of current methods  

http://news.bbc.co.uk/1/hi/health/2780325.stm

http://www.health-news.co.uk/showstory.asp?id=107274

http://www.betterhumans.com/News/news.aspx?articleID=2003-02-24-3

http://reuters.com/newsArticle.jhtml?type=healthNews&storyID=2278965

22/02/03: New DMD community: Fight for a Future

22/02/03: Autotransplantation in mdx mice of mdx myoblasts genetically corrected by an HSV-1 amplicon vector

17/02/03: Nutritional Assessment of Patients with Neuromuscular Diseases 

Pessolano FA, Su´ arez AA, Monteiro SG, Mesa L, Dubrovsky A, Roncoroni AJ, De Vito EL - Argentina

Am J Phys Med Rehabil 2003;82:182–185.

ABSTRACT

Objective: To study the nutritional status of patients with Duchenne muscular dystrophy and amyotrophic lateral sclerosis.

Design: A total of 34 Duchenne muscular dystrophy and seven amyotrophic lateral sclerosis patients were studied. Body mass index, patient’s body weight for zero muscle mass as a percentage of the theoretical weight for zero muscle mass, and creatinine-height index were calculated.

Results: Substantial differences were found between body mass index and percentage of expected weight for zero muscle mass. No amyotrophic lateral sclerosis patients were classified as overweight by body mass index, whereas five were overweight by the percentage of expected weight for zero muscle mass method. Five Duchenne muscular dystrophy patients were classified as overweight by body mass index, and 30 were overweight by the percentage of expected weight for zero muscle mass. According to the creatinine-height index, no patient with amyotrophic lateral sclerosis or Duchenne muscular dystrophy showed normal body muscle mass. No correlation was found between creatinine-height index, percentage of expected weight for zero muscle mass, and body mass index.

Conclusions: The body mass index should be used with caution for the evaluation of the nutritional status of patients with amyotrophic lateral sclerosis and Duchenne muscular dystrophy. Indices that incorporate the assessment of the compartmental distribution of muscle and fat are more sensitive.

17/02/03: Expression of tumor necrosis factor-α in regenerating muscle fibers in inflammatory and non-inflammatory myopathies

Satoshi Kuru,Akira Inukai, Takashi Kato, Yideng Liang,  Seigo Kimura, Gen Sobue

Department of Neurology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan e-mail: [email protected]

Acta Neuropathol (2003) 105 :217–224

Abstract The expression level of tumor necrosis factor (TNF)-α is elevated in idiopathic inflammatory myopathies and Duchenne muscular dystrophy (DMD), but the precise role of TNF-α is unknown. To elucidate the possible role of TNF-α , we investigated the expression of TNF-α and its receptor in polymyositis (PM), dermatomyositis (DM), and DMD using in situ hybridization (ISH) and immunohistochemistry. We showed that TNF-α mRNA and protein were present in muscle fibers. TNF-α-positive fibers were observed in all cases of PM, DM and DMD, but were rare or absent in neurogenic disorders and normal controls. The proportion of TNF-α-positive fiber showed a significant positive correlation with the proportion of regenerating fibers that were positive for the developmental form of myosin heavy chain (MHC-d). The number of TNF receptor-positive fibers was small. Some muscle fibers expressed both TNF-α and its receptor simultaneously. Our results indicate that TNF-α is produced and expressed by muscle fibers and associated with muscle regeneration. 

16/02/03: Selected Abstracts that will be presented on the Annual Meeting of American Academy of Neurology - march 29 - april 5,2003 Hawaii

15/02/03: Long-term improvement of cardiac function in rats after infarction by transplantation of embryonic stem cells  

15/02/03: Scientists Replace Stem Cell Genes


10/02/03: (Neuromuscular Disorders in Press)  Persistent over-expression of specific CC class chemokines correlates with macrophage and T-cell recruitment in mdx skeletal muscle

John D. Portera, Wei Guoa, Anita P. Merriama, Sangeeta Khannaa, Georgiana Chenga, Xiaohua Zhoua, Francisco H. Andradeb, Chellah Richmondsb, Henry J. Kaminskib

Prior studies and the efficacy of immunotherapies provide evidence that inflammation is mechanistic in pathogenesis of Duchenne muscular dystrophy. Duchenne muscular dystrophy (DMD) is the consequence of inherited mutations in dystrophin  A correlate of dystrophinopathy is displacement of the multimeric dystrophin-glycoprotein complex (DGC) from the sarcolemma; it is widely accepted that an ensuing mechanical destabilization leads to myofiber death. However, recent studies have identified other, non-mechanical roles fordystrophin and the DGC. Moreover, dystrophin deficiency does not invariably produce progressive muscle degeneration in all species, life stages, and muscle phenotypes. While these alternative functions do not dismiss the mechanical hypothesis, they led to the suggestion that the dystrophin deficiency alone is conditional, rather than determinant, in the pathogenesis of DMD . Secondary mechanisms (e.g. inflammation, ischemia, compromise of energy metabolism, or fibrosis) can have a substantial role in pathophysiology and may condition the ultimate fate of dystrophin-deficient muscle fibers. Taken together, DMD is a multi-factorial disease and current pathogenic models oversimplify or neglect interactions between the primary dystrophin deficiency and key secondary mechanisms. In contrast to the view that secondary events are only nonspecific responses to mechanically damaged muscle, there is compelling evidence that inflammation contributes to dystrophinopathy. Lymphoid and myeloid cells are prominent in dystrophic muscle and DNA microarray data show that inflammatory mediators/effectors dominate the expression profile in mdx hindlimb muscle. Moreover, while anti-inflammatory therapy has yielded inconsistent results, some studies show that corticosteroids may add years to DMD patient ambulation. An understanding of the character and progression of inflammation in ystrophinopathy might facilitate more effective treatment design in the absence of a primary genetic cure. Chemokines are small molecular weight cytokines (,8–13kDa), grouped into four distinct classes (C or g, CC or b, CXC or a, and CX3Cor d), that are induced by awide range of stimuli and are considered essential for leukocyte extravasation and effector T-cell differentiation . To identify putative pro-inflammatory mechanisms, we evaluated chemokine gene/protein expression patterns in skeletal muscle of mdx mice. Convergent evidence established the induction of six distinct CC class chemokine ligands in adult mdx: CCL2/MCP-1, CCL5/RANTES, CCL6/mu C10, CCL7/MCP-3, CCL8/MCP-2, and CCL9/MIP-1g. CCL receptors, CCR2, CCR1, and CCR5, also showed increased expression in mdx muscle. CCL2 and CCL6 were localized to both monocular cells and muscle fibers, suggesting that dystrophic muscle may contribute toward chemotaxis. Temporal patterns of CCL2 and CCL6 showed early induction and maintained expression in mdx limb muscle. These data raise the possibility that chemokine signaling pathways coordinate a spatially and temporally discrete immune response that may contribute toward muscular dystrophy. The chemokine pro-inflammatory pathways described here in mdx may represent new targets for treatment of Duchenne muscular dystrophy.

08/02/03: Daytime predictors of sleep disordered breathing in children and adolescents with neuromuscular disorders (Neuromuscular Disorders – 13 (2003):123-8)  

Uwe Mellies, Regine Ragette, Christian Schwake, Holger Boehm, Thomas Voit, Helmut Teschler

Abstract

Sleep disordered breathing with or without nocturnal hypercapnic hypoventilation is a common complication of respiratory muscle weakness in childhood neuromuscular disorders. Nocturnal hypercapnic hypoventilation as a sign of respiratory muscle fatigue, portendsa particularly poor prognosis. We aimed at identifying daytime predictors of sleep disordered breathing at its onset and sleep disordered breathing with nocturnal hypercapnic hypoventilation. Forty-nine children and adolescents (11.3 + 4.4 years) with progressive neuromuscular disorders were studied with inspiratory vital capacity, peak inspiratory pressure, arterial blood gases, polysomnography, and a ten-item symptoms questionnaire. Daytime respiratory function was prospectively compared with polysomnographic variables. Sleep disordered breathing was found in 35/49 patients (71%). Twenty-four (49%) had sleep disordered breathing with nocturnal hypercapnic hypoventilation. Inspiratory vital capacity and peak inspiratory pressure, but not symptom score, correlated with sleep disordered breathing and severity of nocturnal hypercapnic hypoventilation. Sleep disordered breathing-onset was predicted by inspiratory vital capacity , 60% (sens. 97%, spec. 87%). Sleep disordered breathing with nocturnal hypercapnic hypoventilation was predicted by inspiratory vital capacity , 40% (sens.96%, spec. 88%) and PaCO2 . 40 mmHg (sens. 92%, spec. 72%,). Sleep disordered breathing can reliably be predicted from simple daytime respiratory function tests, which, if applied systematically, will improve recognition of nocturnal respiratory failure.

04/02/03: IMPORTANT (Neuromuscular Disorders – 13 (2003):166-72) 107th ENMC International Workshop: the management of cardiac involvement in muscular dystrophy and myotonic dystrophy. 7th–9th June 2002, Naarden, the Netherlands

 Sixteen participants from Austria, France, Germany, Italy, the Netherlands and the UK met to discuss the cardiac implications of the diagnosis of muscular dystrophy and myotonic dystrophy. The group included both myologists and cardiologists from nine different European centers. The aims of the workshop were to agree and report minimum recommendations for the investigation and treatment of cardiac involvement in muscular and myotonic dystrophies,and define areas where further research is needed. 

 DMD

1) Patients should have a cardiac investigation (echo and electrocardiogram (ECG)) at diagnosis.

2) DMD patients should have cardiac investigations before any surgery, every 2 years to age 10 and annually after age 10.

3) Respiratory failure is also common in DMD and assessment and treatment of respiratory function should be performed in parallel with the cardiological investigations

4) Patients should be treated with angiotensin-converting enzyme (ACE) inhibitors initially in the presence of progressive abnormalities. Subsequently the addition of beta blockers should be considered.

5) There is no evidence that the currently used steroid treatment regimes have a detrimental effect on cardiac involvement or are a contraindication for the concurrent use of ACE inhibitors.

6) The multiple other complications of DMD including scoliosis and respiratory failure mean that these patients are rarely fit for cardiac transplantation.

7) There is an urgent need for multi-centre clinical trials to determine whether treatment of patients with cardiomyopathy, prior to the onset of symptoms, improves prognosis and quality of life. There is also unpublished evidence to suggest that treatment even before any impairment of ventricular function is detectable on echocardiogram may delay the onset and progression of cardiomyopathy. Concerns about the possible impact of ACE-inhibition on left ventricular development in very young children, means that treatment in the very young should only be undertaken in the context of a formal clinical trial, at the present time.

8) There is a case for continued evaluation of more sophisticated tools (echo tissue Doppler imaging, cardiac magnetic resonance imaging (MRI), etc.) for earlier detection of abnormalities, but these are not required for routine management.

 BMD

Cardiac involvement in BMD is common and is frequently out of proportion to the skeletal muscle involvement.

1) BMD patients should have cardiac evaluation (ECG and echo) at diagnosis.

2) BMD patients should be screened for the development of cardiomyopathy at least every 5 years.

3) They should be seen more regularly and treated with ACE inhibitors and, if indicated, beta blockers when progressive abnormality is found.

4) Cardiac transplantation may be a viable treatment in this group of patients.

 Female carriers of DMD and BMD

There is unequivocal evidence that approximately 10% of female carriers of dystrophin mutations, either DMD or BMD develop overt cardiac failure even in the absence of any skeletal muscle involvement.

1)All carriers of DMD or BMD should have echo and ECG at diagnosis or after the age of 16 years and at least every 5 years thereafter, or more frequently in patients with abnormalities on investigation.

2) Carriers manifesting severe skeletal muscle symptoms or cardiac symptoms require more frequent investigation.

3) Once significant abnormalities are detected patients may benefit from treatment with ACE inhibitors and additional medication as indicated.

4) Ultimately cardiac transplantation may be appropriate

01/02/03: Full-length dystrophin cDNA transfer into skeletal muscle of adult mdx mice by electroporation

01/02/03: Inhibition of myostatin in adult mice increases skeletal muscle mass and strength  

01/02/03: Creatine monohydrate in DM2/PROMM - A double-blind placebo-controlled clinical study

C. Schneider–Gold, MD; M. Beck, MD; C. Wessig, MD; A. George, MD; H. Kele, MD; K. Reiners, MD; and K.V. Toyka, MD

Abstract—The efficacy and safety of creatine monohydrate (Cr) in patients with myotonic dystrophy type 2/proximal myotonic myopathy were studied in a small placebo-controlled double-blind trial. Twenty patients received either Cr or placebo for 3 months. After 3 months, there were no significant differences of muscle strength as assessed by hand-held dynamometry, testing of maximum grip strength, Medical Research Council scoring, and the Neuromuscular Symptom Score between the two groups. Some measures indicated trends toward mild improvement with Cr. Myalgia improved intwo patients.

NEUROLOGY 2003;60:500–502

01/02/03: Stem cell route to neuromuscular therapies  

01/02/03: Assessment of left ventricular systolic and diastolic functions in children with merosin-positive congenital muscular dystrophy

 

JANUARY/2003

28/01/03: Early prednisone treatment in Duchenne muscular dystrophy  

28/01/03: Paralyzed "Superman" star urges Australians to support therapeutic cloning

28/01/03:Sizing up supplements - How to find safe products that work

26/01/03: e-mail from researcher of the article "Antisense-induced exon skipping restores dystrophin expression in DMD patient derived muscle cells" obtained by Berit Sofie:

Dear Parents,
Although our results on antisense-induced exon skipping are very promising (we have now successfuly applied it to cultured muscle cells from 10 DMD patients affected by different deletions), it will still take some 5-10 years more to develop this technique into a clinically applicable therapy. We are currently working very hard to find a safe and efficient method to get the antisense drugs into muscle tissue of mice. We are looking for a way that allows systemic delivery (instead of intramuscular injections). We are in collaboration with a pharmaceutical company that helps us to develop this into a drug. 
We are very happy with the support of various (inter)national funds and organizations.
However, this type of research just also needs time.
 
Are you familiar with the Duchenne Parent Project ?
http://www.parentprojectmd.org/news/latest/index.html
http://www.duchenne.nl
http://www.dmd.nl
 
Best wishes
Judith. 

25/01/03: Effect of zinc-carnosine complex on muscular function in frail distrophin-deficient (mdx) mice

25/01/03: Grant funds muscular dystrophy research at Children's

18/01/03: Cardiac assessment in childhood carriers of Duchenne and Becker muscular dystrophies (IN PRESS: Neuromuscular Disorders):

M.A. Nolan, O.D.H. Jones, R.L. Pedersen, H.M. Johnston

Cardiac disease in adult female carriers of the X-linked dystrophinopathies, Duchenne and Becker muscular dystrophies, is a wellrecognised entity. A single study has reported a 15% incidence of cardiac abnormalities in female carriers under 16 years. Our study aims, clinically and with electrocardiograph and echocardiograph, to determine the incidence of cardiac abnormality in young girls who are proven carriers of X-linked dystrophinopathies. Twenty-three girls aged 6.2–15.9 years were assessed. All had normal cardiac examination. None had electrocardiograph abnormalities consistent with dystrophic cardiomyopathy. Left ventricular fractional shortening ranged from 33 to 55% (normal . 28%). Septal thickness, posterior wall thickness and wall thickness ratio were within normal limits. No cardiac abnormalities have been demonstrated in young girls who are proven carriers of X-linked dystrophinopathies in our study. This has important implications for planning timing of carrier determination and cardiac assessment.

18/01/03: Current Concepts in Malignant Hyperthermia

Journal of Clinical Neuromuscular Disease 2002; 4(2):64-74 

Josef Finsterer, MD, PhD

Malignant hyperthermia (MH) is a rare, potentially lethal, clinically and genetically heterogeneous pharmacogenic myopathy, which during or after general anesthesia manifests as MH crisis (MHC) in genetically predisposed, but otherwise mostly normal, individuals (MH susceptibles) in response to anesthetic-triggering agents. MHC can also occur in patients with central core disease. MCH-like crises have been reported in those with Duchenne/Becker muscular dystrophy, myotonic dystrophy, mitochondriopathy, and various other conditions. MH susceptibility is diagnosed if there is an MHC in the individual or family history or by the in vitro caffeine-halothane contracture test. Although screening for mutations in the ryanodine-receptor-1 gene and the dihydropyridine-receptor gene, respectively, could further substantiate the diagnosis, the caffeine-halothane-contracture test still remains the gold standard for diagnosing MH susceptibility. The most well-known triggers of an MHC are depolarizing muscle relaxants and volatile anesthetics. Therapy of an MHC comprises discontinuation of triggering agents, oxygenation, and correction of the acidosis and electrolyte disturbances, treatment of arrhythmias, cooling, and dantrolene. If MH susceptibility is not known preoperatively and an MHC unexpectedly interrupts anesthesia, consultation by a specialist in MH susceptibility after anesthesia is essential to investigate the patient for MH susceptibility or subclinical myopathy, guide laboratory investigations, manage therapy, and counsel the family on further risk. To further reduce morbidity and mortality of those with MHC, anesthesiologists and neurologists should be well educated and should strengthen their clinical vigilance. Research should be intensified and extended with regard to the development of new in vitro tests to further elucidate the heterogeneous genetic background of MH susceptibility.

18/01/03: Inspiratory loading does not accelerate dystrophy in mdx mouse diaphragm: implications for regenerative therapy  

18/01/03: Umbilical cord matrix, a rich new stem cell source, study shows  

18/01/03: PharmaGap Patents new Method to Grow Skin Stem Cells

18/01/03: 2nd Cancer Is Attributed to Gene Used in French Test   

14/01/03: FDA PLACES TEMPORARY HALT ON GENE THERAPY TRIALS USING RETROVIRAL VECTORS IN BLOOD STEM CELLS

http://www.washingtonpost.com/wp-dyn/articles/A55889-2003Jan14.html

12/01/03: Designer Molecules Correct RNA Splicing Defects: New Strategy for Treating Many Diseases  

11/01/03: Comparative Effects of Two Ventilatory Modes on Speech in Tracheostomized Patients with Neuromuscular Disease

10/01/03: Reduction of blood loss using aprotonin during spinal surgery in children for non-idiopathic scoliosis. 

10/01/03: Advances in gene transfer into haematopoietic stem cells by adenoviral vectors

10/01/03: Autologous bone-marrow stem-cell transplantation for myocardial regeneration 

Reprogramming of bone marrow mesenchymal stem cells into cardiomyocytes

10/01/03: Melusin, a muscle-specific integrin beta(1)-interacting protein, is required to prevent cardiac failure in response to chronic pressure overload

10/01/03: High-efficiency recovery of functional hematopoietic progenitor and stem cells from human cord blood cryopreserved for 15 years

10/01/03: Distinct progenitor populations in skeletal muscle are bone marrow derived and exhibit different cell fates during vascular regeneration

07/01/03: e-mail from researchers 

- e-mail from Eric van Lunteren to our friend Julie Garcia:

Inotrophic effects of the K(+) channel blocker TEA on dystrophic (mdx and dy/dy) mouse diaphragm

I am not aware of any data on the use of K+ channel blockers for the treatment of humans with muscular dystrophy, so I really can't tell you how useful this will turn out to be clinically.  Although I do basic research in this area, I am not very involved in the clinical treatment of people with muscular dystrophies.  Thus it is possible that there may be some information along the lines you are seeking without my being aware of it.  Sorry I can't be of much help beyond this.

Erik van Lunteren


- e-mail from Jeffrey S. Chamberlain  to our friend Berit Sofie:

Gene therapy of muscular dystrophy

Adeno-associated virus vector-mediated gene transfer into dystrophin-deficient skeletal muscles evokes enhanced immune response against the transgene product

Functional correction of adult mdx mouse muscle using gutted adenoviral vectors expressing full-length dystrophin

Dear Berit,

Thank you for your interest in our work.  The goal of our lab, and many others, is to find a way to use gene therapy to treat muscular dystrophy.  Our main focus is on Duchenne Muscular Dystrophy (DMD), but we feel that the methods used to deliver a gene to muscle should be generally applicable to most types of muscular dystrophy.  The difficulties in developing gene therapy are many, but we are making good progress.  The studies now being performed all use animal models for muscular dystrophy.  My lab studies a strain of mice that have the same genetic defect as do patients with DMD.  These mice therefore allow us to test many potential approaches for therapy.  Previous work in mice has shown that if a new dystrophin gene can be delivered to muscle before the disease develops, that dystrophy can be prevented from occurring.  However, we are also interested to find out whether it might be possible to halt the disease, or even reverse some of the muscle damage, after the disease has already developed.  

We have taken several approaches to answering these questions.  First, we have been developing ‘shuttles’ that allow genes to be transferred into muscle cells.  Second, we have been developing ways to measure muscle function in the mice, so that we can find out what effects gene transfer has on muscle.  Third, we have been making many different types of dystrophin genes, both large and small versions, so that we have available several options to use with our different shuttles.  The shuttles are made from viruses, but first we remove from the virus those genes that might otherwise cause illness.  We have obtained encouraging results with two shuttles, adeno-associated virus, and adenoviral shuttles, each of which have been stripped of all viral genes.  Our most recent studies showed that the so-called “gutted’ adenoviral shuttle could transfer the full dystrophin protein to muscle cells.  Importantly, we found that when the gene was delivered to muscles of mice that had already developed a lot of muscle damage, we were able to reverse some of that damage. The importance of this work is that we now know that if the dystrophin gene and protein can be replaced in muscles, then it should be possible to not only halt the disease from getting worse, but also to reverse at least some of the pre-existing muscle damage.
It is important to remember that all of this work has been done in mice.  Also, the shuttles we are using have not been fully tested for their safety in humans.  Third, at present we are able to treat only a fairly small amount of muscle, even in the mice.  Thus, we still have a lot of work to do before we can hope to apply these results to patients.  We are continuing to test the safety of the shuttles, and we are working hard to find ways to deliver them to all the muscles of the body.  It is likely that we will be able to begin some very limited human clinical trials in the next 2-3 years that will be intended to test safety, and safety alone. We hope to use the adeno-associated virus vector in these studies.  If those studies go well, and if we can improve our methods to deliver shuttles to muscle, we would then be in a position to begin trying to improve muscle strength in patients.  I hope this work can proceed quickly, but it is very difficult work and very time consuming.  Nonetheless, I have a very dedicated group of scientists working extremely hard on these problems. 

 With best wishes

Jeffrey S. Chamberlain, Ph.D.

02/01/03: High-efficiency growth hormone releasing hormone plasmid vector administration into skeletal muscle mediated by electroporation in pigs

02/01/03: Heterogous Dystrophin mRNA Produced by a Novel Splice Acceptor Site Mutation in Intermediate Dystrophinopathy

 

                   2002 NEWS (JANUARY- DECEMBER)