Therapeutics in Duchenne muscular dystrophy

SummaryDuchenne muscular dystrophy (DMD) is a fatal disorder affecting approximately 1 in 3500 live born males, characterized by progressive muscle weakness. Several different strategies are being investigated in developing a cure for this disorder. Until a cure is found, therapeutic and supportive care is essential in preventing complications and improving the afflicted child’s quality of life. Currently, corticosteroids are the only class of drug that has been extensively studied in this condition, with controversy existing over the use of these drugs, especially in light of the multiple side effects that may occur. The use of nutritional supplements has expanded in recent years as researchers improve our abilities to use gene and stem cell therapies, which will hopefully lead to a cure soon. This article discusses the importance of therapeutic interventions in children with DMD, the current debate over the use of corticosteroids to treat this disease, the growing use of natural supplements as a new means of treating these boys and provides an update on the current state of gene and stem cell therapies.

[1]  J. Miller,et al.  Clinical investigation of Duchenne muscular dystrophy. Interesting results in a trial of prednisone. , 1987, Archives of neurology.

[2]  M. Tarnopolsky,et al.  Nutritional therapy improves function and complements corticosteroid intervention in mdx mice , 2006, Muscle & nerve.

[3]  E. Barton,et al.  Systemic administration of L‐arginine benefits mdx skeletal muscle function , 2005, Muscle & nerve.

[4]  A. Pestronk,et al.  CINRG randomized controlled trial of creatine and glutamine in Duchenne muscular dystrophy , 2005, Annals of neurology.

[5]  K. Fischbeck,et al.  Gentamicin treatment of Duchenne and Becker muscular dystrophy due to nonsense mutations , 2001, Annals of neurology.

[6]  M. Tijssen,et al.  Transfer of the Full-Length Dystrophin-Coding Sequence into Muscle Cells by a Dual High-Capacity Hybrid Viral Vector with Site-Specific Integration Ability , 2005, Journal of Virology.

[7]  J. Deutekom.  Gene Therapy: The ‘pro-sense’ approach to Duchenne muscular dystrophy , 2005, European Journal of Human Genetics.

[8]  T. Rando,et al.  Rescue of dystrophin expression in mdx mouse muscle by RNA/DNA oligonucleotides. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[9]  Tor Ansved,et al.  Muscular dystrophies: influence of physical conditioning on the disease evolution , 2003, Current opinion in clinical nutrition and metabolic care.

[10]  N. Laing,et al.  Revertant fibres: a possible genetic therapy for Duchenne muscular dystrophy? , 1997, Neuromuscular Disorders.

[11]  Feste Nv.  Liberation of patients. , 1966 .

[12]  T. Krahn,et al.  First human myoblast transfer therapy continues to show dystrophin after 6 years. , 1997, Cell transplantation.

[13]  N. Stupka,et al.  The calcineurin signal transduction pathway is essential for successful muscle regeneration in mdx dystrophic mice , 2004, Acta Neuropathologica.

[14]  T. Do.  Orthopedic management of the muscular dystrophies , 2002, Current opinion in pediatrics.

[15]  P. Law.  Myoblast transfer therapy , 1993, The Lancet.

[16]  G. Hawker,et al.  Alendronate in the treatment of low bone mass in steroid-treated boys with Duchennes muscular dystrophy. , 2005, Archives of physical medicine and rehabilitation.

[17]  K. Davies,et al.  Dystrophin and related proteins. , 1993, Current opinion in genetics & development.

[18]  B. Nico,et al.  A multidisciplinary evaluation of the effectiveness of cyclosporine a in dystrophic mdx mice. , 2005, The American journal of pathology.

[19]  B. Benabdallah,et al.  Improved Success of Myoblast Transplantation in mdx Mice by Blocking the Myostatin Signal , 2005, Transplantation.

[20]  A. Manzur,et al.  Glucocorticoid corticosteroids for Duchenne muscular dystrophy. , 2004, The Cochrane database of systematic reviews.

[21]  G. Vrbóva,et al.  Therapeutic possibilities of chronic low frequency electrical stimulation in children with Duchenne muscular dystrophy , 1990, Journal of the Neurological Sciences.

[22]  T. Furlong.  Myoblast transplantation. , 1992, Science.

[23]  E. Hoffman,et al.  Prednisolone‐induced changes in dystrophic skeletal muscle , 2005, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[24]  D. Birnkrant,et al.  Management of the respiratory complications of neuromuscular diseases in the pediatric intensive care unit. , 1999, Journal of child neurology.

[25]  V. Dubowitz.  Prednisone in Duchenne dystrophy , 1991, Neuromuscular Disorders.

[26]  M. Grounds,et al.  Evidence of fusion between host and donor myoblasts in skeletal muscle grafts , 1978, Nature.

[27]  V. Dubowitz.  Responses of diseased muscle to electrical and mechanical intervention. , 1988, Ciba Foundation symposium.

[28]  S. Wilton,et al.  Antisense oligonucleotides in the treatment of Duchenne muscular dystrophy: Where are we now? , 2005, Neuromuscular Disorders.

[29]  E. Bertini,et al.  Motor function–muscle strength relationship in spinal muscular atrophy , 2004, Muscle & nerve.

[30]  I. Siegel,et al.  Failure of corticosteroid in the treatment of Duchenne (pseudo-hypertrophic) muscular dystrophy. Report of a clinically matched three year double-blind study. , 1974, IMJ. Illinois medical journal.

[31]  C. Mann,et al.  Functional amounts of dystrophin produced by skipping the mutated exon in the mdx dystrophic mouse , 2003, Nature Medicine.

[32]  U. Ruegg,et al.  Creatine supplementation reduces skeletal muscle degeneration and enhances mitochondrial function in mdx mice , 2002, Neuromuscular Disorders.

[33]  B. Alman,et al.  Deflazacort in Duchenne muscular dystrophy: a comparison of two different protocols , 2004, Neuromuscular Disorders.

[34]  D. Birnkrant,et al.  Topical Review: Management of the Respiratory Complications of Neuromuscular Diseases in the Pediatric Intensive Care Unit , 1999 .

[35]  J. Mendell,et al.  Mononuclear cell analysis of muscle biopsies in prednisone‐treated and untreated Duchenne muscular dystrophy , 1991, Neurology.

[36]  K. Wagner,et al.  Loss of myostatin attenuates severity of muscular dystrophy in mdx mice , 2002, Annals of neurology.

[37]  L. Kunkel,et al.  Conversion of mdx myofibres from dystrophin-negative to -positive by injection of normal myoblasts , 1989, Nature.

[38]  M. Brooke,et al.  Mononuclear cell analysis of muscle biopsies in prednisone‐ and azathioprine‐treated Duchenne muscular dystrophy , 1993, Neurology.

[39]  B. D. de Lateur,et al.  Effect on maximal strength of submaximal exercise in Duchenne muscular dystrophy. , 1979, American journal of physical medicine.

[40]  J. Miller,et al.  Randomized, double-blind six-month trial of prednisone in Duchenne's muscular dystrophy. , 1989, The New England journal of medicine.

[41]  L. McIntosh,et al.  Deflazacort but not prednisone improves both muscle repair and fiber growth in diaphragm and limb muscle in vivo in the mdx dystrophic mouse , 1996, Muscle & nerve.

[42]  J. Fock,et al.  Functional ability and muscle force in healthy children and ambulant Duchenne muscular dystrophy patients. , 2005, European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society.

[43]  C. Campbell,et al.  Deflazacort for the treatment of Duchenne Dystrophy: A systematic review , 2003, BMC neurology.

[44]  L. Kunkel,et al.  Long-term persistence of donor nuclei in a Duchenne muscular dystrophy patient receiving bone marrow transplantation. , 2002, The Journal of clinical investigation.

[45]  J. Bach,et al.  Prevention of pulmonary morbidity for patients with Duchenne muscular dystrophy. , 1997, Chest.

[46]  P. Fossier,et al.  Muscular nitric oxide synthase (muNOS) and utrophin , 2002, Journal of Physiology-Paris.

[47]  C. Schramm.  Current concepts of respiratory complications of neuromuscular disease in children , 2000, Current opinion in pediatrics.

[48]  A. Simonds,et al.  Impact of nasal ventilation on survival in hypercapnic Duchenne muscular dystrophy , 1998, Thorax.

[49]  D. Watt,et al.  Incorporation of donor muscle precursor cells into an area of muscle regeneration in the host mouse , 1982, Journal of the Neurological Sciences.

[50]  C. Caskey,et al.  A new adenoviral vector: Replacement of all viral coding sequences with 28 kb of DNA independently expressing both full-length dystrophin and beta-galactosidase. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[51]  S. Pandya,et al.  Practice Parameter: Corticosteroid treatment of Duchenne dystrophy , 2005, Neurology.

[52]  L. Merlini,et al.  Early prednisone treatment in Duchenne muscular dystrophy , 2003, Muscle & nerve.

[53]  I. Graham,et al.  Recombinant adeno-associated viral (rAAV) vectors as therapeutic tools for Duchenne muscular dystrophy (DMD) , 2004, Gene therapy.

[54]  M. Eagle.  Report on the Muscular Dystrophy Campaign workshop: Exercise in neuromuscular diseases Newcastle, January 2002 , 2002, Neuromuscular Disorders.

[55]  M. Tarnopolsky,et al.  Creatine monohydrate enhances strength and body composition in Duchenne muscular dystrophy , 2004, Neurology.

[56]  C. Silversides,et al.  Effects of deflazacort on left ventricular function in patients with Duchenne muscular dystrophy. , 2003, The American journal of cardiology.

[57]  Simon C Watkins,et al.  Gene transfer to muscle using herpes simplex virus-based vectors , 1997, Neuromuscular Disorders.

[58]  S. Matecki,et al.  l-arginine improves dystrophic phenotype in mdx mice , 2005, Neurobiology of Disease.

[59]  C. Angelini,et al.  Deflazacort in Duchenne dystrophy: Study of long‐term effect , 1994 .

[60]  Marc S. Williams.  Myostatin mutation associated with gross muscle hypertrophy in a child. , 2004, The New England journal of medicine.

[61]  P. Royston,et al.  Steroids in Duchenne muscular dystrophy; Pilot study of a new low-dosage schedule , 1993, Neuromuscular Disorders.

[62]  R. Mulligan,et al.  Dystrophin expression in the mdx mouse restored by stem cell transplantation , 1999, Nature.

[63]  Simon C Watkins,et al.  Herpes simplex virus vector‐mediated dystrophin gene transfer and expression in MDX mouse skeletal muscle , 1999, The journal of gene medicine.

[64]  Se-Jin Lee,et al.  Regulation of skeletal muscle mass in mice by a new TGF-p superfamily member , 1997, nature.

[65]  R. Kuncl,et al.  Prednisone treatment in Duchenne muscular dystrophy. Long-term benefit. , 1987, Archives of neurology.

[66]  R. Ahima,et al.  Functional improvement of dystrophic muscle by myostatin blockade , 2002, Nature.

[67]  N. Romero,et al.  Phase I study of dystrophin plasmid-based gene therapy in Duchenne/Becker muscular dystrophy. , 2004, Human gene therapy.

[68]  A. Pestronk,et al.  A randomized efficacy and safety trial of oxandrolone in the treatment of Duchenne dystrophy , 2001, Neurology.

[69]  G. V. Ommen,et al.  128th ENMC International Workshop on ‘Preclinical optimization and Phase I/II Clinical Trials Using Antisense Oligonucleotides in Duchenne Muscular Dystrophy’ 22–24 October 2004, Naarden, The Netherlands , 2005, Neuromuscular Disorders.

[70]  A. Pestronk,et al.  Long‐term benefit from prednisone therapy in Duchenne muscular dystrophy , 1991, Neurology.

[71]  D. Fehlings,et al.  Deflazacort treatment of Duchenne muscular dystrophy. , 2001, The Journal of pediatrics.

[72]  Robert G. Miller,et al.  Cyclosporine increases muscular force generation in Duhenne muscular dystrophy , 1993, Neurology.

[73]  Ice,et al.  MYOBLAST TRANSFER IN THE TREATMENT OF DUCHENNE ’ S MUSCULAR DYSTROPHY , 2000 .

[74]  Erwin Hauser,et al.  Recruitment of bone-marrow-derived cells by skeletal and cardiac muscle in adult dystrophic mdx mice , 1999, Anatomy and Embryology.

[75]  M. Tarnopolsky,et al.  Creatine monohydrate increases strength in patients with neuromuscular disease , 1999, Neurology.

[76]  J. Miller,et al.  Duchenne muscular dystrophy , 1989, Neurology.

[77]  A. Pestronk,et al.  Duchenne dystrophy , 1993, Neurology.

[78]  H. Sweeney,et al.  Aminoglycoside antibiotics restore dystrophin function to skeletal muscles of mdx mice. , 1999, The Journal of clinical investigation.

[79]  S. Braun,et al.  Immune rejection of human dystrophin following intramuscular injections of naked DNA in mdx mice , 2000, Gene Therapy.

[80]  Dongsheng Duan,et al.  Modular flexibility of dystrophin: Implications for gene therapy of Duchenne muscular dystrophy , 2002, Nature Medicine.

[81]  J. V. van Deutekom.  Gene Therapy: The ‘pro-sense’ approach to Duchenne muscular dystrophy , 2005, European journal of human genetics : EJHG.

[82]  A. Connolly,et al.  High dose weekly oral prednisone improves strength in boys with Duchenne muscular dystrophy , 2002, Neuromuscular Disorders.

[83]  M. Main,et al.  An effective, low-dosage, intermittent schedule of prednisolone in the long-term treatment of early cases of Duchenne dystrophy , 2002, Neuromuscular Disorders.

[84]  Juan Li,et al.  Adeno-associated virus vector carrying human minidystrophin genes effectively ameliorates muscular dystrophy in mdx mouse model. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[85]  J. Bach.  The historical role of the physiatrist in the management of Duchenne muscular dystrophy. A commentary. , 1996, American journal of physical medicine & rehabilitation.

[86]  S. Orcesi,et al.  A multicenter, double‐blind, randomized trial of deflazacort versus prednisone in Duchenne muscular dystrophy , 2000, Muscle & nerve.

[87]  H. Blau,et al.  Myoblast implantation in Duchenne muscular dystrophy: The San Francisco study , 1997, Muscle & nerve.

[88]  D. Watt,et al.  Use of mononuclear precursor cells to insert allogeneic genes into growing mouse muscles , 1984, Muscle & nerve.

[89]  E. Beckung,et al.  Muscle strength and motor function in children and adolescents with spinal muscular atrophy II and III. , 2001, European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society.

[90]  D. Wells,et al.  Immunological hurdles in the path to gene therapy for Duchenne muscular dystrophy , 2002, Expert Reviews in Molecular Medicine.

[91]  J. Galsworthy.  A commentary , 1908 .

[92]  A. Pestronk,et al.  Prednisone in Duchenne dystrophy. A randomized, controlled trial defining the time course and dose response. Clinical Investigation of Duchenne Dystrophy Group. , 1991, Archives of neurology.

[93]  A. Dubrovsky,et al.  Steroids in Duchenne muscular dystrophy--deflazacort trial. , 1991, Neuromuscular disorders : NMD.

[94]  R. Kapsa,et al.  For Personal Use. Only Reproduce with Permission from the Lancet Publishing Group. Molecular Pathology of Dmd Novel Therapies for Dmd Novel Therapies for Duchenne Muscular Dystrophy , 2022 .

[95]  F. Mavilio,et al.  Myogenic stem cells from the bone marrow: a therapeutic alternative for muscular dystrophy? , 2002, Neuromuscular Disorders.

[96]  A. Pestronk,et al.  A comparison of daily and alternate-day prednisone therapy in the treatment of Duchenne muscular dystrophy. , 1991, Archives of neurology.

[97]  B. Wong,et al.  Steroid Therapy and Cardiac Function in Duchenne Muscular Dystrophy , 2005, Pediatric Cardiology.

[98]  K. Patel,et al.  The function of Myostatin and strategies of Myostatin blockade—new hope for therapies aimed at promoting growth of skeletal muscle , 2005, Neuromuscular Disorders.