Muscle disease represents an important health threat to the general population. There is essentially no cure. Gene therapy holds great promise to correct the genetic defects and eventually achieve full recovery in these diseases. Significant progresses have been made in the field of muscle gene therapy over the last few years. The development of novel gene delivery vectors has substantially enhanced specificity and efficiency of muscle gene delivery. The new knowledge on the immune response to viral vectors has added new insight in overcoming the immune obstacles. Most importantly, the field has finally moved from small experimental animal models to human patients. This book will bring together the leaders in the field of muscle gene transfer to provide an updated overview on the progress of muscle gene therapy. It will also highlight important clinical applications of muscle gene therapy.
Gene therapy offers many conceptual advantages to treat muscle diseases, especially various forms of muscular dystrophies; however, it faces a number of unique challenges, including the need to deliver a therapeutic vector to all muscles throughout the body. In Muscle Gene Therapy: Methods and Protocols, expert researchers in the field present a collection of techniques aimed at bridging the translational gap in muscle gene therapy between the prevalent rodent models and vitally important larger animal models. Divided into three sections, this volume examines basic protocols for optimizing the muscle gene expression cassette and for evaluating the therapeutic outcomes, new developments in muscle gene therapy technology such as adeno-associated viral vector (AAV), oligonucleotide-mediated exon-skipping, and novel RNA-based strategies, and step-by-step guidance on muscle gene delivery in swine, ovine, canine, and non-human primates. Written in the highly successful Methods in Molecular BiologyTM series format, chapters include introductions to their respective topics, lists of the necessary materials and reagents, detailed, readily reproducible laboratory protocols, and tips on troubleshooting and avoiding known pitfalls. Authoritative and cutting-edge, Muscle Gene Therapy: Methods and Protocols serves as an invaluable resource for graduate students, post-doctoral fellows, and principle investigators pursuing the crucial advancement of muscle disease gene therapy in the hope of someday curing these debilitating disorders.
Duchenne Muscular Dystrophy (DMD) is one of the most prevalent genetic disorders of childhood and currently stands as an incurable condition. This authoritative guide provides a clear overview of the latest current and experimental approaches to the treatment of DMD and examines the clinical, genetic, and pathophysiological aspects of the disease i
Duchenne muscular dystrophy (DMD) is a fatal genetic muscle disease with no cure. DMD results from mutations in a critical muscle protein called dystrophin. Children born with DMD suffer severe muscle wasting leading to progressive weakness and paralysis. Patients usually die of respiratory or heart failure before the age of thirty. Gene therapy raises the hope of a cure for DMD heart disease. While significant strides have been made towards therapy for skeletal muscle disease, development of heart gene therapy lags behind. The seminal questions for realization of heart gene therapy of DMD include; developing an animal model, determining dosage, finding the correct gene, developing the vehicle for gene therapy and optimizing gene delivery. This dissertation details critical advancements towards gene therapy for DMD heart disease. First, we developed an animal model of DMD heart disease in the mdx mouse. We then determined that 50% mosaic dystrophin expression was sufficient to prevent DMD heart disease in this model. Next, we established that the truncated mini-dystrophin gene was capable of ameliorating DMD heart disease in the mdx mouse through cardiac specific transgenic expression. Then, we established the adeno-associated virus (AAV) as a vehicle for DMD heart gene therapy regardless of mouse age or the route of administration. Finally, we discovered that AAV-mediated truncated dystrophin gene therapy prevented DMD heart disease in neonatal mdx mice and ameliorated heart disease in symptomatic mdx mice. This work represents significant progress towards realization of an effective therapy for DMD heart disease.
Muscle disease represents an important health threat to the general population. There is essentially no cure. Gene therapy holds great promise to correct the genetic defects and eventually achieve full recovery in these diseases. Significant progresses have been made in the field of muscle gene therapy over the last few years. The development of novel gene delivery vectors has substantially enhanced specificity and efficiency of muscle gene delivery. The new knowledge on the immune response to viral vectors has added new insight in overcoming the immune obstacles. Most importantly, the field has finally moved from small experimental animal models to human patients. This book will bring together the leaders in the field of muscle gene transfer to provide an updated overview on the progress of muscle gene therapy. It will also highlight important clinical applications of muscle gene therapy.
Duchenne Muscular Dystrophy, an inherited and progressive muscle wasting disease, is one of the most common single gene disorders found in the developed world. In this fourth edition of the classic monograph on the topic, Alan Emery and Francesco Muntoni are joined by Rosaline Quinlivan, Consultant in Neuromuscular Disorders, to provide a thorough update on all aspects of the disorder. Recent understanding of the nature of the genetic defect responsible for Duchenne Muscular Dystrophy and isolation of the protein dystrophin has led to the development of new theories for the disease's pathogenesis. This new edition incorporates these advances from the field of molecular biology, and describes the resultant opportunities for screening, prenatal diagnosis, genetic counselling and from recent pioneering work with anti-sense oligonucleotides, the possibility of effective RNA therapy. Although there is still no cure for the disorder, there have been significant developments concerning the gene basis, publication of standards of care guidelines, and improvements in management leading to significantly longer survival, particularly with cardio-pulmonary care. The authors also investigate other forms of pharmacological, cellular and gene therapies. Duchenne Muscular Dystrophy will be essential reading not only for scientists and clinicians, but will also appeal to therapists and other professionals involved in the care of patients with muscular dystrophy.
Duchenne muscular dystrophy (DMD) is a lethal disease caused by the loss of the dystrophin protein. Loss of mobility is a key clinical presentation in DMD. It is believed that deterioration in the mechanical properties (contractile and passive properties) of skeletal muscle contribute to reduction in mobility. These two sets of properties are inseparable aspects of muscle function. For example, elbow flexion is accomplished by the contraction of muscles in the anterior compartment of the upper arm and the passive stretch of muscles in the posterior compartment of the upper arm. To improve mobility of patients, both contractile and passive properties must be restored. Gene therapy holds great promise for treating DMD. Restoration of dystrophin expression using gene replacement strategies has improved the contractile force in mouse models of DMD. However, it is not yet known if gene replacement can also improve the passive properties. To address this concern, I performed comprehensive studies in my dissertation that provided new information on the passive properties changes in skeletal muscles of murine models of DMD, and have also offered new insights on how different strategies of gene replacement therapy may help improve the passive muscle properties in DMD. Together, these studies provided support to further develop dystrophin gene therapy to improve the loss of mobility in DMD patients.
Skeletal muscle is a highly plastic organ that is modulated by various pathways controlling protein turnover. Muscle loss is common in muscular dystrophy, in which marked loss of various proteins such as the dystrophin-glycoprotein complex occurs around muscle fibers. This book provides a comprehensive overview of the various muscular dystrophies, including characteristics, diagnosis, and classification. General treatment of drugs (e.g. corticosteroids) and physical therapy for muscular dystrophies are discussed. In addition, current applications for cell and tissue engineering using muscle stem cells or gene therapy are introduced. This book also deals with the recent advances in appropriate models of drug screening using cell cultures or mammalian organs in vitro in this field.
This illustrated and comprehensive historical account deals successively with the early history of muscular dystrophy, refinements of its clinical picture, heterogeneity and the classification and description of the disease, the biochemistry, pathogenesis and the molecular genetics of the disorder and, finally, gene therapy.
This book presents muscular dystrophy (MD) as a group of genetic diseases with a worldwide occurrence of about 1 in 3,500 births that causes muscle wasting and weakening. It describes Duchenne MD as the most common type of MD, almost exclusively affecting males at a rate of about 1 in 5,000 boys, and eight rarer types of MD that are categorized by age of onset, muscles affected, disease progression, severity of symptoms, and health complications. The author describes how physical examination, muscle biopsy, medical imaging, and genetic testing is used to diagnose MD He further explains the underlying causes of the various types of MD as mutations in genes that encode proteins needed for the development, function, maintenance, and replacement of muscle cells and illustrates patterns by which they are inherited. There is no treatment that can reverse the progressive deterioration of muscles caused by MD, but the book offers insight into drug treatments and physical therapies that help maintain muscle strength and reduce health complications. It concludes with explanations of promising new ways to treat or perhaps cure MD, including experimental drugs, stem cell therapy, and gene therapy.
Inhaltsangabe:Abstract: Muscle injuries constitute up to 55% of all injuries sustained in sport events. The incidence and severity of these injuries is certainly greater in some sport modalities than in others. Significant morbidity, such as early functional and structural deficits, reinjury, atrophy, contracture, and pain, often occurs following muscle injuries, leading to loss of training and competition time. Healing of these injuries is a complex phenomenon depending of multiple factors, which are both within and outside the control of the clinician. On the whole, the best treatment regime has not yet been clearly defined, and the recommended treatment regimens have varied widely, depending on the severity of the injury. Injuries to skeletal muscle during sport can occur by different mechanisms including blunt trauma in the case of contusions or stretch-induced injury in muscle strains. Another type of injury are those induced by laceration to the muscle but these are not particularly relevant in sport. A further complication of muscle injuries is the compartment syndrome, which generally occurs when tissues within an osteofascial compartment are compromised by increased pressure within the compartment. Muscle strain may be a consequence of eccentric exercise, when the muscle develops tension during this type of lengthening contraction. These injuries are especially common in high-velocity situations in sports that require sprinting or jumping such as basketball, American football, rugby or soccer. The most susceptible muscles are the biarticular muscles such as the rectus femoris, the hamstrings and the gastrocnemius. Interestingly, a high percentage of type II fibers or fast twitch fibers has been attributed to make muscles susceptible to strains because of their ability to contract fast and produce high forces. Furthermore, most muscle strains occur at or very near to the myotendinous junction (MTJ) of the superficial muscles working across two joints. In the worst case, muscle stretch-induced injuries can lead to muscle ruptures or tears. Jarvinen et al. have classified muscle strains into three categories according to their severity: Mild (first degree) strains where a few muscle fibers are torn, with minor swelling and discomfort but no or only minimal loss of strength and restriction of movements; Moderate (second degree) strains where there is a greater damage of the muscle with detection of a bleeding in the MRI scan and a moderate [...]
