Duchenne Muscular Dystrophy: Advances in Therapeutics PDF

Preface

Duchenne muscular dystrophy is a disease with both ancient and modern significance. It has likely been present in humans since the emergence of the species. The phenotype may have been recognized and recorded in ancient cave drawings, and the clinical and hereditary patterns were described in the medical literature a century and a half ago. Its modern significance lies in the fact that it was the first hereditary disorder whose genetic basis was identified by positional cloning in the molecular biology revolution of the late 20th century. Duchenne muscular dystrophy is among the most prevalent genetic disorders of childhood, it is the most common inherited disease in terms of new genetic mutations, and it is a lethal disease. Still, none of these factors have resulted in any major advances in treatment and it remains, to this day, an incurable and nearly untreatable condition. Corticosteroids provide temporary benefit, but with unacceptable side effects for long-term use. Physical therapy and prosthetics optimize muscle function but have no impact on disease progression. Assisted ventilation can prolong survival. However, even in combination, the prognosis for a boy diagnosed with Duchenne muscular dystrophy remains grim and the disease is almost as devastating today as it was when described by Edward Meryon in England and Guillaume Duchenne in France in the mid 19th century.

Nevertheless, hope persists and investigators relentlessly pursue therapeutic breakthroughs for the treatment of Duchenne muscular dystrophy and related disorders. As an X-linked recessive, single gene defect, the promise of gene therapy looms large. As a disease that may share common pathophysiological mechanisms with a plethora of related muscular dystrophies, the hope of pharmacological therapy that would be beneficial to all such disorders remains high. As a disease with progressive tissue degeneration, the emerging field of regenerative medicine offers optimism.

This book is intended to provide a summary on the state-of-the-art of current experimental approaches to treatments for Duchenne muscular dystrophy that are under active investigation. The clinical, genetic, and pathophysiological aspects of the disease are reviewed in the context of emerging therapeutic modalities. Next, the importance of accurate detection is highlighted by chapters on principles of diagnostic modalities and advances in molecular diagnostics. These fundamental considerations are then followed by chapters on advances in experimental therapeutics. Challenges to the development of treatments for Duchenne muscular dystrophy are emphasized, and guiding principles of therapeutics are laid out. The chapters on individual therapeutic modalities are divided, somewhat arbitrarily, into sections on pharmacological interventions, therapy based on principles of regenerative medicine, and last but not least, gene therapy. The authors have written these chapters within a historical context and with an eye to the future. Ultimately, these emerging therapeutics will need to be tested in human clinical trials, which for cell and gene therapy require navigating a large number of regulatory issues that vary from one country to another. As such, therapeutic advances will depend not only on scientific progress, but also on coordinated efforts of investigators, clinicians, ethicists, and policy makers. We hope that this book will be of interest to students of muscular dystrophies, whether they be clinicians or scientists, whose interests are directed to the ultimate challenge—finding a treatment and, finally, a cure for Duchenne muscular dystrophy and all other muscular dystrophies.