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J. Andoni Urtizberea
Innovative therapies & neuromuscular disorders: the clinician’s perspective
Neuromuscular disorders are a quite heterogeneous group of disorders a great majority of which are genetically determined. All have in common a defect in one component of the motor that usually leads, up to a point, to paralysis. They have been considered for decades as incurable due to the complexity of their pathogenesis and also because they were essentially rare diseases. Among the main innovative therapies available nowadays at bedside is gene therapy and antisense-oligonucleotides (ASO).
Gene therapy is a concept born more than thirty years ago that went through ups and downs, swaying between really impressive biological achievements, overoptimism and safety concerns. The current landscape has totally changed within a couple of years. Gene therapy is a fairly sophisticated technique now being mastered not only at the benchside but also by pharmaceutical manufacturers capable of designing successful industrial processes meant to meet the needs. Gene therapy has gradually invaded the neuromuscular field at the clinical level, notably in three emblematic diseases: spinal muscular atrophy (SMA), Duchenne Muscular Dystrophy (DMD) and myotubular myopathy (MTM) with variable outcomes. Other conditions should follow soon (Limb Girdle Muscular Dystrophies, for instance). For clinicians and as potential prescribers, though, the principle ‘Do no harm’ should always apply. Expectations in terms of function and quality of life must be weighed against the magnitude of risks taken. Uneasy access to these hitherto very expensive cutting-edge therapies on the one hand and safety issues on the other are the two major real-life concerns that may impede the clinical development of gene therapy.
Anti-sense oligonucleotides (ASO) are small pieces of RNA, rather easy to get synthesized and capable of fixing a faulty disease-causing gene. Injected regionally or systemically, they allow the re-expression of the missing protein with a fairly good safety profile. To achieve this prowess, some of them are targeted to skip specific exons of interest. An outstanding illustration of personalized medicine. ASO showed effectiveness both in SMA and DMD. The main difference with gene therapy lies in the need to re-administer such molecules on a regular basis in order to achieve a sustainable clinical benefit.
Isabelle Richard
Innovative therapies in neuromuscular disorders: the scientist's perspective
Muscular dystrophies (MD) are a group of diseases where the main innovative therapies available nowadays (gene replacement and antisense-oligonucleotides) have been tested at clinical level. The most frequent MD forms include Duchenne Muscular Dystrophy (DMD), due to mutations in Dystrophin, a large protein important for the resistance of muscle fibers and the groups of Limb-girdle muscular dystrophies (LGMD). More than 30 different genetic identities have been identified so far in the latter group. MD are characterized by weakness and progressive muscular atrophy, leading to loss of motor function that can be associated with respiratory and cardiac problems. None of these diseases is curable today.
Gene replacement utilizes viral vectors derived from the Adeno-Associated Virus (AAV) to deliver a normal copy of the gene in muscle. AAV vectors have emerged as effective for in vivo gene therapy. Even if the muscle tissue represents a challenge both in term of delivery and vector production, gene therapy is now at clinical level for both DMD and LGMD. In the case of DMD, because the size of the dystrophin gene exceed the encapsidation capacity of this vector, strategies relying on the use of a reduced form of dystrophin called minidystrophin have been designed. We have demonstrated the proof-of-principle of the efficiency of the gene therapy approach for several forms of LGMD. Interestingly, each gene transfer can present particularities that may requires specific adaptations to ensure the efficiency and safety of the approach. Efforts are being pursued towards clinical applications in these diseases.
Orchard Therapeutics, North America
Dr. Denise Carbonaro-Sarracino is the Senior Manager of Medical Affairs at Orchard Therapeutics. She received her B.A. in Biology and Psychology at Ithaca College, New York, followed by an M.S. degree in Animal science and behavior from Texas A&M University. She received her PhD on Systems Biology and Disease in 2009 at the University of Southern California in Los Angeles.
She was a research specialist at Children's Hospital Los Angeles in California and project scientist in the department of Microbiology, Immunology, and Molecular Genetics at the University of California. She worked as a pre-clinical scientist at Orchard Therapeutics. She has great interest in the gene therapy of immunodeficiencys, about which she has given multiple talks, in addition to the gene therapy of mitochondrial disease and lysosomal disorders, as well as an interest in gene transfer using viral vectors.
Genethon, France
Dr. Isabelle RICHARD is a research Director at the CNRS. She is heading the Muscular Dystrophy team within the INSERM unit U951 at Genethon, Evry, France. Isabelle Richard is an expert in neuromuscular diseases. She has published more than 170 scientific publications on genetics of muscular dystrophies, identification of pathophysiological mechanism of the diseases, identification of biomarkers, development of animal models and proof-of principle of therapeutic strategies especially gene therapy. She is also involved in translating different gene therapies for LGMD into the clinics. She is a cofounder of the biotech company, Atamyo Therapeutics.
Institut de Myologie, France
J. Andoni URTIZBEREA, (MD, MSc), aged 62, is a French physician trained in Paris University (1983-1987) and certified both in paediatrics and PMR (physical medicine and rehabilitation). After graduating in parallel from the Institut d’Etudes Politiques de Paris in 1987, he served many years as Medical Director of the AFM-Telethon and then as General Delegate of the Institut de Myologie of Paris (1993-2000). As Scientific Director of the European Neuromuscular Center in the Netherlands and together with AFM’s support (ENMC, 1999-2005), he contributed to the establishment of many worldwide networks in myology, an emerging discipline dedicated to muscle and related disorders (Duchenne muscular dystrophy and spinal muscular atrophy among others).
He served until December 2019 as a part-time clinical myologist in Hendaye, France (APHP) and as deputy coordinator of the French Neuromuscular Network (FILNEMUS) in Marseilles. Over the past twenty years, he headed various worldwide educational events dedicated to myology (in France, Russia, Latin America and, more recently in the Middle-East). He is a regular visiting professor in various countries and a consultant for many pharma involved in the field. Ideally located at the intersection of industry, patient advocacy groups and academia, his main objective is to raise more awareness about these rare conditions notably in emerging countries and more specifically in the context of novel cutting-edge therapies. Dr. Urtizberea knows quite well the Middle-East, the Indian sub-continent, Russia and Latin America. More recently (2016), and together with Prof. André Megarbané (Beirut, Lebanon), he co-founded ‘Maladies Orphelines Sans Frontières’ (MOSF), an NGO dedicated to humanitarian relief in the field of rare diseases.
