The Neuromuscular and Neurogenetic Disorders of Childhood Section (NNDCS) is dedicated to elucidating the genetic and pathophysiologic basis of early-onset neuromuscular disorders, to exploring therapeutic approaches to these conditions and to bringing first clinical trials to patients affected by these disorders. To accomplish these goals, we are using next generation genomic technology, tissue, cellular and animal models in the laboratory, while in the clinic we are using outcome measures and biomarker research, the development of phenotyping tools and novel trial designs to enable first clinical trials in patients. A particular focus in the section is on early onset muscle disorders caused by mutations in genes coding for components of the muscle extracellular matrix and its receptors (often falling within the group of Congenital Muscular Dystrophies, CMD) and on reducing body myopathy, a severe early onset myopathy with aggregate formation. For the matrix myopathies we will be studying the mechanisms of muscle involvement in mouse models, in particular as they relate to atrophy, failing regeneration and abnormal growth factor signaling in the muscle. A pathway independent approach directed at the causative mutation will be developed for dominant negative mutations in collagen VI. We also discovered a novel deep intronic mutation in COL6A1 causing inclusion of a dominant negative pseudo-exon and are developing a therapeutic approach to this mutation. In a clinical cohort of patients with the most common of the matrix CMDs (COL6 and LAMA2) we are now conduction a phase I pk study under sponsorship of Santhera pharmaceutical (Congenital Muscular Dystrophy Ascending Multiple Dose Cohort Study Analyzing Pharmacokinetics at Three Dose Levels In Children and Adolescents With Assessment of Safety and Tolerability of Omigapil (CALLISTO, NCT01805024). This trial is based on our careful natural history and clinical outcomes study. We are using next generation sequencing technology to identify new genes in our cohort of undiagnosed patients, including a novel syndrome of congenital muscular dystrophy with sensorineural deafness and a group of patients with collagen VI-like disorders, and a novel syndrome of PIEZO2 deficiency, leading to loss of proprioception and touch and significant musculoskeletal deformities. Finally, in collaboration with Dr Steven Gray at the University of North Carolina we are performing a first trial of intrathecal gene transfer in giant axonal neuropathy, using scAAV9/JeT-GAN, (Intrathecal Administration of scAAV9/JeT-GAN for the Treatment of Giant Axonal Neuropathy, NCT02362438). We are also participating in a study to define natural history and outcome measures in the congenital myopathy myotubular myopathy (A Clinical Assessment Study in X-Linked Myotubular Myopathy (XLMTM) Subjects (INCEPTUS, NCT02704273) in preparation for a gene transfer study in this condition, under the sponsorship of Audentes Therapsutics.
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