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 performing 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 are studying disease driving 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 have completed 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 was based on our careful natural history and clinical outcomes study. We are also adding novel clinical outcome measures such as dynamic breathing MRI to directly visualize the involvement of respiratory muscles. We are using and developing new next generation sequencing technology to identify new genes in our cohort of undiagnosed patients in collaboration with the as a member of the Center of Mendelian Genomics at MGH/Broad, continuously identifying novel disease genes, including the a novel syndrome of PIEZO2 deficiency, leading to loss of proprioception and touch and significant musculoskeletal deformities. We are continuing the evaluation of all the diverse manifestations of the PIEZO2 deficiency and in collaboration with the engineers in the NIH Gait Lab are working on developing a sensory exo-suit to help compensate for the deficiency of proprioception. Finally, in collaboration with Dr Steven Gray at UTSW 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) and are initiating a gene transfer study in this condition (ASPIRO), under the sponsorship of Audentes Therapeutics. Finally we are also initiating an AAV mediated gene transfer trial in infantile Pompe disease in collaboration with Dr Barry Byrne at the University of Florida under U01 mechanism with NHLBI.
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