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. In a clinical cohort of patients with the most common of the matrix CMDs (COL6 and LAMA2) we are preparing for clinical trial with a 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. 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.
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