Molecular and Clinical Manifestations of Matrix and Aggregate Myopathies

National Institute Of Neurological Disorders And Stroke

Investigators

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Abstract

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 are 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 is under development 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 specially created humanized mouse model. In a clinical cohort of patients with the most common of the matrix CMDs (COL6 and LAMA2), we have completed a phase I pharmacokinetics 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 as well as those for younger patients. 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 a new form of childhood ALS (SPTLC1) as well as several new muscle disorders (TAMM41, HNRNPA2B1, FXR1). 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), which continues with dose escalation and protocol refinements. 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 participating in a gene transfer study in this condition (ASPIRO), under the sponsorship of Astellas Gene Therapies. Finally we are also working with NCATS to develop a platform gene therapy approach to ultrarare disorders of the neuromuscular junction (PaveGT).