Last year, I became a Tenure Track Investigator and Chief of the Neuromuscular Symptoms Unit in the Tissue Injury Branch of the NINR. Prior to that, I was an Assistant Clinical Investigator in the same branch, a position I started in September of 2012. Over the past year, I have enrolled participants in three active protocols. The first protocol is a study to develop the first proxy motor outcome assessment in young children with neuromuscular disease, entitled Development of a Proxy Motor Outcome Measure in Young Children with Neuromuscular Disease. Over the past 2 years, we completed all necessary qualitative phone interviews for Aim 1 of the protocol. After new items were developed for the scale from these phone interviews and a meeting with a focus group of experts, the same focus group was queried via 2 rounds of emailing, using the Delphi method, to finalize the items of the new scale. We are presently setting up cognitive interviews for parents to assess whether the items developed have captured their intended meaning. The goal is to use the new scale in future clinical trials to decrease parent stress related to travel to research centers for clinical trials and to improve ecological validity of motor function by utilizing parent insight in the home setting. My team also continues to enroll participants in the second active protocol, The Calibration and Validation of the PROMIS and Neuro-QOL Questionnaires in Cerebral Palsy and Congenital Muscular Dystrophy. Preliminary item response theory analyses has begun with Columbia University, the collaborating institution, to validate these two questionnaires for use in neuromuscular disease patients. A third study, which received the Bench to Bedside Award in 2014, has also progressed over the past year. This is the first clinical trial in the world in any congenital myopathy, including RYR1-related congenital myopathy (RYR1-RM). It is a clinical trial of antioxidant therapy in patients with RYR1-RM, and 47 participants with this rare disease have been enrolled since March 2015. We have identified preliminary findings showing decreased oxidative stress in humans with RYR1, which are consistent with findings in three preclinical models (mice, zebrafish, human myotubes) and need to be substantiated with a larger sample size. This finding is encouraging because the treatment in this trial is a known antioxidant. We are also analyzing data describing the natural history of the disease from the first part of the study (prior to study drug/placebo administration). To date, we have confirmed that patients without treatment are stable over the 6 month time frame of the study, suggesting that if the trial shows improvement in the treatment arm compared to the placebo arm, the improvement will be attributed to the antioxidant. We continue to analyze significant date from cardiopulmonary exercise testing, arterial occlusion with near infrared spectroscopy, forced vital capacity, and the six minute walk test. We also identified changes in muscle ultrasound and muscle MRI in specific muscle groups in these patients. We have also drafted 3 manuscripts about the baseline findings of this research and will be publishing them this coming year. I continue to be an Associate Investigator on an NINDS protocol entitled Clinical and Molecular Manifestations of Neuromuscular and Neurogenetic Disorders of Childhood. As part of this protocol, I took a 5-year project with me from NINDS when left NINDS and started with NINR. The project was a 5-year study of clinical outcome measures in two subtypes of congenital muscular dystrophy, Collagen VI-Related Myopathy and Laminin 2 Related Muscular Dystrophy. The 5 year data is now in final stages of analysis and a manuscript is being prepared describing sensitivity to change of the main outcome measures over the entire 5 years. Several manuscripts arose from this data. A manuscript on the validation of the ActiGraph accelerometer in this population is being revised and resubmitted by my team. Another manuscript describing the validation of the PedsQoL is also in final stages of preparation. Finally, a report of the findings of all 5 years will be published later this year. Finally, I received the NIH Innovation Award with Dr. Brandon Harvey and Dr. Carsten Bonnemann this year to test drug compounds in primary cell culture and zebrafish models of RYR1-related myopathy using a novel calcium channel biomarker, which Dr. Harvey developed. Compounds that successfully treat these two preclinical models will then be tested at the NIH Clinical Center by my team in patients with RYR1-related myopathy to accelerate treatment for this condition. Manuscripts: 1. Jain, MS, Meilleur, KG...Bonnemann, C.G. (in preparation) Sensitivity to change of motor capacity measures in COL6-RD and LAMA2-RD. 2. Nichols. C., Jain, M.S., Meilleur, K.G., Wu, T., Collins, J.J., Waite, M., Dastgir, J., Donkervoort, S., Doung, T., Keller, K., Leach, M.E., Lott, D.J., McGuire, M.N., Nelson, L., Rutkowski, A., Vuillerot, C., Bnnemann, C.G., Lehky, T.J. (2017) Electrical impedance myography (EIM) in individuals with COL6 and LAMA2 congenital muscular dystrophy: a cross-sectional and two-year analysis. Muscle & Nerve, doi:10.1002/mus.25629 3. Bendixen, R.M., Butrum, J., Jain, M., Parks, R., Hodsdon, B., Nichols, C., Hsia, M., Nelson, L., Keller, K.C., McGuire, M., Elliott., J.S., Linton, M.M., Arveson, I.C., Tounkara, F., Vasavada, R., Hartnett, E., Punjabi, M., Donkervoort, S., Dastgir, J., Leach, M.E., Rutkowski, A., Waite, M., Collins, J., Bonnemann, C.G., Meilleur, K.G. (2017). Upper Extremity Outcome Measures for Collagen VI-related Myopathy and LAMA2-related Muscular Dystrophy. Neuromusc Disord doi: 10.1016/j.nmd.2016.11.017. 4. Witherspoon, J.W. & Meilleur, K.G. (2016) Review of RyR1 Pathway and Associated Pathomechanisms. Acta Neuropath Comm.
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