Since November 2016, I have been a Tenure Track Investigator and the 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 completed data collection on all three of my clinical protocols. Additionally, the lab component of my program has grown substantially. Data collection for the following three protocols was completed: 1) 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, was completed through Aims 1 and 2. The goal of this study 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.
Aim 1 : My team completed all necessary qualitative phone interviews. After a meeting with the focus group of experts, items were developed for the new scale from these interviews. Then, the same focus group was queried via 2 rounds of emailing, using the Delphi method, to finalize the items. This year, we completed the cognitive interviews with parents to assess whether the items captured their intended meaning. The next step will be to finalize the items using qualitative data analysis and then validate them in a future protocol with different parent participants. 2) My team also completed enrollment of participants in a second protocol, The Calibration and Validation of the PROMIS and Neuro-QOL Questionnaires in Cerebral Palsy and Congenital Muscular Dystrophy. This data is currently being cleaned, and preliminary item response theory analyses have begun with Columbia University, the lead institution, to validate these two questionnaires for use in neuromuscular disease patients. 3) A third study, which received the Bench to Bedside Award in 2013, has also completed enrollment over the past year. This was the first clinical trial in the world in any congenital myopathy, including RYR1-related congenital myopathy (RYR1-RM). In this trial of antioxidant therapy in patients with RYR1-RM, 53 participants with this rare disease and 10 healthy volunteers were enrolled since March 2015. We have identified preliminary findings showing increased oxidative stress in humans with RYR1, which are consistent with findings in three preclinical models (mice, zebrafish, human myotubes). This finding is encouraging because the treatment in this trial is a known antioxidant. Data is now locked and under final analysis. We have also been analyzing 6-month natural history data describing from the first part of the study (prior to study drug/placebo administration). We have observed that subjects without treatment are stable over the 6-month time frame of the study, as expected. For example, we recently published a stable 6-month time course, as evaluated by the 6-minute walk test. This suggests that if the trial shows improvement in the treatment arm compared to the placebo arm, the improvement may be attributed to the antioxidant. We continue to analyze natural history data from additional outcomes such as cardiopulmonary exercise testing, arterial occlusion with near infrared spectroscopy, and forced vital capacity. The lab component of my research program has grown substantially, in large part due to my team receiving the Innovation Award last year in collaboration with Drs. Harvey (NIDA) and Bonnemann (NINDS).
The aims of the award were 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. This year, one of the lead FDA approved compounds identified through a drug screen with Dr. Henderson at NCATS showed improvement in our hands in both primary muscle cells from healthy donors and the RYR1 zebrafish model. We are repeating this experiment in the fish and in primary myoblasts from patients as well as testing additional compounds. Additional work in the lab includes the study of variants of uncertain significance in RYR1, which is a very large gene. Many participants in the recently completed NAC trial have genetic variations in the RYR1 gene that are classified as VUS due little or no clinical and/or functional information. My laboratory is setting up a calcium imaging workstation that will allow us to functionally characterize some of these variants, using the base-editing technology of CRISPR-Cas9 to introduce the variations into human iPSCs and HEK-293 cells. I also received the NIH Bench to Bedside award this year to perform a clinical trial of a novel compound over the next two years in collaboration with a pharmaceutical sponsor. Finally, 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 I left NINDS and started with NINR. The project was a 5-year natural history and clinical outcome measure validation study 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 manuscript preparation and describes sensitivity to change of the main outcome measures over the entire 5 years. Another manuscript describing the validation of the PedsQoL is also in final stages of preparation.
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