The NAMDC Pilot Project program was initiated in 2011 as an important component of our RDCRN U54 Cooperative Agreement. Three pilot awards have been given. The first, led by Dr. Juan Pascual (University of Texas Southwestern Medical School) will use 7T nuclear magnetic resonance (NMR) spectroscopy (MRS) to characterize metabolites in brain and skeletal muscle of patients with mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). This project will non-invasively reveal MELAS metabolic biomarkers that may be relevant to other mitochondrial disorders and could potentially be used to monitor disease progression and outcomes in clinical trials. The second pilot grant, directed by Dr. Marni Falk, (Children's Hospital of Philadelphia), will support development of critical software pipeline for the Mitochondrial Disease Sequence Data Resource (MSeqDR) Consortium, an international collaborative effort to identify and prioritize the specific whole-exome sequence (WES) data analysis needs of the mitochondrial disease community. After being developed, the MSeqDR will be linked to the NAMDC Clinical Registry where it will provide a powerful data-mining tool to study genotype-phenotype relationships. The third pilot award is a natural history study led by Dr. Sumit Parikh (Cleveland Clinic). This study will characterize the phenotypes, genotypes, and progression of Pearson syndrome. This study will be continued as part of the NAMDC Clinical Registry (Project 1). Dr. Fernando Scaglia proposes a novel phase I dose-finding and safety study of long-term citrulline supplementation in patients with MELAS due to the m.3243A>G mitochondrial DNA mutation. Dr. Scaglia's strong preliminary studies indicate that patients with MELAS have a deficiency of nitric oxide (NO), which can be ameliorated by citrulline over short periods (up to 48 hours). In this 2-year pilot study. Dr. Scaglia proposes to administer citrulline to subjects with MELAS to identify the maximum tolerated dose over four months of follow-up. Once established, this dose will be used in a future clinical trial. Data on NO synthesis production, biomarkers of mitochondrial dysfunction, and cerebral blood flow in the study subjects will also be collected as pilot data.

RELEVANCE (See instructions): The 3 current and 1 proposed NAMDC pilot projects focus on biomarkers, diagnosis, natural history, and treatment of mitochondrial diseases. Development of biomarkers, improving diagnostic tools, and characterizing natural history, and testing therapies for mitochondrial diseases are critical to advance this field and to help afflicted individuals.