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Anne E. Chiaramello Faculty Member

Positions

My 2001 NINDS-funded study led to the discovery of neuronal-specific regulation of mitochondrial biogenesis, an area largely unexplored. These studies made three substantial findings: 1) NeuroD6 plays an integrative role in coupling mitochondrial biogenesis within the early stages of neuronal differentiation, the timing of which is critical for proper neuritogenesis; 2) NeuroD6 increases the mitochondrial bioenergetic capacity of neuronal progenitors, thereby conferring tolerance to mitochondrial stressors, known to affect neural development; and 3) epigenomic regulation calibrates mitochondrial biogenesis and metabolic functions to match high energetic demand during the onset of neuronal differentiation. Building on these results, I shifted my emphasis toward translational research on the fatal mitochondrial disease MELAS (mitochondrial encephalopathy, lactic acidosis, stroke-like episodes). The two chief objectives of my NINDS-funded translational R21 grant were: 1) to generate a comprehensive biobank of fibroblasts derived from skin biopsies performed on MELAS patients to circumvent the lack of a MELAS animal model; and 2) to design a novel pharmacological therapeutic approach to alleviate the chronic energy deficit associated with MELAS. Our long-time clinical collaborator Dr. Gropman, a pediatric neurologist specializing in mitochondrial diseases at Children’s National Medical Center, has provided skin biopsies from MELAS patients under her care. I have assembled a cohort of 20 MELAS patients, all genetically diagnosed with the m.3243A>G variant, exhibiting an array of symptomatology, heteroplasmy, and age. MELAS fibroblasts were successfully derived and served as an “ex-vivo” cellular model to test our novel pharmaco-epigenomic strategy. Our compelling results show that our lead compound reduces the load of diseased mitochondria, enhances the mitochondrial energy metabolism, and rescues the mitochondrial mass. We expanded our initial study to investigate whether the m.3243A>G MELAS variant altered the nuclear epigenomics given the established mitochondrial-nuclear crosstalk. Our pilot ChIP-seq analysis provides the first evidence of a dysregulated epigenomic signature in MELAS fibroblasts, which offers novel insights into the pathogenic mechanisms of the disease. Our lead compound rescues the histone epigenomic signature of MELAS fibroblasts in several complementary nodes of mitochondrial genes playing central roles in OXPHOS, fatty acid metabolism and mitophagy. A recent axis of investigation in my laboratory pertains to the regulation of mitochondrial biogenesis and energy metabolism and to the development of a pharmacological strategy to rectify mitochondrial dysfunction in patients affected with the mitochondrial disease MELAS. I discovered a novel pharmaco-epigenomic approach to induce mitochondrial biogenesis and metabolic reprogramming in dermal fibroblasts derived from pediatric patients affected with intractable, progressive neurodegenerative diseases. We filed for a patent titled “Treatment for mitochondrial disease” (No. US 10,272,056 B2; international Application No. PCT/US2016/025668), which received notice of issuance by the U.S. Patents and Trademark Office in 2019. In my quest to develop a pharmaco-epigenomic therapeutic avenue for MELAS, I created the Mito-EpiGen Program at the George Washington School of Medicine and Health Sciences. I expanded our metabolic investigations to other inherited mitochondrial diseases, such as LHON-Plus and uncovered dysregulated energy reprogramming due to a defective interplay between mitochondrial oxidative phosphorylation and glycolysis. My translational research on LHON-Plus is funded by a Discovery Award from the U.S. Department of Defense. I generated a comprehensive biobank of fibroblasts derived from skin biopsies performed on MELAS or LHON-Plus patients to circumvent the lack of an animal model. I designed a novel pharmacological therapeutic approach to alleviate the chronic energy deficit due to Complex I deficiency shared MELAS and LHON-Plus patients. This led to our clinical study to investigate our therapeutic candidate in a basket clinical trial on patients affected with MELAS or LHON-Plus. These studies are funded by the National Center for Advancing Translational Sciences (NIH).

Research Areas

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