The Mitochondria – Epigenetics and Genetics Program (Mito-EpiGen) is a multidisciplinary research program dedicated to find a cure for pediatric inherited mitochondrial diseases. These mitochondrial diseases are due to mutations in the nuclear or mitochondrial genome affecting the oxidative phosphorylation (OXPHOS) system responsible for ATP synthesis. Thus, patients affected with a mitochondrial disease suffer from chronic energy deficit and exhibit a constellation of complex neurological and multisystemic symptoms. These diseases can manifest at any age, ranging from the neonatal phase to adulthood with variable severity.
The Mito-EpiGen Program, created at the George Washington University School of Medicine and Health Sciences, is under the directorship of Dr. Anne Chiaramello. It includes two interlinked components to advance innovative biomedical research in mitochondrial diseases:
- Translational research in the laboratory of Dr. Anne Chiaramello at the George Washington University School of Medicine and Health Sciences. Her translational and pre-clinical studies are funded by the Department of Defense and the National Center for Advancing Translational Sciences (NCATS) of the National Institute of Health, respectively. Dr. Martine Uittenbogaard is the Deputy Scientific Director and specialized in mitochondrial functional investigations and mitochondrial genetics. She has established protocols to derive fibroblasts from patient’s skin biopsy to determine the patient’s mitochondrial signature and to screen pharmacological molecules with therapeutic potential for rescuing the mitochondrial phenotype caused by MELAS or LHON-Plus.
- Clinical research is performed in collaboration with Dr. Debra Regier, MD, PhD, and Dr. Wei-Liang Chen, MD, under the auspices of Children’s National Hospital. Dr. Regier is the Director of the Children’s National Rare Disease Institute and Division Chief of Genetics and Metabolism. She has extensive experience in diagnosing and treating patients with suspected mitochondrial disorders. Dr. Chen is a pediatric neurologist, neurogenetic, and neurophysiologist with a clinical expertise in rare neurogenetic conditions, molecular diagnostics and complex genotype-phenotype correlation.
The Mito-EpiGen Program focuses on two maternally inherited mitochondrial diseases, Mitochondrial Encephalopathy Lactic Acidosis and Stroke-like episodes (MELAS) and Leber’s Hereditary Optic Neuropathy (LHON-Plus). Both maternally inherited diseases are incurable and progressive with no effective therapeutic intervention. Currently, patients only have access to palliative therapies that fail to halt progression of their phenotypic manifestations, resulting in poor quality of life and significant morbidity. Patients with MELAS are diagnosed during childhood or young adulthood, while patients with LHON-Plus are predominantly diagnosed during adulthood.
Both diseases have divergent and overlapping clinical neurological and non-neurological symptoms due to chronic energy (ATP) deficit as a consequence of mitochondrial dysfunction caused by specific pathogenic mitochondrial variants. This ATP deficit affects organs with high energy demands such as the nervous, musculoskeletal, and cardiac systems. Patients with MELAS exhibit a heterogenous symptomatology such as stroke-like episodes, lactic acidosis, encephalopathy characterized with seizures, migraines, tremors, cognitive deficits, vision loss, hearing loss, muscle weakness, peripheral neuropathy, and cardiomyopathy. Patients with LHON-Plus exhibit bilateral vision impairment and extra-ocular symptoms, many of them overlapping with those of MELAS patients.
The Mito-EpiGen Program provides an interactive infrastructure for our ongoing collaborative investigations between translational researchers and clinicians to test our small molecule-based mitochondrial therapy in patients with MELAS or LHON-Plus. Pre-clinical studies conducted by Dr. Chiaramello and her team have provided the proof-of-concept of their personalized-based approach showing that this small molecule prodrug rescues the MELAS and LHON-Plus mitochondrial phenotype (profound mitochondrial dysfunction) of patient-derived cells.
Dr. Chiaramello’s clinical studies are currently funded by the National Center for Advancing Translational Sciences (NCATS). She received FDA authorization to conduct the first basket clinical trial on MELAS and LHON-Plus with the chief objective to mitigate the chronic energy deficit, and to ameliorate their quality of life by curtailing key debilitating symptoms.
Dr. Chiaramello has established partnerships with several patient advocacy groups for key input on disease measurements directly relevant to the patient’s quality of life. During Spring 2025, 24 patients with MELAS (12) or LHON-Plus (12) will be enrolled in the NCATS-funded basket clinical trial and be administered orally the investigational drug via a personalized protocol to assess its safety and efficacy.