The Mito-EpiGen Program

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:

  1. 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.
  2. Clinical research is performed in collaboration with Dr. Andrea Gropman, M.D., under the auspices of Children’s National Medical Center. Dr. Gropman is the Chief of the Division of Neurogenetics and Developmental Pediatrics, a clinical and biochemical geneticist, and a pediatric neurologist specialized in mitochondrial diseases. She has extensive experience in diagnosing and treating children with suspected mitochondrial disorders. Dr. Gropman serves as the Deputy Clinical Director of the Mito-EpiGen Program.

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. Most patients are diagnosed during childhood or young adulthood and exhibit a chronic energy deficit, which affects organs with high energy demands such as the nervous, musculoskeletal, and cardiac systems. Patients exhibit a heterogenous symptomatology such as encephalopathy, seizures, migraines, tremors, cognitive deficits, vision loss, hearing loss, muscle weakness, cardiomyopathy, and neuropathy, making clinical diagnosis difficult and hampering treatments. 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.

The Mito-EpiGen Program provides an interactive infrastructure for our ongoing collaborative investigations between translational/clinical researchers and clinicians to test our innovative therapeutic intervention 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. Anne Chiaramello has received FDA authorization to conduct the first basket clinical trial in the U.S. for these two mitochondrial diseases with a common molecular etiology. Their chief objective is twofold: 1) to mitigate their chronic energy deficit; and 2) to curtail some of their debilitating symptoms in order to ameliorate their quality of life. Dr. Chiaramello and Dr. Gropman have established partnerships with patient advocacy groups for MELAS and LHON- Plus who have provided input on disease measurements directly relevant to the quality of life for these patients. During Spring 2024, patients with MELAS or LHON-Plus will be recruited to participate in our NCATS-funded basket clinical trial to test our therapeutic candidate (UH3TR003897). All enrolled patients will receive the therapeutic drug via a personalized protocol. Efficacy will be assessed for each patient using the baseline of the patient’s status determined before the start of the clinical trial.