Exploring a Novel Therapeutic Strategy to Induce Metabolic Reprogramming for Mitochondrial Diseases
Abstract
Topic Area: The proposed study focuses on a novel pharmacological strategy to treat mitochondrial diseases. Mitochondrial disease is one of the topic areas for Fiscal Year 2019 Peer Reviewed Medical Research Program. This topic area has substantial relevance to the healthcare needs of U.S. military Service members, Veterans, and beneficiaries. Statement of Problem: Mitochondria are ubiquitous organelles responsible for converting nutrients into ATP, the main energy currency. Mitochondrial diseases affect both children and adults as a result of inherited mutations in the nuclear and/or mitochondrial genome, impairing the ATP production. Thus, patients exhibit chronic energy deficits that affect various organs with high energy demand, including the nervous system, skeletal and cardiac muscles, kidneys, liver, and endocrine system. U.S. military Service members and Veterans have suffered from mitochondrial dysfunction triggered by environmental toxicants, such as those associated with Agent Orange and Gulf War Syndrome. These patients display a heterogeneous symptomology mimicking that of inherited mitochondrial diseases. Aging Veterans also accumulate somatic mutations in the mitochondrial genome causing mitochondrial dysfunction, which leads to neurodegenerative diseases, such as Parkinson’s disease and Alzheimer’s disease. Mitochondrial diseases have thus far remained intractable. Patients only have access to palliative therapies that fail to halt the progression of mitochondrial disease, resulting in significant disability, poor prognosis, and premature death. Such devastation underscores the urgent need to develop novel therapeutic avenues for mitochondrial diseases. Overview: The proposed research focuses on the maternally inherited mitochondrial disease, Leber’s Hereditary Optic Neuropathy associated with the Multiple Sclerosis-like illness (LHON-MS). Patients have bilateral vision loss due optic nerve degeneration accompanied by non-neurological (cardiac arrhythmias and myopathy) and neurological symptoms (MS-like presentation, tremor, dementia, Parkinsonism, dystonia, and neuropathy). The three most prevalent mitochondrial mutations for LHON-MS provoke insufficient ATP production. We designed a novel two-pronged pharmaco-epigenomic strategy to promote mitochondrial recovery via metabolic reprogramming. Preliminary data on fibroblasts derived from a skin biopsy performed on a LHON-MS patient reveal a boost of the energy metabolism, thereby alleviating the ATP deficit and providing proof-of-concept for the proposed study. Building on our prior work on mitochondrial physiology and disease, we propose to test our pharmacological approach in a well-established preclinical cellular paradigm generated from a cohort of LHON-MS patients. Impact: The impact of our two-pronged pharmacological strategy is not limited to patients with LHON-MS, but is also extended to patients affected by the most prevalent metabolic or neurodegenerative diseases, such as diabetes and Parkinson’s disease. Given the growing evidence of mitochondrial dysfunction in MS, the proposed study could further help these patients. In conclusion, the proposed preclinical study will set the stage for future clinical studies to offer a novel therapeutic option to a diverse population of patients affected by a mitochondrial disease or a mitochondrial dysfunction-related disease, which includes U.S. military Service members, Veterans, and their family members.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010061
Entities
People
- Anne Chiaramello
Organizations
- George Washington University
- United States Army