Development and Clinical Validation of Noninvasive Diagnostics for Mitochondrial Disease
Abstract
OVERALL PROJECT Mitochondrial Diseases, an approved FY21 PRMRP Topic Area, are devastating, multi-systemic disorders that collectively affect at least 1 in 4,300 individuals across all ages, including military members and their families. Mitochondria are responsible for the conversion of energy from nutrients into metabolically useful energy to power our cells and organs, including the muscle, heart, and brain that are highest in energy demand. At least 2,000 – about 1 out of 10 – of all our genes are dedicated to the formation and action of mitochondria. Indeed, one of the cardinal achievements of the human genome project and of Biochemical Genetics over the past two decades has been identification of the genetic basis for many forms of PMD. Currently, we now know of deleterious mutations in more than 350 genes that impair mitochondrial function and disrupt energy production. The associated diseases are called primary (genetic-based) mitochondrial diseases, or PMD, exacting a terrible toll – economic, societal, and psychological. These inherited disorders may affect any organ system at any age with a lamentably high morbidity and mortality. While genome sequencing has revolutionized the ability to accurately diagnosis the basic cause of many PMDs, up to 40% of patients in whom mitochondrial disease is suspected remain without a clear genetic etiology or biochemical confirmation. Even when a PMD genetic etiology is clear in a given individual, their prognosis or actual response to therapeutic interventions remains lamentably unpredictable – a problem we will address by development of the proposed novel technologies. The essential problem is that no satisfactory ways exist to reliably quantify or effectively monitor the degree of mitochondrial function in humans. We aim to develop novel minimally or non-invasive, quantitative technologies that enable safe and rapid ways to detect and monitor mitochondrial dysfunction, a complex disease category that hitherto has proved remarkably elusive to confirm either in those with PMD or secondary disruption of mitochondrial function as may occur in critical illnesses such as respiratory failure, shock, cardiac arrest, concussion, or severe trauma. The technologies we develop and validate for this purpose will further serve as key outcome measures with which to evaluate the efficacy of novel treatments for PMD, a critical need as no approved therapies currently exist. Our overall goal is to develop quantitative biomarkers and objective outcome measures that will improve disease detection, assessment of severity, and ultimately, outcomes in individuals with PMD and secondary mitochondrial disruption such as occurs in individuals with acute illness in the intensive care unit (ICU) and with concussion from traumatic brain injury (TBI). Our tools will be optimized and validated using existing preclinical animal models of PMD, translated to humans in observational clinical research studies, and evaluated for safety and efficacy in early phase clinical trials. The four proposed projects will ultimately lead to effective ways to quantify mitochondrial function in human subjects by: (1) developing and validating a wireless rechargeable nanosensor to directly muscle oxygen (and additional analytes); (2) developing a mitochondrial-breathalyzer to detect the fingerprint of energy deficiency in exhaled breath; (3) evaluating autonomic nervous system dysfunction caused by transient mitochondrial failure in concussion by quantifying the pupillary light reflex and remotely monitoring brain oxygen levels; and (4) determining effects of passive motion on mitochondrial function in non-ambulatory individuals. Of direct relevance to the Department of Defense (DOD), several clinical cohorts to be studied closely resemble soldiers who sustain head trauma or hypoxic injury consequent to shock on the battlefield. Combining these four projects into this Focused Program Award will result in important eff
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210590
Entities
People
- Marni Falk
Organizations
- United States Army