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Researchers Aim to Develop Noninvasive Methods to Diagnose Mitochondrial Diseases

Published on November 9, 2022 in Cornerstone Blog
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shafere1 [at] chop.edu (By Emily Shafer)

Mitochondrial disease

U.S. Department of Defense grant supports development of noninvasive diagnostic methods for mitochondrial disease.

Researchers in the Mitochondrial Medicine Frontier Program at Children’s Hospital of Philadelphia are studying noninvasive methods to diagnose mitochondrial diseases, with support from an $11.85 million grant from the U.S. Department of Defense. Mitochondrial diseases affect at least one in 4,300 individuals across all ages, and they can have significant and devastating effects on multiple organs. Current diagnostic methods, such as muscle biopsy, are invasive and often inconclusive.

“The essential problem is that there are no satisfactory ways to reliably quantify or effectively monitor the degree of mitochondrial function in humans,” said Marni Falk, MD, executive director of the Mitochondrial Medicine Frontier Program, and the principal investigator for the grant. “Our overall goal is to develop quantitative biomarkers and objective outcome measures that will improve disease detection and diagnosis, assessment of disease severity, and ultimately, outcomes in individuals with mitochondrial diseases.”

Marni Falk, MD

Marni Falk, MD

Mitochondria fuel the human body by converting nutrients into chemical energy that powers all of our cells and organs – including muscles, heart, and brain. Genome sequencing has allowed significant diagnostic strides, with pathogenic variants in more than 350 genes now known to cause mitochondrial diseases. Yet, up to 40% of patients with mitochondrial diseases remain without a genetic or biochemical confirmation and no FDA-approved therapies or cures are available.

Researchers in the Mitochondrial Medicine Frontier Program have worked to develop more effective, less-invasive diagnostic methods to quantify mitochondrial function since the program’s inception. The four-year grant from the U.S. Department of Defense Congressionally Directed Medical Research Programs (CDMRP) gives their research efforts a big boost.

The CDMRP grant will fund four different projects aimed to quantify mitochondrial function in humans. For the first project, Dr. Falk and colleagues will develop oxygen nanosensors small enough to be inserted into muscle tissue via fine needle injection to monitor oxygen concentration. The nanosensors will first be evaluated in aquatic models and then be studied in human clinical trials. The team will also develop nanosensors that can measure other metabolites along with oxygen that may better indicate changes in metabolic function.

The second project will capture the unique metabolic signature of a person’s breath as a way to quantify mitochondrial disease. The researchers will analyze the breath of patients with genetically characterized mitochondrial disease to identify and validate patterns of volatile organic chemicals present. Researchers will test the hypothesis that formaldehyde will be increased in the breath, while carbon dioxide is decreased. If verified, this will result in a diagnostic test to be evaluated.

Eyes and pupil response are the focus of the third project, which aims to use pupillometry combined with functional near-infrared spectrometry and exercise testing to evaluate mitochondria function in patients with acute mitochondrial dysfunction from concussion as compared to patients with genetically-based mitochondrial disease. With this project, investigators aim to correlate the degree to which the autonomic nervous system is impaired by mitochondrial function.

The fourth project will focus on passive exercise. Whereas cardiopulmonary exercise testing (CPET) is used to quantify a patient’s whole body mitochondrial oxygen consumption, many patients with mitochondrial disease and acute mitochondrial dysfunction including those in the intensive care unit have limitations that prevent them from participating in aerobic exercise. For the fourth project, researchers will analyze the feasibility of periodic acceleration as passive exercise to measure mitochondrial oxygen consumption as compared to current standard of CPET.

“These four synergistic projects will ultimately lead to effective ways to quantify mitochondrial function due to inherited genetic disorders or other causes and conditions in humans,” Dr. Falk said. “The ability to directly monitor and quantify objective changes in mitochondrial function will serve as a functional biomarker to greatly aid the rigorous development of therapies for patients with mitochondrial diseases.”

The project co-leaders include investigators from several centers and departments across CHOP and the University of Pennsylvania: Zarazuela Zolkipli-Cunningham, MBChB, and Marc Yudkoff, MD, from the Mitochondrial Medicine Frontier Program; Christina Master, MD, and Kristi Arbogast, PhD, from the Minds Matter Concussion Program; Vinay Nadkarni, MD, from the Pediatric Intensive Care Unit; Audrey John, MD, PhD, from the Division of Infectious Diseases; Douglas Wallace, PhD, from the Center for Mitochondrial and Epigenomic Medicine; and Mark Allen, PhD, from the Singh Center for Nanotechnology at Penn School of Engineering & Applied Sciences.

This work was supported by the Office of the Assistant Secretary of Defense for Health Affairs and the Defense Health Agency J9, Research and Development Directorate, or the U.S. Army Medical Research Acquisition Activity at the U.S. Army Medical Research and Development Command, in the amount of $11,855,637.00 through the Peer Reviewed Medical Research Program under Award No. (W81XWH-22-1-0590).  Opinions, interpretations, conclusions and recommendations are those of the author and are not necessarily endorsed by the U.S. Department of Defense.