Mitochondrial Disease Research

Children's Hospital of Philadelphia (CHOP) is a powerful hub for research on mitochondria, the power plants of the cell. Efforts in the Center for Mitochondrial Medicine Frontier Program and in a wide range of collaborating specialties are converging on deeper understanding of how energy production in mitochondria relates to a wide range of diseases and conditions, as well as new approaches to treating conditions known to be connected to mitochondria.

Highlights:

CHOP researchers have harnessed the power of genomics to create a breadth of novel cellular and animal models of mitochondrial disease. These continue to shed light on disease mechanisms and are enabling novel therapeutic development through high-throughput drug library screens and collaborative partnerships of novel therapeutic compounds with both academic colleagues and pharma.
A CHOP expert weighed in on ethical considerations for new reproductive technologies to prevent inheritance of mitochondrial diseases and took part in national and international efforts to speed the development of new therapies for these diseases. New pathways have been created for US families with mitochondrial DNA diseases to have preimplantation genetic diagnosis for their disorders. See Nora’s story.
Cancer biologists have been pursuing the hypothesis that mitochondria could be part of the mechanism by which cancer resists therapies. A new research program Mitochondria Cancer Connections (MC2) comparatively investigates mitochondrial disease and cancer to identify new therapeutic opportunities for both types of disease.
CHOP researchers continue to investigate a mystery surrounding mitochondrial proteins and cellular stress responses.
Researchers from CHOP have discovered functions or possible impairments of mitochondria in the brain related to normal brain functioning, recovery from injury and neuropsychiatric disease.
A newly funded Department of Defense research program unites nearly 50 researchers to develop noninvasive diagnostics for mitochondrial function and disease.
A wide range of collaborative partnerships with Mitochondrial Disease foundations and advocacy groups has enabled the launch of multiple new natural history studies and research programs.
Extensive genomic and medical database capabilities have been created to support CHOP Mitochondrial Medicine clinical research and external partnerships to design patient data informed clinical trials.
Marni Falk, MD, Executive Director of the program, discusses Examining Special Nutritional Requirements in Disease States at a workshop.

If mitochondrial disease is suspected to be the underlying cause of your or your child’s medical concerns, you will have the opportunity to participate in various ongoing research studies at Children’s Hospital of Philadelphia. Researchers are currently working on identifying better ways to diagnose and treat mitochondrial disease, identifying new genetic causes of mitochondrial disease, and characterizing exactly how mitochondrial disease affects the body. View our latest abstracts presented at UMDF Symposium 2022.

Several other initiatives are underway to advancing understanding of mitochondrial biology and health. Marni Falk, MD, and Eiko Nakamaru-Ogiso, PhD, co-lead the CHOP Mitochondria Research Affinity Group (MITO RAG) established in 2008, bringing together researchers engaged in mitochondria-focused research across all scientific disciplines and medical domains. the Center of Mitochondrial and Epigenomic Medicine (CMEM) was established as a Center of Emphasis in 2010. The center is investigating mitochondrial and epigenomic dysfunction for which few effective clinical treatments currently exist.

Current research studies

Measuring Mitochondrial Function and Better Detecting Mitochondrial disease

Researchers at CHOP, led by Dr. Falk, were awarded $11.85 million from the U.S. Department of Defense in October 2022 to fund four projects over four years (2022-25) aimed at developing and validating minimally invasive or noninvasive diagnostic techniques to quantify mitochondrial function in living people. A team of nearly 50 researchers are partnering to develop quantitative biomarkers and objective measure to:

Improve measurement of mitochondrial function and detection of mitochondrial disease
Better assess disease severity and progression
Monitor outcomes after therapeutic interventions in patients with primary mitochondrial disease, and secondary mitochondrial disruption

The four projects include:

Developing and validating a wireless, rechargeable nanosensor to measure oxygen levels in muscle after exercise
Developing a “mitochondrial breathalyzer” to detect signs of energy deficiency in exhaled breath
Measuring pupillary light reflex and remotely monitoring brain oxygen levels to determine autonomic nervous system dysfunction caused by mitochondrial failure
Determining effects of passive acceleration (i.e., movement without effort caused by an external force) on mitochondrial function

Researchers from Mitochondrial Medicine will collaborate with CHOP experts from the Minds Matter Concussion Program, the Pediatric Intensive Care Unit (PICU), the Division of Infectious Diseases, and CMEM, as well as experts with the Singh Center for Nanotechnology at the University of Pennsylvania.

NOTICE: This work is supported by The Assistant Secretary of Defense for Health Affairs endorsed by the Department of Defense, in the amount of $11,855,637, through the Peer Reviewed Medical Research Program (PRMRP) under Award No. W81XWH-22-1-0590. Opinions, interpretations, conclusions and recommendations are those of the author and are not necessarily endorsed by the Department of Defense.

Mitochondria and Cancer Connections (MC2) Research

Researchers from the Mitochondrial Medicine Frontier Program and the Center for Data-Driven Discovery in Biomedicine (D3B) are collaborating to form the Mitochondria and Cancer Connections (MC2) Research Program. By working together, they hope to uncover important insights into energy deficiency, as well as how cancer cells find the energy to grow, and find ways to prevent their return.

While mitochondria function as the biological batteries that produce energy within our body's cells, those with mitochondrial disease have dysfunctional mitochondria. Their mitochondria fail to produce enough energy for cells to function, causing a range of health concerns. While people with mitochondrial disease have an average of 16 major medical problems, cancer is not among them — an observation the team believes is due to cancer's need for functional mitochondria to live and grow.

"We realized there's an inherent difference in survival strategies and death mechanisms between a cell with mitochondrial disease and one with cancer," Dr. Falk said. “Ultimately, we aim to steal strategies from cancer to help mitochondrial disease cells grow and function better, while at the same time stealing strategies from mitochondrial disease to slow down cancer … If we're lucky, we'll find therapies for both classes of diseases."

MC² is all about gathering, integrating and analyzing complex data. By enhancing a data analysis and sharing platform – developed by D3B, the MC² team will be able to provide open access to pediatric genomic data and establish a first-of-its-kind multi-omics data dynamic modeling infrastructure. MC2 was launched in September 2021 as a three-year CHOP research program, with funding support of Patricia and David Holveck.

CureARS and CHOP Collaborate on Drug Repurposing Research

When two parents were told there was no approved treatment for their children’s form of mitochondrial disease, they founded a nonprofit – CureARS – and began partnering with CHOP’s Mitochondrial Medicine Frontier Program in October 2022 by supporting the launch of a preclinical research project. The aim of this innovative research is to establish and study a full set of animal models for all 19 mitochondrial aminoacyl tRNA synthetase (ARS) genes and evaluate potential therapies in these models via high-throughput screening.

Led by Dr. Falk and Neal D. Mathew, PhD, researchers will evaluate existing drugs and the potential to repurpose them for a different medical condition than what they were originally developed. This strategy can offer expedited development and cost savings compared to traditional drug development that can take years or decades.

“CHOP gave our family hope that not only could we push science forward for my daughter and others affected, but we might be able to identify life-saving treatments within her lifetime.”
-Ashley Rowland, Co-Founder of CureARS

CureARS was founded in 2021 by parents Desiree Magee and Ashley Rowland, who are hopeful this research will offer treatment options for their children diagnosed with a neurodegenerative mitochondrial disease caused by different mutations in one of the mitochondrial ARS genes.

Metabolic Consequences of Primary Mitochondrial Disease

The purpose of this research study is to identify the causes and effects mitochondrial disease has on the body and to find ways to better diagnose mitochondrial disease.

Currently, there is no single laboratory test that can accurately diagnose mitochondrial disease in most people, and no effective treatments exist for many individuals with mitochondrial disease. Identifying the effects of mitochondrial disease on body tissues such as blood and skin may offer the opportunity for improved diagnosis and treatment.

North American Mitochondrial Disease Consortium Patient Registry and Biorepository

The main purpose of this research study is to collect and store information about people with mitochondrial diseases to better understand the underlying causes and natural history of these diseases, as well as to develop new treatment options.

This study is being organized by the North American Mitochondrial Disease Consortium (NAMDC). The NAMDC is a group of doctors and researchers in North America who specialize in mitochondrial disease. Children’s Hospital of Philadelphia is an active NAMDC site. We hope that the information and samples in the NAMDC patient registry and repository will help researchers learn more about mitochondrial disease and find the causes and treatments for these conditions.

Magnetic Resonance Imaging (MRI) Creatine-CEST Muscle Phenotyping in Mitochondrial Disease

The purpose of the study is to use a new, non-invasive research imaging technique – Creatine-CEST, which is a kind of MRI – to measure important metabolic features of muscle, including mitochondrial function, in people with mitochondrial disease and in healthy individuals.

It is hoped that this new strategy will help physicians to better understand the health problems of people with mitochondrial disease. Eventually, this could lead to better diagnostic and treatment approaches.

United Mitochondrial Disease Foundation (UMDF) Collaborative Research Programs

CHOP Mitochondrial Medicine has established multiple collaborative research programs with the United Mitochondrial Disease Foundation, including:

Mitochondrial Disease Sequence Data Resource (MSeqDR) Consortium. This initiative began in 2012, and with continued UMDF funding for more than a decade, a centralized community website to integrate highly complex genomic and clinical phenotype data has been live since 2014 (www.mseqdr.org). The tools and knowledge in this website support mitochondrial disease diagnostic laboratories, researchers, and collaborative programs from around the world.
In 2022, a CHOP research study – accessible to patients and families who join the UMDF patient registry, MitoShare – was launched to enable mitochondrial disease patients and families to deposit their genomic data into a user-friendly resource for their doctors and researchers to analyze at their own discretion. CHOP genetic counselors also provide focused review of all genomic data in the registry to assist with report interpretation and disease classification.
In 2022, an international Leigh Syndrome Roadmap Program Natural History Study was launched, with CHOP as the Data Coordinating Center. Prospective assessments are done of Leigh syndrome patients from around the world to compile outcomes data that will enable improved design and success of future clinical treatment trials.

The Center of Mitochondrial and Epigenomic Medicine (CMEM)

CMEM was established as a Center of Emphasis in 2010. The Center is investigating mitochondrial and epigenomic dysfunction in a wide range of clinical problems. One focus of the CMEM team is on preclinical studies relevant to developing therapies for mitochondrial dysfunction, for which few effective clinical treatments currently exist.

Future of research

More research efforts are being placed in mitochondrial disease here at CHOP, such as drug therapy research and a growing cadre of clinical research treatment trials. Our clinical and research teams meet at monthly seminars to share the exciting research being conducted in mitochondrial disease at Children’s Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania, as well as other institutions locally and worldwide.