Unraveling Mechanisms and Potential Treatment of Cardiomyopathy in Friedreich’s Ataxia

By Kate Knab

Consider a photograph of a green leaf. Zoom in, and depending on the quality of the photo, you could find clusters of blurry green pixels. Now consider the cell makeup of a human heart. Until recently, scientists lacked the ability to “zoom in” on each individual “pixel,” or cell, to develop a more comprehensive, detailed picture of how different cardiac cells function together, especially in relation to disease.

Funding from the Department of Defense will enable two scientists from Children’s Hospital of Philadelphia Research Institute to combine their expertise in heart disease and neuro- and cardio-degenerative mitochondrial disorders to understand the heart’s cell biology in patients with Friedreich’s ataxia (FA).

FA is a rare, progressive, neuro- and cardio-degenerative disorder that affects the function of the cerebellum, which is the part of the brain that helps coordinate muscle movements. Patients could begin to lose their ability to walk by their early 20s, and most are affected by cardiomyopathy, which hinders the heart’s ability to pump effectively and is the most common cause of premature death.

Critical to this characterization of cell function is single-cell omics technology developed by Liming Pei, PhD, an investigator in the Department of Pathology and Laboratory Medicine and the Center for Mitochondrial and Epigenomic Medicine, that lets researchers explore how the interactions of multiple cardiac cell types in FA heart cells compare to those of healthy heart cells.

“This technology allows us to study biochemical details of each individual cell in their natural environments in a way we couldn’t before,” Dr. Pei said.

Traditional mechanisms for gene expression do not typically provide an in-depth breakdown of how the gene is expressed. For example, if a gene’s expression is increased 20%, it’s difficult to determine whether it’s a 20% increase in all heart cells, or a 100% increase in 20% of heart cells. Dr. Pei’s approach analyzes one cell at a time, which allows the unique nature of cellular expression changes to be determined.

Dr. Pei will work closely with Robert B. Wilson, MD, PhD, Co-director of the Friedreich’s Ataxia Center of Excellence at CHOP and Penn Medicine, who brings to the project years’ worth of research in foundational models to study FA.

Studying both patient-derived cardiac cells and zebrafish models will help Drs. Wilson and Pei to identify potential inflammatory signaling that may exacerbate FA. The first model uses new technology that cultivates the growth of heart muscle cells derived from patients — cardiomyocytes — that beat in a dish. This is helpful to study the mechanisms and defects that could be present in FA. Researchers also are working with a zebrafish model that has characteristics similar to human hearts and can closely model FA cardiomyopathy.

In this chart, titled “Plot of cell types in the heart from single-cell RNA-seq,” each dot represents the gene expression pattern of a single cell. (Courtesy of Drs. Wilson and Pei)

“There's a great synergy between basic science and translational science for the development of therapeutics,” Dr. Wilson said. “If you understand more about what's going on, more potential points of therapeutic intervention present themselves as possibilities, and you can test those if you have good model systems.”

Supported by their grant, Drs. Wilson and Pei will study thousands of cells from both models through single-cell technology to understand their behavior. The technology is applicable to all types of cells found in the heart, and their gene-expression patterns will let researchers know which kind of cell they are studying, whether it’s the beating cardiomyocytes, the structure-binding fibroblasts, or blood vessel cells.

The comprehensive data collected from these models will eventually be compared to serum samples collected from dozens of FA patients and controls by David R. Lynch, MD, PhD, a neurologist at CHOP and Co-director of the Friedreich’s Ataxia Center of Excellence. To eventually translate the results of this study to clinical trials, Dr. Wilson and Dr. Pei aim to identify whether inflammatory markers present in the models are also present in the serum samples.

“[Our] passion is to find ways to advance our understanding of biology and disease and hopefully advance the field for those patients who are suffering from such a terrible disease,” Dr. Pei said.