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Headshot of Zarazuela Zolkipli-Cunningham, MBChB, MRCP

Early Stage Investigator Spotlight: Zarazuela Zolkipli-Cunningham Designs Novel Outcome Measures for Mitochondrial Disease

May 19 2022

Zarazuela Zolkipli-Cunningham, MBChB, MRCP, is an attending physician in the Mitochondrial Medicine Frontier Program (MMFP) at Children's Hospital of Philadelphia (CHOP) and a member of the North American Mitochondrial Disease Consortium (NAMDC). Her research focuses on conducting natural history studies with an emphasis on longitudinal objective measures for mitochondrial disease. Here, she shares her start in rare disease research, exciting discoveries, and future goals.

How and why did you get involved with rare disease research?

During my residency training at Great Ormond Street Hospital in London, United Kingdom, I developed a deep-seated interest in mitochondrial disease upon encountering patients who suffered through the diagnostic odyssey. These patient encounters inspired me to pursue a Neurometabolic Research Fellowship at the Hospital for Sick Children, Toronto, to study mitochondrial short-chain acyl-CoA dehydrogenase (SCAD) deficiency in patient fibroblasts and tissue carnitine deficiency in the mdx mouse model of Duchenne muscular dystrophy.

I then completed a Mitochondrial Medicine Fellowship at the Mitochondrial and Metabolic Disease Center at the University of California San Diego (UCSD) where I studied the hypometabolic consequences of mitochondrial ATP in mice, alongside clinical training in mitochondrial disease adult and child patient evaluations.

When did you join the NAMDC as an early stage researcher?

To ensure understanding of complementary disciplines of mitochondrial disease translational research, I pursued clinical trials training as the first NAMDC Fellow in 2012-2013, mentored by Dr. Richard Haas of the UCSD School of Medicine and the NAMDC Fellowship Director. I was also an RDCRN Scholar in 2016.

What were your experiences working with the NAMDC and how has the experience shaped your research career?

My NAMDC Fellowship determined the path of my research career. During my fellowship training, I was struck by the realization that compared to the relative abundance of mitochondrial basic researchers, the field is lacking physician-scientists trained specifically in rigorous mitochondrial disease clinical trial methodology.

I have since established a Mitochondrial Myopathy Clinical Translational Research Program that leverages the expertise of multidisciplinary physicians and researchers at CHOP and the University of Pennsylvania (UPenn). The focus of my research is quantitation of myopathy and muscle mitochondrial function. My clinical research is focused on development and validation of objective clinical outcome measures of mitochondrial myopathy. My translational research focuses on quantitation of in vivo muscle mitochondrial function using novel technologies.

I continue to contribute to NAMDC scholarly activities as a member of the NAMDC Education Committee, as well as the RDCRN Career Enhancement Committee meetings.

Can you share a recent discovery with us, and what it adds to our knowledge of the field?

We have validated and published the Mitochondrial Myopathy Composite Assessment Tool (MM-COAST), a novel composite measure to monitor disease severity and progression in patients with impaired skeletal muscle function caused by mitochondrial disease. The MM-COAST fully captures the mutually interactive key domains of muscle strength, muscle fatigue, balance, dexterity, and exercise intolerance in individuals with mitochondrial myopathy. For the first time, longitudinal objective measures of myopathy can be captured in mitochondrial disease patients. The MM-COAST holds great promise as a tool that may directly improve the design and success of clinical intervention trials, as well as natural history studies.

Where are you heading next with your research?

Currently, I am the principal investigator of several translational research studies focusing on measurement of in vivo muscle mitochondrial function. Together with Drs. Marni Falk, attending physician and executive director of the MMFP, and Mark Allen, scientific director at the University of Pennsylvania Singh Center for Nanotechnology, we are about to embark on the first in-human testing of the oxygen (O2) nanosensor in primary mitochondrial disease patients to provide an in vivo measure of muscle oxidative phosphorylation (OXPHOS) capacity. I was awarded a NAMDC Pilot Grant to conduct this first in-human O2 nanosensor clinical trial.

I am also about to launch a study to evaluate the diagnostic utility of whole-body periodic acceleration (pGz) passive exercise approach in mitochondrial disease and am studying the utility of muscle CrCest imaging that quantifies the recovery of muscle creatine levels post-exercise as an in vivo marker of muscle OXPHOS in pediatric and adult patients with mitochondrial disease.

What advice would you offer to other early stage researchers?

Strong and supportive mentorship from clinicians and researchers working in the same field, and related disorders, is essential. Be persistent, always have an academic goal and timeline in mind, and empower your team to conduct rigorous research.

The North American Mitochondrial Disease Consortium (NAMDC) is part of the Rare Diseases Clinical Research Network (RDCRN), which is funded by the National Institutes of Health (NIH) and led by the National Center for Advancing Translational Sciences (NCATS) through its Division of Rare Diseases Research Innovation (DRDRI). NAMDC is funded under grant number U54NS078059 as a collaboration between NCATS, the National Institute of Neurological Disorders and Stroke (NINDS), the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), and the Office of Dietary Supplements (ODS).

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