A major limitation in many therapeutic interventions is the inability to follow how they affect the early biochemical steps of chronic disease. In some cases, patients and clinicians spend months tracking symptoms to figure out if a treatment is working.
A new approach being developed at The Children’s Hospital of Philadelphia and the University of Pennsylvania could allow investigators to know within days if a chosen therapy reverses the intracellular mechanisms that go awry in Friedreich’s Ataxia (FA), a genetic mitochondrial disease, and other more common secondary mitochondrial disorders such as Parkinson’s disease and Alzheimer’s.
FA is a rare, progressive neurodegenerative disease that is heavily disabling because it affects a variety of body systems. People diagnosed with FA experience general unsteadiness, motor speech problems, increased heart wall thickness, and a higher tendency to develop diabetes over time. Most people with FA are wheelchair bound within 10 years of their symptoms’ initial presentation and die from heart disease by the age of 35.
CHOP clinicians and researchers have developed remarkable expertise in FA, and they help about 250 patients, which is approximately 5 percent of the population with this disease in the U.S. Earlier this year, a new Penn Medicine/CHOP Friedreich’s Ataxia Center of Excellence opened to carry on this work under the direction of Robert B. Wilson, MD, PhD, professor of pathology and laboratory medicine at the Perelman School of Medicine, and David Lynch, MD, PhD, FA program director at CHOP.
“We are the center for research on FA for the world,” Dr. Lynch said.
One of the center’s first goals was to establish a biomarker development program with the expertise of Ian Blair, PhD, of the Perelman School of Medicine. This collaboration is the focus of a new National Institute of Neurological Disorders and Stroke grant awarded to Dr. Lynch.
“A unique aspect of this grant is our chance to partner on a technique that not only may be useful for understanding the mitochondrial abnormalities that are proposed in FA, but also for monitoring it and related diseases in clinical trials,” Dr. Lynch said. “So it may be crucial for developing new therapies for individuals, but it also is likely to be a key tool in defining the ability of people with FA to respond to such interventions.”
Dr. Blair has discovered a way using mass spectrometry techniques — a highly accurate, quantitative method for exploring compounds — to follow the metabolic events of live behaving mitochondria isolated from platelets of a person with FA. Mitochondria, traditionally known as the powerhouses of cells, are specialized to perform specific functions within tissues. The investigators suspect that the metabolic functions of mitochondria might be crucially compromised in FA, leading to tissue-selective metabolic dysfunction.
“We know that the disease affects the whole body, so what we see happening in platelets is likely to be a mirror of what’s happening everywhere,” Dr. Lynch said.
One of the places where his study team has seen abnormalities is in the Krebs cycle, also known as the tricarboxylic acid cycle, which produces adenosine triphosphate (ATP) that transports chemical energy within cells for metabolism. ATP feeds electrons on the electron transport chain for cells to make more ATP. The investigators suggest that insufficient bioenergetic capacity may lead to decreased metabolism through fatty acid pathways.
“We find that in FA there are specific blockages in this pathway,” Dr. Lynch explained. “This might suggest therapy because it would allow you to bypass those blockages if you gave people the right nutritional supplementation and ameliorate, if not cure, the features of the disease.”
In principle, this approach could be applicable to any mitochondrial disease, Dr. Lynch said, not only on the therapeutic side to identify which metabolic steps to circumvent, but also on the monitoring and biomarker side to measure response to a therapeutic agent. If an intervention works, scientists would expect the metabolic abnormalities that Dr. Blair identified to reverse.
“It provides a powerful way to follow the disease and an ideal biomarker of therapeutic success,” Dr. Lynch said. “This is potentially a way that we could follow many, many disorders.”
In the near future, Dr. Lynch anticipates his study team’s early successes will spin off into investigations of novel nutritional therapies for FA and also be used as an outcomes measure in ongoing clinical trials of FA.