Few things are more frustrating than finally getting a clear diagnosis of an elusive disease only to realize that treatment options are limited by a lack of tools to measure what works.
For patients dealing with the effects of inherited and acquired mitochondrial mutations, that situation could begin changing early next year as UAB prepares to launch a dual clinical and research program in cooperation with the Foundation for Mitochondrial Medicine and Seahorse Bioscience. The program will combine multidisciplinary clinical resources under one roof with cutting edge research using new technologies to measure and track the bioenergetic health and function of mitochondria.
Beyond the neuromuscular disorders that will be the initial focus of the program, information gleaned from this work could provide the keys to advancing research into new treatments for a broad spectrum of other conditions where mitochondrial disruptions are suspected—diabetes, Alzheimer’s, Parkinson’s, autism, ALS, Huntington’s, lupus, MS, arthritis, kidney disease, cardiometabolic syndromes, solid tumors and even many of the effects of aging.
Disorders linked to mitochondrial dysfunctions are as ubiquitous as the weather, and like the weather, there has been little anyone could do about the course of these disruptions beyond trying to limit the damage.
“Until now, research into possible treatments for mitochondrial diseases has been limited by the difficulty in measuring changes in mitochondrial function to determine whether a patient is responding,” program scientific director Victor Darley-Usmar, PhD said. “Muscle biopsies are painful and expensive. Blood tests we used in the past took weeks. They weren’t sensitive enough to give us the answers we needed, and between being cost prohibitive to repeat and taking too much blood from patients who were already weak, they couldn’t be repeated often enough to follow changes in a specific patient.”
The likely game-changer in mitochondrial disease research is the new XF technology from Seahorse Bioscience used with a bioenergetics stress test to form the basis of a Bioenergetic Health Index (BHI). Validating Clinical Laboratory Improvement Amendments (CLIA) tests for using the new tools to measure and analyze respiratory complex activities and mitochondrial DNA damage in white blood cells and platelets will be a primary focus of the program’s early research.
Darley-Usmar is enthusiastic about the new technology’s high precision.
“It is 100 times more sensitive in measuring how a patient’s mitochondria are using oxygen, and it only requires small samples. The high throughput lets us analyze up to 90 samples at the same time and get results the same day instead of waiting weeks. Being able to measure mitochondrial function so precisely and efficiently is going to make meaningful research possible,” he said.
“We’ll be able to test whether potential interventions to improve or protect mitochondrial function actually work in an individual patient and specific disorder. If function declines, it should help us narrow the list of factors that may be causing problems.”
Director of the clinical side of the program, neurologist Eroboghene Ubogu, MD, is working toward having all clinic resources in place and ready to begin seeing patients early in 2016.
“We’re recruiting a nurse coordinator, working on regulatory details and lining up adult and pediatric neurologists, and a comprehensive range of other specialists. Our team will include nutritionists, occupational therapists and all the other resources our patients might need under one roof,” Ubogu said. “The clinic’s beginning focus will be caring for patients with neuromuscular diseases that have well-defined links to mitochondrial dysfunction, including specific types of myopathies, visual disorders related to eye muscles, and such conditions as MERRF, which combines muscle weakness and epilepsy, and MELAS, a muscle disease with the complication of a specific type of stroke.
“We want to provide a good place for the diagnosis and treatment of patients in this region. Many of these patients go undiagnosed for a long time. Advances in biochemistry and a better understanding of how the nuclear genome interacts with the mitochondrial genome are helping us give them better answers. Working with the research side of the program, we’ll be able to track changes in each patient’s mitochondrial function so we can quickly see what might be helping them and what isn’t.”
There are few specific therapies for these disorders beyond nutritional support based on general theories. Now, data gathered through the program should be able to test whether interventions work and how well in different conditions.
“In some rare disorders, infusions of proteins may help, but generally we give patients a cocktail of vitamins to maximize and protect the function of surviving mitochondria. The thinking is that Coenzyme Q10, riboflavin and antioxidants may be helpful. In some cases we include creatine and a variety of other nutrients, depending on what patients can tolerate. If we can identify new substrates that boost response, our nutritionists will be able to help patients increase their intake.”
In phase two of research, the lab will be looking at how the technology can be used to design new tests to look for changes in the relationship between the mitochondria and other parts of the cell. Because mitochondria perform so many different functions in different types of tissues, there are hundreds of different diseases where changes in mitochondrial function may play a role.
Scientific director Darley-Usmar said, “Changes in how cells use energy occur in many disorders. Cancer was the first disease where a change in metabolism was detected and now the unique ability of cancer cells to use glucose is being targeted as a strategy for improving the effectiveness of treatment.
“Over the past six years, we’ve learned a lot about how cells use energy, and how it is affected by both genetics and environmental factors in individuals and populations. In general, people have very different capacities to exercise and live their lives. Some tire faster. Even people with the same BMI can use energy very differently. A bioenergetic health index gives us a better understanding of how this is true, integrating genetics, metabolism and acquired changes in response to different factors that individuals experience.
“In the past, we didn’t know about lactose intolerance or gluten intolerance. There must be many metabolic interactions that work in a similar way. In the future, we may learn more about how to protect mitochondrial function by avoiding the causes of dysfunction.
“As we learn to look at what mitochondria do in cells that control immunity, we should get a better understanding of how it relates to innate immunity, infectious diseases and possibly autoimmune disorders. Down the line, we may eventually be able to move from looking at symptoms to identify pathology and shift from diagnostic to prognostic testing. Someday we may measure everyone’s bioenergetic health at birth and at key points in their lives. This could help predict who is at greater risk for mitochondrial changes related to specific diseases so we can start working early to prevent them before they happen,” Darley-Usmar said.
“It’s a long way down the road, but now we have tools that can help us make a start in that direction.”