If your child had a serious and complex disease, one that affected multiple organs and systems — perhaps impairing her growth, her ability to move, her liver function, her vision, her heart, her brain, or a combination of several or all of these with progressive involvement occurring in other parts of the body — you would want an explanation of what went awry in her health and development. You would also want treatments to help restore her health, prevent further decline, improve her quality of life, or to extend her life if it were endangered by her condition.
This unthinkable scenario is unfortunately familiar to families who experience mitochondrial diseases, a type of inherited metabolic disorder caused by genetic changes affecting the organelles inside cells that produce energy. Scientists have made substantial advances in answering families’ need for explanations, uncovering numerous distinct genetic defects in the genes carried within mitochondria themselves and in the genes in the cell’s nucleus that are essential to mitochondrial functions. In total, mutations in about 300 genes are now recognized to cause mitochondrial diseases, with different flaws in different genes manifesting with varied patterns of symptoms affecting potentially any systems in the body.
But doctors do not yet have a good response to families’ wish for proven treatments. There are not yet any therapies for mitochondrial diseases demonstrated to work in randomized, controlled trials or approved by the Food and Drug Administration (FDA). Marni Falk, MD, director of the Mitochondrial Disease Clinical Center at Children’s Hospital of Philadelphia and an associate professor of Pediatrics in the division of Human Genetics at the Perelman School of Medicine at the University of Pennsylvania, is a central figure in national and international collaborative efforts to bring together parties involved in mitochondrial disease research, clinical care, advocacy, pharmaceutical development, funding, and regulation, to move toward getting evidence-based and approved therapies to patients.
“There’s now growing recognition that, even though there have been no FDA approved therapies yet, we’re going to get there, but we have to work together,” Dr. Falk said.
National and International Collaborations Converge on Key Questions
An article published in the November 2016 issue of Molecular Genetics and Metabolism and co-authored by Dr. Falk summarizes the current state of research and is an outgrowth of that collaborative spirit. The report stems from a December 2014 meeting hosted by the Office of Dietary Supplements at the National Institutes of Health (NIH) that focused on the need for better study of the safety and efficacy of nutritional interventions for mitochondrial disease. Unable to write a prescription for a proven therapy, doctors often suggest a stop at the health food store, guiding patients toward nutritional supplements such as vitamins and cofactors that are thought to help boost cellular energy metabolism. There are added challenges for evaluating these supplements as potential therapies, including the fact that the FDA regulates supplements less stringently than drugs.
Dr. Falk noted that even more significant progress on finding new treatments for mitochondrial disease, both nutritional and pharmaceutical ones, gained momentum after the NIH meeting. In October 2015, Dr. Falk organized a Critical Path Innovation Meeting (CPIM) hosted by the FDA that focused on a series of thought questions for open discussion — not about a specific drug or a specific therapy — but on the leading challenges mitochondrial experts collectively face, such as how to most efficiently, practically, and effectively get to therapy.
“Patients have on average 16 different symptoms, so which ones are we going to pick to target?” Dr. Falk asked. “Are we going to test therapies that exist in the health food store, and if so is our goal to obtain FDA approval? Are we going to test therapies that are brand-new ideas that a pharmaceutical company has come up with, regardless of pre-clinical evidence in mitochondrial disease models? What’s the standard of care? What’s the right way to design a trial in such a heterogeneous disease? There’s hundreds of different manifestations and causes, so how are we going to classify and treat patients? These diseases involve 300 different genes, with every potential organ being involved, so how are you going to know if the drug worked? That was the overall scope of the conversation.”
Dr. Falk also continues to contribute to larger international collaborations. Following the CPIM, she joined the program organizing committee of a new biannual meeting sponsored by the Wellcome Trust in the U.K. to convene researchers and pharma together for focused discussion of developing and testing therapies in mitochondrial disease. The Mitochondrial Disease Sequence Data Resource (MSeqDR) web portal she helped develop was recently adopted as the data use and sharing platform for a multi-national European consortium of mitochondrial disease researchers, Genomit.
Charting the Path from Basic Discovery to Clinical Trials
In Dr. Falk’s lab and other basic research labs, scientists are making substantive progress in describing how the cell’s molecular pathways are affected by changes in mitochondrial genes, and in testing compounds that improve functioning in cell and animal models. For instance, Dr. Falk recently received renewed NIH funding for studies of drug therapies in animal models of mitochondrial complex I disease. In the first phase of this work, her team found a series of drug candidates that were effective in improving the lifespan of worms, C. elegans, with mitochondrial defects equivalent to those in subsets of human disease.
In the new phase, they will test these drugs in various combinations and range of mitochondrial defects, as well as extend their work in collaboration with the recently established CHOP Zebrafish Core Facility into zebrafish, a vertebrate animal model with distinct organ systems. Dr. Falk’s lab is making similar progress in extending this pre-clinical translational research approach to create additional animal and human cell models of disease based on individual patients’ genetic mutations, in work funded with philanthropic support of family foundations, as well as with the support of research contracts from pharmaceutical companies to test the efficacy and toxicity of emerging therapeutic candidates across different forms of mitochondrial disease.
But the next stretch of the journey, taking promising drugs from animal models into clinical trials to evaluate whether they benefit human patients with mitochondrial disease, is more of a rocky unknown. Charting this path is why it was so important for national and international collaborators to exchange ideas with regulators.
Many of the challenges facing mitochondrial disease are similar to those involved in other rare diseases, such as pediatric cancers. Because there are few patients with these diseases at all, and even fewer with any given genetic subtype of disease, it is difficult or impossible to form large enough populations to conduct traditional clinical trials for precision therapies — even more so when clinical symptoms vary between individuals. The discussion at the CPIM laid groundwork for researchers to understand the types of trials the FDA could find useful in generating meaningful evidence with smaller subgroups of patients or with individualized outcome measures. The discussion also made it clear to researchers that it is essential to involve the FDA early in the process of planning these trials.
Knowledge about the natural history of mitochondrial diseases is also lacking, making it difficult to know whether or not changes in a patient’s symptoms over time are the result of a specific intervention. Efforts are now underway to collaboratively build up that knowledge of the natural history of mitochondrial diseases, including through the NIH-supported North American Mitochondrial Disease Consortium, of which CHOP is an active site.
The shortage of good outcome measures for mitochondrial diseases is also a roadblock to progress in clinical trials and clinical management of disease, but multiple efforts underway at CHOP and elsewhere are building better technologies, biomarkers, and surveys that can measure meaningful progress.
Closely involving the mitochondrial disease patient community is also essential in learning the aspects of disease that patients prioritize to participate in treatment trials. For example, a survey being prepared for publication that was conducted across both CHOP and national mitochondrial disease patient cohorts revealed fatigue and exercise intolerance to be the most common and prioritized treatment symptoms across all disease causes. A Family Advisory Council was also recently established to directly involve families in the growth and activities of the CHOP Mitochondrial Disease Clinical Center.
Building a ‘Critical Mass’ to Help Families at CHOP and Worldwide
At CHOP, Dr. Falk is building the groundwork for what she hopes will be new clinical trials for mitochondrial diseases in the next year or two. CHOP is already a site for a pharmaceutical company-sponsored trial for adults with mitochondrial myopathy. Active discussions are underway with additional pharmaceutical companies, patient advocacy organizations including the United Mitochondrial Disease Foundation, and families to shape and fund anticipated future efforts.
In the clinic, the national and global efforts manifest as a movement toward getting families what they most want and deserve — not just explanations, but also solutions. The Mitochondrial Disease Clinical Center is expanding, integrating care with more than a dozen specialists across CHOP who recognize and can treat various aspects of mitochondrial diseases. Dr. Falk envisions a near future when, just like a child who receives a diagnosis of cancer, a child diagnosed with mitochondrial disease will be offered a standard of care treatment plan and options for clinical trials of new therapies tailored to their subtype of disease.
“I think we’re getting enough critical mass to make CHOP poised to be very successful at coming up with better understanding of mitochondrial disease mechanisms, better understanding of lead treatment candidates, and then doing the transition right here from the preclinical ‘aha!’ moment to the clinical trial, and establishing new standards of care that we can then make available to our patients in the clinic,” Dr. Falk said. “Because it’s all being done right here, we hope it will be a shorter, collapsed cycle of discovery, to get to evidence-based treatments faster than ever before.”