Waste Not
Dr. Jeffery Mokentin is a researcher in the Division of Molecular Cardiovascular Biology at Cincinnati Children’s and professor in the Department of Pediatrics at the University of Cincinnati College of Medicine.
Learn more about Dr. Molkentin’s research.
Dr. Jeffrey Molkentin and his team are getting to the heart of muscle degeneration.
A Cincinnati Children’s cardiology researcher just might have the clue to stopping muscle degeneration that contributes to heart disease, muscular dystrophy and other conditions.
In a paper recently published in the journal Nature Medicine, Jeffery Molkentin, PhD, and a multi-institutional team led by Cincinnati Children’s discuss how an investigational antiviral drug may have the
potential to reduce muscle cell damage in Duchenne and other forms of muscular dystrophy.
Because Duchenne muscular dystrophy leads to degeneration of heart muscle, cardiac researchers like Dr. Molkentin, of the Division of Molecular Cardiovascular Biology, are an integral part of a multi-disciplinary team working to understand and repair damage caused by the disease.
The work reflects the range of research projects pursued by Dr. Molkentin and his team to understand the heart’s molecular mechanisms and identify new treatments for muscular dystrophy. Underscoring the significance of this research, the Howard Hughes Medical Institute (HHMI) named Dr. Molkentin one of their 56 new investigators in the spring of 2008.
Since 1953, HHMI has identified the nation’s most promising scientists and challenged them to push the boundaries of biological science by pursuing bold and creative research. The institute provides long-term, flexible funding to the investigators that allows them to pursue their scientific interests no matter where they lead.
Getting Down to Basics
The success of Dr. Molkentin’s lab is rooted in the fundamentals. His team studies the heart at its most basic molecular level to understand the signaling mechanisms and pathways that control cell growth, differentiation and death.
A quick read through some of the team’s current projects bears this out: regulation of cell death through mitochondria; regulations of cardiac hypertrophy; regulation of cardiac development; regulation of transcription; the mechanisms of Duchenne muscular dystrophy and Miyoshi myopathy, to name just a few.
Muscular dystrophy is an especially challenging disease that affects multiple systems in the body.
“The big problem in muscular dystrophy is a structural alteration that’s usually due to a mutation in a gene like dystrophin,” explains Dr. Molkentin. “That causes muscle cells to degenerate.”
The effect of the degeneration is catastrophic. “The fibers break down and eventually get replaced with fat tissue and fibrotic tissue,” he says. “And the muscle just keeps dying. Over time it can’t be regenerated and replaced fast enough. That’s what progresses and causes kids to lose ambulation and all the other problems.”
Stopping Muscle Wasting in its Tracks
Dr. Molkentin’s published study described his team’s work with the investigational antiviral drug Debio-025 to combat the degenerative process behind muscle death. Debio-025 is a known inhibitor of the protein cyclophilin D, which regulates the swelling of mitochondria in response to cellular injury. It is currently in Phase II clinical trials in Europe for the treatment of Hepatitis C.
The Debio-025 study may have implications beyond skeletal muscle disease, since deleting the cyclophilin D protein reduces cardiac dysfunction caused by calcium overload-induced necrosis.
“Even though the initial insult is there that makes the muscle die, we short circuit the ability of the muscle to die through one pathway,” he explains. “We could add years to the progression of the disease and slow it down considerably. We have molecular pathways that we can inhibit to prevent the muscle cell from degenerating. We think it could be a novel treatment for muscular dystrophy.”
Early Clinical Trials Show Safety
The advantage of Debio-025 is that it inhibits cyclophilin D and blocks cell death in a number of situations, but does not suppress the immune system or block calcineurin, a protein crucial to skeletal muscle cell repair and development.
“Debio-025 is already in Phase II clinical trials and it appears safe,” says Dr. Molkentin. “It’s a cyclosporin analog and we currently give cyclosporin to patients for a number of indications. Some patients are on cyclosporin for a decade or two. Debio-025 is based on that drug, so it’s not that different from a toxicity profile.”
Further testing is needed, but if it continues to go well, Dr. Molkentin and his team will be able to explore the possibility of conducting clinical trials with Debio-025 in patients with Duchenne muscular dystrophy.
