For decades, cardiac researcher James McCully, PhD, has been spellbound by the idea of using mitochondria, the “batteries” of the body’s cells, as a therapy to boost heart function. Finally, a clinical trial at Boston Children’s Hospital is bringing his vision — a therapy called mitochondrial transplantation — to life.
Mitochondria, small structures inside all of our cells, synthesize the essential energy that our cells need to function. In the field of cardiac surgery, a well-known condition called ischemia often damages mitochondria and its mitochondrial DNA inside the heart’s muscle cells, causing the heart to weaken and pump blood less efficiently. Ischemia, a condition of reduced or restricted blood flow, can be caused by congenital heart defects, coronary artery disease and cardiac arrest.
For the smallest and most vulnerable patients who are born with severe heart defects, a heart-lung bypass machine called extracorporeal membrane oxygenation (ECMO) can help restore blood flow and oxygenation to the heart. But even after blood flow has returned, the mitochondria and their DNA remain damaged.
“In the very young and the very old, especially, their hearts are not able to bounce back,” says McCully.
Ischemia can be fatal for the tiniest patients
After cardiac arrest, for instance, a child’s mortality rate jumps to above 40 percent because of ischemia’s effects on mitochondria. If a child’s heart is too weak to function without the support of ECMO, his or her risk of dying increases each additional day spent connected to the machine.
But what if healthy mitochondria could come to the rescue and replace the damaged ones?
In his laboratory, McCully spent years working to perfect a method to very, very quickly extract healthy mitochondria from cells and then deliver a purified dose of mitochondria into ailing heart muscle.
Now, McCully is working with heart surgeon Sitaram Emani, MD, to bring mitochondrial transplantation to humans in a clinical trial at the Boston Children’s Heart Center. From the clinical trial data, McCully and Emani hope to pinpoint exactly when mitochondrial transplantation should be performed to be the most effective. So far, it appears that the sooner the better.
Against all odds
Looking after the sickest of the sick patients in the Cardiac Intensive Care Unit (CICU), Emani offers the experimental therapy to those patients on ECMO whose hearts are failing to regain function on their own. As they spend more time on ECMO, their chance of recovery grows more and more slim.
“We know this is their only chance to come off ECMO,” says Emani. “Since we use the patient’s own mitochondria, the risks are relatively low.”
With consent from a patient’s family, Emani and McCully spring into action.
To perform mitochondrial transplantation, Emani harvests a small, pencil-eraser-sized piece of tissue from an area of the patient’s skeletal muscle that has been unaffected by ischemia. Then, from the harvested tissue — which can contain upwards of 100 million mitochondria — McCully works fast to purify the mitochondria and prepare the transplant.
“Time is of the essence,” McCully explains. “The healthy mitochondria must be extracted and transplanted quickly before they, too, become damaged by lack of blood flow.”
McCully uses cell lysis and centrifugation to isolate mitochondria from the tissue. In less than 30 minutes, he hands over purified, viable mitochondria to Emani, who then injects the healthy mitochondria directly into the areas of the patient’s heart affected by ischemia. He uses echocardiography to guide him to the weakest areas of heart muscle that most desperately need an energy boost.
A resurgence of heart function after mitochondrial transplantation
After transplantation, echocardiography reveals the procedure’s effect on heart function in real time. Hearts that had beat feebly begin to pump more efficiently. At the cellular level, the transplanted mitochondria immediately provide usable energy to surrounding heart muscle cells. Then, over time, the mitochondria migrate deeper inside the myocardial cells to repair damaged mitochondrial DNA.
“Within 48 hours of mitochondrial transplantation, we start to see heart function improve in our patients,” said Emani. “By day four, their heart function has nearly normalized.”
During their first few uses of mitochondrial transplantation in humans, the team worried that the injection process itself – directly into the cardiac muscle via needle – might cause heart arrhythmias. But Emani and McCully are thrilled to see that injecting a patient’s mitochondria into their heart muscle hasn’t caused complications. Today, they’ve already treated 11 patients with mitochondrial transplantation. Although three of the patients were too sick to ultimately make a recovery, most of the patients were able to separate from ECMO and are thriving today.
“After so many years of work, it’s extremely exciting to see mitochondrial transplantations finally helping patients,” says McCully.
Looking ahead, Emani and McCully are already working on various animal models to demonstrate that mitochondrial transplantation can rescue other organs affected by ischemia, such as the brain, liver, kidney and lungs. In addition, they are developing minimally-invasive ways to deliver mitochondria to different areas of the body through veins that feed into the targeted organ(s).
“We believe we could use this during all major heart operations to speed up recovery,” says Emani. “Now that we’ve demonstrated that it works on the heart, we want to expand it to treat other organs and diseases.”