A team at the Boston Children’s Hospital Heart Center has performed the first human application of a groundbreaking new therapy that transplants a patient’s own mitochondria into their heart, where it can revive heart muscle weakened by ischemia. Called mitochondrial transplantation, its first clinical uses were recently described in the Journal of Thoracic and Cardiovascular Surgery.
Open-heart surgery requires a reduction in blood flow to the heart. This ischemia damages the mitochondria that power the heart’s myocardial cells, leaving the heart stunned. Even after the heart is re-perfused with blood following surgery, the damaged mitochondria prevent the heart from pumping blood properly. Until now, a direct therapy to reverse mitochondrial damage imparted by ischemia has not been available to patients.
As a result, many patients who undergo open-heart surgery simply never regain their full heart function. For the most vulnerable patients, they may not survive the surgery recovery process.
"In the very young and the very old, especially, their hearts are not able to bounce back,” says James McCully, PhD, a cardiac researcher who has been investigating the therapeutic uses of mitochondria for decades. “Ischemia causes long-term damage to their mitochondrial DNA.”
A new kind of self-help
To overcome this longstanding problem, McCully used rabbit, pig and sheep models to develop a procedure for transplanting one’s own healthy mitochondria into ischemia-damaged cardiac muscle.
"It was like putting a booster pack on a car battery,” McCully says about the mitochondrial transplantation’s effect on the animals’ heart.
Subsequently, McCully has teamed up with Sitaram Emani, MD, to give the first-ever human mitochondrial transplantations to very young cardiac patients who were battling to recover from open-heart surgery. Through Boston Children’s innovative therapies process, experimental measures like this are available to patients who are not improving by standard approaches.
At the Heart Center, patients who were still dependent on central ECMO support for several days after open-heart surgery were identified as potential candidates under Emani’s supervision. With their hearts failing to regain function, hope of recovery diminished the longer they spent connected to ECMO.
"We knew this was their only chance to come off ECMO,” says Emani. “Since we would be using the patients’ own mitochondria, the risks were relatively low. Still, we worried the injection process itself – directly into the cardiac muscle via needle – might cause heart arrhythmias.”
Emani and the families of the patients discussed at length the risks and the novelty of the procedure. Together, they agreed to move forward.
From bench to bedside, literally
To perform mitochondrial transplantation, Emani harvests a small piece of tissue from a nearby area of non-ischemic skeletal muscle. A surgical punch, commonly used by dermatologists to remove moles, is sufficient to collect the small amount of tissue that’s necessary. Emani then gives the tissue to McCully to isolate viable mitochondria for transplant.
"Time is of the essence,” McCully explained. “The healthy mitochondria must be transplanted quickly before they, too, become damaged.”
McCully uses cell lysis and centrifugation to isolate healthy mitochondria from the tissue. The mitochondria are isolated in less than 30 minutes and then are returned to Emani, who performs a series of injections of purified mitochondria into the patient’s myocardium.
Post-transplant data gathered from animal models has shown just how quickly the healthy mitochondria start rescuing the heart through extracellular and internal mechanisms. First, the transplanted mitochondria synthesize high energy that is usable by surrounding heart muscle, and then they migrate inside the myocardial cells to repair damaged mitochondrial DNA.
In Emani’s patients, the mitochondrial rescue missions seem to have worked just as well.
"Within 48 hours of mitochondrial transplantation, we started to see heart function improve in our patients,” said Emani. “By day four, heart function had nearly normalized.”
Towards a new standard of care
So far, mitochondrial transplantation via injection has proven to be a safe procedure. All of the patients experienced a resurgence in his or her heart’s ability to pump blood, thanks to the boost given by mitochondrial transplantation. 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 preparing for a formal clinical trial to further study the effects and safety of mitochondrial transplantation. In the laboratory, the team is 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 also designing a variety of minimally invasive, targeted ways to deliver mitochondria to different areas of the body.