If you skin your knee, your body makes new skin. If you donate a portion of your liver, what’s left will grow back to near-normal size. But if you lose a billion heart cells during a heart attack, only a small fraction of those will be replaced. In the words of Ke Cheng, an associate professor of regenerative medicine at N.C. State, “The heart’s self-repair potency is very limited.”
Cheng has designed a nanomedicine he hopes will give the heart some help. It consists of an engineered nanoparticle that gathers the body’s own self-repair cells and brings them to the injured heart tissue.
In this case, the self-repair cells are adult stem cells. “A stem cell is a very rich biological factory,” Cheng said. “Stem cells can become heart muscle, or they can produce growth factors that are beneficial to the regrowth of heart muscle.”
After a heart attack, dying and dead heart cells release chemical signals that alert stem cells circulating in the blood to move to the injured site. But there just aren’t very many stem cells in the bloodstream, and sometimes they are not sufficiently attracted to the injured tissue.
‘Matchmakers’ with ‘hooks’
The nanomedicine Cheng designed consists of an iron-based nanoparticle festooned with two different kinds of “hooks” – one kind of hook grabs adult stem cells, and the other kind of hook grabs injured heart tissue. Cheng calls the nanomedicine a “matchmaker,” because it brings together cells that can make repairs with cells that need repairs.
The “hooks” are antibodies that seek and grab certain types of cells. Because the antibodies are situated on an iron nanoparticle, they – and the stem cells they’ve grabbed – can be physically directed to the heart using an external magnet. Cheng calls the nanomedicine “MagBICE,” for magnetic bifunctional cell engager.
The magnet is a “first pass” to get the iron-based particles and antibodies near the heart. Once there, the antibodies are able to identify and stick to the injured heart tissue, bringing the stem cells right where they need to go. Using two methods of targeting – the magnet and the antibodies – improves the chances of being able to bring a large number of stem cells at the site of injury.
In addition to providing a way to physically move the stem cells to the heart, the iron nanoparticles are visible on MRI machines, which allows MagBICE to be visualized after it’s infused into the bloodstream.
Cheng doesn’t foresee much toxicity from the nanomedicine unless someone is allergic or particularly sensitive to iron. In fact, the iron-based nanoparticle that forms the platform for the antibodies is an FDA-approved IV treatment for anemia.
More than 30 FDA-approved therapies already use engineered antibodies to seek out a target – such as a cancer cell – and deliver a payload – such as a cancer-killing chemical. Some cancer drugs that are still in clinical trials combine two different antibodies to bring together the body’s own tumor-destroying T-cells and cancer cells. These drugs, called bispecific T-cell engagers, were the inspiration for MagBICE. Cheng said, “MagBICE has the potential to be the first bifunctional antibody drug not for killing something but for repairing something.”
In September, Cheng and his colleagues published results in the journal Nature Communications demonstrating the effectiveness of MagBICE in rats. Rats that received an infusion of the engineered nanoparticles after a heart attack recovered significantly more heart function than the control rats.
While the results of the rat study are promising, MagBICE has many more hurdles to clear before it could become a marketable drug for humans. “It’s a long journey,” Cheng said. The next step is to prove that it’s safe in large animals, such as pigs. Then the antibodies need to be engineered specifically for humans. Finally, it will have to go through several phases of clinical trials in humans.
Adaptations for other diseases
If MagBICE works for heart attacks, it could be modified for other conditions and diseases, bringing together fix-it cells and broken cells of various types. As scientists identify more and more cells in the body that are implicated in various types of disease or injury – from heart failure to stroke – antibodies could be engineered to attach to those cells. And on the other side, as scientists identify more and more types of cells in the body that can make repairs and speed healing, antibodies could be engineered to attach to those cells. “It’s not a single type of drug,” Cheng said of MagBICE. “It’s a platform technology that’s multipurpose.”
Emily Day, an assistant professor of biomedical engineering at the University of Delaware who was not involved in the design or study of MagBICE, called it “innovating and exciting,” and said, “I think it has great potential, largely because of the fact that it recruits a patient’s own cells.”
Day added that being able to see the iron nanoparticles with an MRI would be useful in confirming that the medicine reached its target. She said sometimes when therapies fail, it can be difficult to know whether a molecular mechanism didn’t play out as expected or whether the medicine didn’t get to where it needed to go.
Cheng has also worked with colleagues on another potential heart-attack therapy, which involves removing some of the patient’s stem cells, growing them in the laboratory, then injecting the cells back into the patient into an artery near the heart. The drawback to this method is that it takes 30 to 40 days to grow the stem cells. MagBICE could be given without any such delay, giving the heart a head start on the repair process.
Cheng came to N.C. State about a year ago from Cedars-Sinai Medical Center, in Los Angeles, where he was working when he came up with the idea for MagBICE. He has a joint appointment at the N.C. State College of Veterinary Medicine and the UNC Chapel Hill/N.C. State Joint Department of Biomedical Engineering. He is also an adjunct associate professor at the UNC School of Medicine. He said his “interdisciplinary appointment” allows him to leverage resources from veterinary medicine, human medicine and engineering. “We need resources from all three for successful biomedical research,” he said.