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Hina Chaudhry
Hina Chaudhry
Shortly after Dr. Hina Chaudhry began her cardiology fellowship at the University ofPennsylvania, her mother drove into the city to treat her daughter to lunch. They met in the hospital’s lobby — the same place where the two stood 20 years earlier after her father suffered, but survived, a heart attack.
   “She told me that I had promised her then that I’d become a heart specialist so I could help people like my father,” Dr. Chaudhry says. “I remember always being interested in the heart as a kid, but I think I was at an age when my father’s heart attack really affected me.”
   In a way, Dr. Chaudhry, now an Irving Assistant Professor of Medicine, still finds inspiration in childhood as she investigates new ways to prevent heart failure, a condition that frequently ensues after cells are killed during a heart attack.
Unlike in the adult heart, muscle cells in the fetal heart divide to create new muscle cells. Once this capacity is turned off around 3 months of age, it remains dormant for the rest of one’s life.  
   “A single heart attack can take out over a billion heart cells in one blow, but
adults can not regenerate those cells,” Dr. Chaudhry says. To prevent heart failure, a therapy needs to replace lost cells. So far, attempts at using adult stem cells to restore lost muscle cells haven’t worked. “Tapping into the embryonic program is the ideal strategy because it relies on the cells’ own machinery to reawaken the heart.”
   For many heart attack survivors, the inability to replace lost cells places a large burden on the remaining heart tissue, which must propel blood through 12,000 miles of arteries, veins and capillaries each day. Heart failure ensues when the remaining cells can’t cope and the heart slowly loses its ability to pump blood.
   Though drugs and lifestyle changes can slow the progression of heart failure, at a certain point a heart transplant is the only option. But with 5 million people in the United States with heart failure at any one time and only about 2,200 heart donors available a year, the need to develop alternatives that can benefit more people is clear.
   At the center of Dr. Chaudhry’s strategy is the gene responsible for turning off the heart’s ability to produce new cells: cyclin A2. When cyclin A2 is active, heart cells multiply; when it is shut off, cell division stops.
   Dr. Chaudhry found that if this gene is tweaked so that it stays on all the time, adult mice will continue to produce new heart cells throughout their lives. And that ability saves the mice from heart failure after experiencing a heart attack.
   “When we presented these findings at the American Heart Association, the response was, ‘Great, but how are you going to apply this clinically?’” she says. “That really got us thinking about designing a gene therapy that would deliver cyclin A2 to the heart and regenerate damaged tissue.”
   To develop the therapy, Dr. Chaudhry constructed a deactivated adenovirus that carries the cyclin A2 gene and then collaborated with Joseph Woo, M.D., at the University of Pennsylvania to deliver the gene into infarcted hearts of rats.
   Delivered in this way, the gene prevented heart failure in rats that had experienced heart attacks. The results were published in the July 4 issue of Circulation.
   “What’s so exciting is that one injection did so much,” Dr. Chaudhry says. “That surprised us. It shows there’s potential to use this gene in a therapeutic manner in people.”
   Before they test the therapy in patients, the researchers will redesign the gene therapy with a different virus that does not elicit as strong an immune response as the adenovirus and test the design on large animals. An adenovirus-based gene therapy was responsible for the death of a patient during a different clinical trial in 1999.
   It may also be possible to turn cyclin A2 on with a drug. “If we can figure out how the cyclin A2 gene is shut off in adult heart cells then hopefully we can design a small molecule – a drug – that will turn it back on,” Dr. Chaudhry says.
   That would certainly please Dr. Chaudhry’s father. “My dad is very excited,” Dr. Chaudhry says. “He’s been my biggest supporter all along.”

—Susan Conova

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