As pediatrics chairman, Dr. Terence Flotte oversees a department growing to meet the needs of young patients

A year after stepping into the dual role of pediatrics chairman and medical director of Shands Children’s Hospital, Terence Flotte, M.D., is launching new research and educational initiatives and strengthening existing programs to improve care of children with difficult-to-treat diseases.

Through faculty recruitments and administrative appointments, Flotte is ensuring the best medical minds continue to serve Florida’s children. He leads 228 full- and part-time faculty members at UF campuses in Gainesville, Jacksonville and Pensacola. Areas of focus include pediatric neuroscience, genetics, cancer and children/family issues.

An internationally known pioneer in human gene therapy, Flotte’s research has shaped one of his important departmental goals: to create a new division of cellular and molecular therapy.

“One of the key features of an academic department is the ability to add to the body of new knowledge and to use that knowledge to directly benefit patients suffering with diseases that currently do not have adequate therapy,” Flotte said. “One of the most direct ways to do that is to perform gene transfer to replace genes that have been identified as the cause of specific diseases, such as cystic fibrosis. The emergence of safe gene transfer technology has, for the first time, made it possible to test this concept in a way that ultimately could provide a new treatment for a previously incurable disease.”

Flotte currently is investigating the use of gene therapy for genetic diseases that affect children, mainly cystic fibrosis, a disorder that causes thick mucus to block the breathing passages of the lungs. Patients with the disease are predisposed to chronic lung infections.

“Children who have cystic fibrosis are in the hospital a lot, and they require frequent follow-up clinic visits, so we develop long-term relationships with them,” Flotte said.

Meticulous care by health professionals has resulted in longer lives for many patients with the disease, but Flotte says gene therapy may be key to finding a cure.

“At the beginning of my research fellowship (at the Johns Hopkins Hospital in Baltimore), I started trying to devise a way to deliver a normal copy of the gene to cells in the lung,” Flotte said.

“Theoretically, because it is a recessive disease (inherited from both parents), you only need one normal copy of the gene to restore the beneficial effect and prevent lung complications.”

In 1995, Flotte and his colleagues at the Johns Hopkins University School of Medicine became the first to use the apparently harmless adeno-associated virus, or AAV, as a vehicle to deliver corrective genes to targeted sites in the body, including the damaged airways of adults with cystic fibrosis. These pioneering clinical trials were conducted at Shands at UF medical center.

Since joining the UF faculty in 1996, Flotte has continued clinical trials and basic laboratory research to determine how to treat genetic disorders using vectors, viruses modified to carry corrective genes.

“The original vector we made back in 1990 has progressed all the way through phase 2 clinical trials since 1995, when the first patients were treated and showed some early signs of some beneficial effects,” said Flotte, who formerly directed the UF Genetics Institute and the UF Powell Gene Therapy Center.

Now he and fellow investigators are studying why those beneficial effects last less than two months.

“We discovered that when you change the virus into a vector — alter the virus and splice in the normal gene that you want to deliver — you actually change the behavior of the virus,” Flotte explained. “It still sticks with the cell for a long time if that cell lasts a long time, but it doesn’t insert its DNA into the chromosome as a natural virus does. It doesn’t ‘integrate’ anymore.

“Our lab was the first to describe this phenomenon, which has implications for how long it might last if cells are turning over,” Flotte said. “There are some cells — in the eye, the brain and even in the muscle — that don’t turn over. But in the lungs, particularly in the lungs of cystic fibrosis patients that are infected and inflamed and the cells are turning over, that probably results in the virus not staying around very long.”

Researchers also are preparing to conduct a clinical trial for the genetic disorder alpha-1 antitrypsin deficiency. A protective protein produced in the liver, alpha-1 antitrypsin normally circulates through the bloodstream. Patients with the disorder are more vulnerable to serious lung and/or liver disease when the protein accumulates in the liver.

Through the clinical trial, Flotte and Mark Brantly, M.D., a professor of medicine and of molecular genetics and microbiology at the College of Medicine, will determine whether gene therapy is an effective treatment for the deficiency.

"Our institution has made this material (vectors) for the first time at the Evelyn F. and William L. McKnight Brain Institute,” Flotte said. “We now have a clinical-grade facility for producing alpha-1 antitrypsin vector and other vectors.”

The National Institutes of Health funds both the cystic fibrosis and alpha-1 antitrypsin research.

UF pediatric scientists also are investigating gene therapy for metabolic diseases and spinal muscular atrophy, or SMA, a disease of the anterior horn cells of the spinal cord. Flotte has received a two-year, $242,602 grant from the nonprofit organization Families of SMA to study the disease.

“The disease only affects newborn babies, and they lose all of their spinal cord function,” Flotte said. “They then will have breathing failure because they lose the ability to drive the respiratory muscles.”

Flotte’s team also is working with diabetes researcher Mark Atkinson, Ph.D., a professor of pathology, immunology and laboratory medicine at the College of Medicine, to develop a system for delivering chemical signals that might reverse the immune system’s destruction of insulin-producing cells.

Growth in Numbers

Flotte’s new faculty recruits include physician-scientist Melissa Elder, M.D., Ph.D., the new chief of immunology, rheumatology and infectious diseases.

“We’ve also recruited four new faculty members in pediatric cardiology and soon will hire a new pediatric cardiac surgeon,” Flotte said. “They have brought in a lot of new technologies, including prenatal echocardiography for the diagnosis of heart defects before babies are born.”

That diagnostic tool, brought by Carolyn Spencer, M.D, an assistant professor, is being applied in patient care. New interventional cardiologist Joseph Paolillo, M.D., a clinical assistant professor, is expanding the use of cardiac catherization to correct various congenital heart defects. Recruits Margaret Samyn, M.D., and Arwa Saidi, M.D., provide expertise in preventive cardiology, cardiac intensive care and clinical trials.

Paul Carney, M.D., chief of pediatric neurology, also is recruiting new faculty in the subspeciality and is working with a multidisciplinary team, the UF Comprehensive Epilepsy Program, to develop new ways to predict seizures.

Flotte’s leadership style is reflected in his recruitment techniques.

“I pick good people and give them what they need to succeed,” Flotte said. “My main job is to remove obstacles to their success.”

Department faculty members have succeeded in developing innovative programs for patients and their families. John Nackashi, M.D., vice chairman for managed-care programs, and Michael Chen, M.D., of the department of surgery, are heading a new initiative to provide proactive treatment for children with special health-care needs — chronic conditions requiring ongoing, specialty care. Flotte says the Integrated Care System, or ICS, is designed “to get more preventive health-care resources to these children to prevent their needing to use emergency rooms and hospital beds.”

Another important departmental goal is to expand the effectiveness of the Shands Children’s Hospital, which is staffed by UF faculty physicians.

“Some of the new programs, funded by Children’s Miracle Network, provide support services, such as free or subsidized parking and meal tickets, to family members of patients who are in the hospital for a long time,” Flotte said.

As medical director of the children’s hospital, Flotte hopes to see the pediatric emphasis continue to grow.

“I’d like to see the hospital take the next step into a more visible, discrete unit, both in the physical sense and in terms of how it’s structured in the Shands HealthCare system,” Flotte said. “Ultimately, I would like to see us as a separate wing or tower as part of the hospital,” Flotte said.

Flotte’s busy work schedule doesn’t keep him from his family. He enjoys relaxing with his wife, Kye, at their home in Alachua. He says their six-acre property is perfect for outdoor activities with his three children: David, 13; Lindsay, 8; and Jesse, 5.

“My kids are my hobby,” he said. “Any spare time is spent with them.”