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By Melanie Fridl Ross

GAINESVILLE, Fla. - These days the stork barely begins to circle and parents already know whether to stock up on pink or blue. Now a growing number of researchers are pondering whether gene therapy to prevent an array of devastating disorders detectable before birth might someday also be part of the prenatal package.

In the most recent study of its kind, University of Florida scientists report they have used gene therapy targeted to the womb to reverse respiratory muscle weakness in unborn mice predisposed to an inherited muscle disease that affects breathing, a condition that also plagues people. Although it's not the first time gene therapy has been tested in utero, the UF study, published this month in the journal Development, yielded some of the more successful findings to date, dramatically improving the ability of respiratory muscles to function.

Researchers are keen on the approach in part because delivering gene therapy before birth, as the immune system itself is still forming, would theoretically help correct birth defects or lethal hereditary diseases while evading a common complication: an attack mounted when the body identifies as foreign the virus used to transport corrective genes and the proteins they produce. Various metabolic diseases, some of which appear soon after birth and are associated with early death, are collectively quite common and could possibly be among the first ailments to benefit from the method, which would seek to replace missing or defective enzymes.

Yet UF scientists caution that substantial political and philosophical hurdles would have to be overcome before in utero gene therapy could be tested in people, much less adopted clinically. And, they point out, their study was designed more as a proof of principle than as the first step toward designing trials aimed at humans.

"We wanted to prove the concept that with earlier treatment, inherited metabolic diseases can be corrected before birth, so it's a demonstration of that approach," said the study's senior author Barry Byrne, M.D., Ph.D., a UF pediatric cardiologist who is a member of the UF Genetics Institute and director of the Powell Gene Therapy Center. "In some genetic diseases it's clear that there are a whole variety of deficits that occur even by the time of birth that would ideally be treated with in utero gene therapy. This was a very early study that was not meant to justify doing fetal gene transfer for the sake of going to the clinic with that strategy, but was conducted to really understandhow the disease progresses. That's not to say that it can't be the first step toward that, and for some diseases that cause developmental abnormalities at the time of birth that would be an advantage, if one could make an in utero diagnosis."

UF researchers studied mice with a rare, incurable form of muscular dystrophy known as glycogen storage disease type II, which is caused by a single defective gene that fails to produce adequate levels of an enzyme that normally breaks down the carbohydrate glycogen, used to store energy. The disease causes gradual weakening of muscle and heart tissue when glycogen accumulates in muscles, limiting their ability to contract. Total absence of the enzyme is referred to as Pompe's disease, which is usually fatal during the first year of life.

Some therapies are under study for various forms of glycogen storage disease, but currently no long-term treatments are available, Byrne said. According to the National Organization for Rare Disorders, glycogen storage disease type II is one of 6,000 rare disorders that afflict an estimated 25 million Americans.

The scientists injected the apparently harmless adeno-associated virus, modified to contain copies of a therapeutic gene that pumps out the missing enzyme, into the livers of eight mice three-quarters of the way through gestation, and into the abdomens of three others, said the study's lead author, Mary Rucker, Ph.D., a former UF graduate student. The gene readily spread to its intended location, the diaphragm, in five of the eight mice, and in all three that received abdominal delivery. Researchers noted these mice had enzyme activity levels up to 10-fold higher than normal, a sign the gene was working, Rucker said. An additional three mice received a less potent dose and had almost normal muscle function at six months of age compared with age-matched controls.

"What we wanted to know was whether early treatment had better outcomes," Byrne said. "The approach was to replace the gene during development. That prevented the accumulation of glycogen in the diaphragm and improved the strength of that muscle in the mouse model.

"As we learn more about the potential for systemic gene transfer to correct genetic diseases, it's conceivable that this approach, either the one used in these mice or one with more clinical relevance, could be used," he added. "For instance, in the same manner an obstetrician draws blood from a baby in the uterus, it would be possible to inject gene therapy into the circulation, possibly introducing a corrective gene."

UF scientists are now collaborating with researchers at the University of California at Davis on similar studies in primates.

As public interest in technological advances for correcting genetic deficiencies, preventing diseases and treating related infertility problems soars, gene therapy - and other controversial topics such as preimplantation diagnoses and sex selection - are sure to be hotly debated, Byrne said.

In utero gene therapy is not without risk, potentially to both the mother and the fetus, scientists caution. In addition, some fear the approach could cause developmental abnormalities, cancer or permanent changes to developing eggs or sperm, resulting in modified genes being passed on to future offspring. These risks will need to be assessed in future studies, Byrne said.

"This study is a milestone in gene therapy in utero," said Xiao Xiao, Ph.D., an associate professor of molecular genetics and biochemistry at the University of Pittsburgh Medical Center. "The authors demonstrated profound therapeutic effects in a clinically relevant animal model for Pompe's disease. If in utero gene therapy finds its way to treating human patients, the early childhood lethal genetic diseases like Pompe's will be the first candidates to benefit."

UF expert: for some physicians, alcohol and drugs are prescription for addiction

By Melanie Fridl Ross GAINESVILLE, Fla. - In the wake of news that Vice President Dick Cheney's personal physician is battling an addiction to prescription narcotics, a University of Florida physician cautions the problem is more widespread than patients and practitioners might think. An estimated 4 percent to 6 percent of doctors - tens of thousands - will at some point in their lives be hooked on drugs and as many as 15 percent on alcohol, a number that mirrors trends in the general population, says UF addiction medicine expert Kenneth W. Thompson, M.D., who once struggled with a personal addiction to prescription drugs and now serves as medical director of the Florida Recovery Center, located at Shands at Vista. But for health-care practitioners, facing up to an addiction can be a tough pill to swallow: Recovery can be hampered by a reluctance to seek help from fellow physicians and by stress and sheer accessibility of prescription medicines, he said. "Addiction is often misdiagnosed as depression, stress or marital problems because many health-care and mental health-care practitioners are unaware of the numerous manifestations and symptoms of addiction," Thompson said. "Addiction is not the result of life problems but rather the cause and therefore requires treatment that specifically addresses the addiction. I was blessed that the treatment providers that cared for me understood this." Thompson, also an associate professor of psychiatry at UF's College of Medicine, was featured this morning on "Good Morning America" and has treated more than 10,000 patients who suffer with chemical dependency, including 1,700 health-care professionals. UF researchers who studied doctors enrolled in recovery programs have found that long-term treatment and close monitoring of addicted physicians gives them the best chance of remaining employed and drug-free. Successful rehabilitation is possible, noted Thompson, who said physicians must undergo counseling and treatment and agree to random drug tests if they wish to retain their medical licenses. The good news: Compared with other patient groups, physicians are much more likely to return to work and never relapse, he said.