In the early 1990s, gene therapy was one of the hottest fields in modern science. But the 1999 death of Jesse Gelsinger -- an 18-year old test subject at Penn -- sparked a series of setbacks that quickly halted advancement in the field.
Since then, however, gene therapy has slowly been making progress and is beginning to regain its momentum, experts say.
The implementation of new safety measures, as well as promising results from recent rounds of animal testing, is bringing the field of gene therapy back to the prominence it experienced in the mid-1990s.
According to the Human Genome Project Web site, gene therapy is a technique for correcting defective genes responsible for disease development. This is accomplished by utilizing benign viruses as carriers of normal genes using them as a mechanism to replace any abnormal, disease-causing genes.
Gelsinger was being treated for a liver problem, and died of organ failure within days of being injected with a genetically modified cold virus.
Just eight years before his death, the field of gene therapy began with its first test in September of 1990 and grew exponentially until a series of incidents in the late 1990s caused a significant dropoff in research.
"The Gelsinger death absolutely set back gene therapy work internationally," Arthur Caplan, the Chair of the Department of Bioethics said. "It was basically a lot of optimism, and then in the first human trial, someone died."
According to Caplan, Gelsinger's death provoked questions surrounding the experiment's protocol, and most testing was subsequently put on hold.
"The notion after this incident was that gene therapy was filled with buccaneers, people on the edge," Caplan said.
Paul Gelsinger, Jesse's father, stated that the loss of his son has made him very leery of the field.
"What happened to Jesse has made people much more conservative," Gelsinger said. "If people are saying they're doing great [in gene therapy tests], I would be highly suspicious."
Caplan attributed the immediate backlash to the Gelsinger death in part to the excessive hype of the field prior to the incident.
"Gene therapy was hyped to draw investment, and after investors saw it being a 10 to 20 year project, they moved on to stem cell research," Caplan said.
He also noted that other fields, including organ transplantation, have had rocky starts.
"It is very difficult to make something work right away, and with organ transplants, dozens of people died in the beginning, there just wasn't as much money invested in the process," Caplan said.
Although the heavy investment and hype led to a big drop-off in the field after Gelsinger's death and other incidents, it is slowly being rejuvenated by programs like Penn's Office of Human Research and new, more successful tests.
The Office of Human Research was created in 1999 with the purpose of balancing effective research with safety concerns.
"There are now a number of safety mechanisms in place and the tools we use have improved tremendously," said Jean Bennett, a Professor in Ophthalmology and Cell Biology who has been performing various tests in gene therapy with some successes.
Bennett and her team have been working on developing treatments to correct blindness in infant children. Up to this point their tests have consisted of work on animals such as mice and dogs.
"The process is fairly simple -- there is one particular defect gene in the retina, and we deliver a normal copy of the gene and bypass the biochemical defect," Bennett said.
In some trials, vision has been restored in dogs in a matter of months, and there have been no noticeable side effects.
"I think the success of this experiment is one incremental step for gene therapy, and it is very exciting," Bennett said.
Other scientists have seen similar success in different types of experiments -- such as those of Katherine High, a hematologist at the Children's Hospital of Philadelphia. High's team has had some success in implanting genes that work to improve blood-clotting factors.
"The whole field needs a huge demonstration on humans that is safe and effective, and we are hoping to do that," Bennett said.
These advancements have brought a sense of hope back to the field.
"Gene therapy is still moving forward, and it will succeed and will have a major role in 21st century medicine," said Nelson Wivel, the associate head of the Gene Therapy Program at Penn. "The real question is how long it will take."
Despite these advancements, some people are still skeptical, and cite the possibility of more accidents in the future.
"I think gene therapy is greatly diminished in its viability, and there has been a lack of progress in the field in terms of efficacy," Gelsinger said. "You hardly ever see gene therapy in the news, and the hype has really caught up to reality."
Gelsinger also questioned the recent success of many gene therapy tests involving animals,
"In the clinical trial [with Jesse], they achieved success with mice, and that was the treatment Jesse got. There was no efficacy because mice didn't have the same response as humans," Gelsinger said, "Just because something works in animals, that does not mean it is going to work in a human."
Caplan underscored the need for more successful testing.
"The government and investors are still leery, but they have to understand that the process can take about 20-25 years," Caplan said. "If we could get a breakthrough reversing a disease with little side effects, it could create some momentum."
"The bottom line is, when you pass into new, uncharted territory, it is never risk free. In gene therapy, you have to be in there for the long haul, and I think it is absolutely worth pursuing."
