Rocky past for gene therapy at Penn Med

A video shows a young boy wearing an eye patch as he tries to make his way through an obstacle course.

“This is hard,” he says, struggling to take more than a couple of steps. Ten minutes later, he tries to navigate through the obstacle course again, this time with his other eye — which received a gene therapy injection three months earlier — covered. He is able to make it through easily.

The young boy has Leber’s congenital amaurosis, or LCA — a form of retinal degeneration that leads to total blindness.

Yet, in perhaps one of the most successful gene therapy clinical trials, Penn School of Medicine professors Katherine High, Jean Bennett and Albert Maguire successfully injected genes that produce light-sensitive pigments into his eyes.

His — and several other patients’ — vision improved enough that he is no longer considered legally blind.

“It is actually the first demonstration of a gene therapy delivered to an intact individual by these somatic methods … that actually corrects the disease,” said Glen Gaulton, the chief scientific officer at the Medical School.

The team’s work began in the 1980s and only came to fruition within the last three to four years, explained Gaulton. “It’s a long time frame.”

Since the early days of gene therapy research, Penn has played a large role in its development, gaining attention for the renowned body of research it has produced, such as the LCA study.

But on the road to its current level of success, the University also had to overcome the national controversy and ethical dilemmas surrounding the unforeseen death of a clinical patient.

The Beginning

“I think that I was the first one on campus that did … gene therapy,” said John Wolfe, a professor of Pathology and Medical Genetics at the School of Veterinary Medicine, who started gene therapy research at Penn in January of 1988.

“I remember having to tell the bio-safety committee how they should regulate my work because no one had done that before.”

Despite Wolfe’s earlier work, it was not until 1993 that Penn entered full swing into the field, establishing the Institute for Human Gene Therapy, the first institute in the world to embody an interdisciplinary approach to gene therapy.

Heading the IHGT was James Wilson, a well-known pioneer of gene therapy research.

According to Wilson, IHGT sought to recruit faculty, build infrastructure and implement an educational program — establishing the first gene therapy doctoral program in the world. Its infrastructure included an animal laboratory and a lab for making vectors — viruses that serve as the primary “delivery vehicles” for bringing genes into living cells. The development of safe and effective vectors was — and continues to be — one of Wilson’s major focuses.

As stated in a grant proposal written by Wilson during the time, it was a period of “tremendous excitement and optimism.” Wilson’s team was the first group outside of the National Institutes of Health that conducted a clinical trial on gene therapy treatment for inherited diseases.

Some of IHGT’s initial projects focused on cystic fibrosis, hemophilia and inherited eye diseases. Many of these areas would later show some of the most promising results in the field.

Death and Controversy

One of the consequences of conducting clinical trials is that “there’s always risk,” explained Gaulton.

Such risk led to the death of Jesse Gelsinger, an 18-year-old clinical patient for a study aiming to cure OTC — ornithine transcarbamylase deficiency— a metabolic disease that has about a 50-percent mortality rate in children.

Gelsinger’s death sparked national controversy because he had a non-fatal form of the disease at the time of the clinical trial. He suffered from a relatively mild version of OTC and was participating in a phase 1 trial designed to test the safety of the treatment to be used later for infants with fatal OTC.

Gelsinger was the 18th patient to receive the dosed vector in September of 1999. Yet Gelsinger experienced multi-organ failure and died in 98 hours.

After a three-month study, the Food and Drug Administration suspended all human experiments at the institute, citing 18 violations of FDA protocol. Penn later stopped all clinical trials and disbanded the IHGT.

The United States Attorney’s office then sued Penn for misleading federal oversight agencies. In February of 2005, the suit finally came to an end, with Penn paying $517,496 to settle the charges. Sanctions were placed on Wilson, Mark Batshaw and Steven Raper, the three researchers who led the study.

Some of the major concerns that arose out of the death of Gelsinger were deviation from protocol, inadequate feedback to the FDA, lack of informed consent and conflict of interest.

“In each of these areas, the government found fault with Penn, and I think Penn mounted a very aggressive response on all of them,” said Arthur Caplan, the director of Penn’s Center for Bioethics. “Now we have a very comprehensive — probably the best in the country — oversight of all medical research.”

The changes made after the death of Gelsinger were more related to the examination of how Penn handles and monitors human-subject research, rather than “a specific critique or modification of gene therapy,” Gaulton said.

As a result of this, the Office of Human Subject Recruitment and Protection was formed.

Risks of Research

Despite the changes that the Gelsinger case brought about in monitoring human-research trials, multiple scientists highlighted the “inherently risky” nature of research.

“All research has some danger, and you certainly have to realize that you could have an adverse event even under the most highly regulated and controlled forms of research — it’s exploring unknown factors and there’s risk,” Caplan said.

“We learned a lot from it,” said Wilson, who has since reflected on Gelsinger’s death. In 2009, Wilson published an article in an issue of Molecular Genetics and Metabolism, which details the clinical trial and its impact on future gene therapy experiments and oversight.

“My deepest regret is that a courageous young man who agreed to participate in this clinical trial with the hope of making life better for others with this disease lost his life in the process,” Wilson wrote.

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