Gene breakthrough after sad setback

Penn researcher James M. Wilson MICHAEL S. WIRTZ / Staff
Penn researcher James M. Wilson MICHAEL S. WIRTZ / Staff
Posted: November 20, 2012

The first gene therapy in the Western Hemisphere will soon be available in Europe.

The approval of Glybera by European regulators happened with little fanfare in September, in contrast to the hype that surrounded gene therapy 20 years ago.

But it is truly a breakthrough for the field, for people with the ultrarare disease it treats - and for University of Pennsylvania scientist James M. Wilson, a creator of the modified virus that delivers the therapeutic gene.

Wilson began to focus on finding safe, efficient gene-delivery viruses, or vectors, after a study he led caused the 1999 death of Arizona teenager Jesse Gelsinger - the world's first gene-therapy victim.

The vector in that study triggered a fatal immune system overreaction. The fallout set off years of government investigations and efforts to improve human-subject protections.

"That tragic event forced me to reevaluate where we were and where the field was," Wilson said. "For this field to succeed, we had to go back to basics. I do believe this is a positive legacy to that."

Wilson publicly apologized and accepted responsibility for the death - almost a decade later.

While his remorse has been dismissed by critics such as Gelsinger's father, Paul, there is no doubt his research has dramatically advanced the science.

Since 2000, he and his team have overcome some of the biggest technological obstacles to harnessing altered viruses to infect cells with helpful, rather than harmful, DNA. They discovered 120 new adeno-associated viruses (AAV) in monkeys and humans - only six were previously known - and created an array of gene transporters. Through animal testing, they identified vectors with an affinity for certain tissues, enabling gene therapy to target organs such as the liver, eyes, and muscle.

Penn Vector Core, a university facililty that Wilson oversees, now provides viral and non-viral vectors - at cost - to academic researchers around the world. Through an affiliated company founded by Penn, ReGenX, biotech corporations can also access novel AAV vectors.

If companies that use Penn's technology make money with the resulting therapy, Penn - and in some cases, Wilson - stands to profit.

That has not yet happened. And experts now predict a relatively limited role for gene therapy in relieving human suffering, at least for the foreseeable future. While dozens of gene therapies are now in human testing, most are for rare, little-known, single-gene defects. Glybera, for example, treats a fat-breakdown disorder that afflicts only two people in a million.

Late last year, British researchers, using a Penn vector, reported success with a gene therapy for a well-known disease - hemophilia. But the bleeding disorder is not common.

Gene therapy is being explored for illnesses such as heart disease and cancer, but the technical challenges remain huge, in part because those diseases involve the interaction of many genes.

Another aspect of gene therapy that is different from conventional drugs: It may need to be given only once. Then, if it works, the corrective gene is in the patient's DNA permanently.

"There may be a surge in the number of gene therapies approved over the next few years," the journal Nature Biotechnology editorialized in September. "What is less certain, however, is whether there will be a noticeable flood of patients treated."

Drugs for such limited markets may be a hard sell to pharmaceutical investors, Wilson said.

"But if the disease is severe and the intervention really helps," he said, "our society has demonstrated the willingness to pay for that."

Contact Marie McCullough at 215-854-2720 or