Jim Wilson has 2 new promising gene therapy studies, but says investment in the cutting-edge field has ‘gotten worse’

Prominent University of Pennsylvania gene-therapy scientist Jim Wilson has published two new studies supporting the promise of the cutting-edge field, finding evidence that the genetic treatments can be beneficial for years without raising the risk of cancer.

The findings come after lackluster results were reported in October for one recent entry in the emerging field, a treatment for a muscle-weakening disease called Duchenne muscular dystrophy. Earlier this year, investor enthusiasm for gene therapy cooled amid concerns about the drugs’ financial viability, Wilson said at an industry conference.

Still, gene therapy and related cell therapies are seen as a key driver of Philadelphia’s growing biotech scene, leading some boosters to nickname the area Cellicon Valley. Since 2017, the FDA has approved half a dozen gene therapies of the kind Wilson studies, in which an inactivated virus “vector” is used to deliver a beneficial gene into the cells of a patient born with a missing or defective copy of that gene. Two of the treatments, for types of blindness and hemophilia, have ties to the Philadelphia area.

In one of Wilson’s new studies, he confirmed earlier findings that these virus vectors sometimes insert their DNA into the recipient’s genome, which can cause cancer when the therapy is given to newborn mice. But no such risk is apparent in monkeys — a key finding because the primates are far more closely related to humans than mice, Wilson and his colleagues reported in the journal Human Gene Therapy.

The other study found evidence that for gene therapies targeting a deficiency in the liver, the impact diminishes within a month. But after the initial decline, the benefit stabilizes over the long term, Wilson and his colleagues reported in Nature Biotechnology.

The Inquirer spoke to Wilson about the results of the two studies and other recent developments in the field.

Both studies focused on a common type of gene-therapy vector called an adeno-associated virus (AAV), which delivers its beneficial genetic cargo into the nucleus of the recipient’s cells. In most cases, these therapeutic genes remain distinct from the recipient’s DNA, but previous studies have found that sometimes they become integrated into the recipient’s genome at low levels, Wilson said.

“There was the concern as to whether this were random, or this integration could cause a cancer,” he said.

In one of the new studies, the Penn team confirmed that these genetic insertions occurred in lab monkeys, but in locations that were not expected to lead to cancer.

The researchers then bolstered their case by showing that similar low-risk DNA insertions occur when monkeys and humans were infected with the natural type of these adeno-associated viruses, which also are not known to cause cancer.

“The bottom line is, this whole observation of an AAV coming into the liver and integrating, it’s also occurring out in the wild,” Wilson said.

The study results also are supported by years of evidence from monkeys and humans that have received various gene therapies, he said.

“In monkeys and humans that have undergone gene therapy, we’ve never seen a formation of a tumor,” he said.

Barry J. Byrne, director of the University of Florida’s Powell Gene Therapy Center, who was not involved with Wilson’s studies, agreed that they were promising. He said there was no evidence that the AAV gene therapy poses a cancer risk for human patients, despite the previous studies in mice.

“The general consensus is that those findings in mice don’t represent any safety concerns in humans,” Byrne said.

Wilson and his colleagues measured the level of expression from the corrective genes administered to monkeys — that is, the level of beneficial proteins made from the “recipe” carried in those genes.

“We were able to do experiments in monkeys in which we could follow the same animals over time, and get biopsy samples to determine what happened with the expression of these genes,” he said. “Within a month, it goes down. But after it settles down, it’s stable.”

“We have evidence that suggests that the reason it’s stable is the DNA that integrates into the genome, and that leads to stable expression,” he added.

Patients who got the treatment did not fare significantly better than those who got a placebo when rated by their scores on a “primary endpoint” — a composite measure of muscle function. But some did better on isolated secondary measures, such as how fast they could walk 10 meters.

Wilson said the results did not necessarily have any bearing on the overall field of gene therapy.

“I think it’s hard to know what impact it’s going to have on the field,” he said. “They met a secondary endpoint, but they didn’t meet the primary endpoint. We’ll have to see how health authorities respond to that.”

“I don’t think there’s any question that some patients with Duchenne muscular dystrophy can benefit from this kind of gene therapy,” he said. “It’s just normal drug development, where a company will work with the FDA and other health authorities to determine what needs to be done.”

“It’s gotten worse. Macroeconomic issues have impacted on investment,” Wilson said. “Interest rates have not helped, from what I understand.”

“The other aspect of this is that there are concerns about the business model, where it’s a one-time delivery for treating really rare diseases,” he said. “Is there enough earning potential there? I think that’s the crux of it.”