The initial headlines were alarming: A pioneer of gene therapy was raising red flags about the safety of the treatments he’d been working on for decades.
The full story, as it emerged in the weeks that followed, was more nuanced.
First, some background: Dr. James Wilson is a widely respected researcher at the University of Pennsylvania. He ran some of the earliest gene therapy trials in the 1990s – including one that led to the death of an 18-year-old patient. The fatality cast a dark shadow over the entire gene therapy industry and stalled progress for years. Wilson, however, never gave up on the concept. Instead, he immersed himself in developing a new, safer vector platform for delivering gene therapies.
The virus that Wilson has been promoting as a vector, adeno-associated virus, or AAV, has been used successfully – and safely – in many experimental gene therapies. It’s used, for instance, in Luxturna, Spark Therapeutics’ breakthrough treatment for an inherited form of blindness. But earlier this year, Wilson published two papers documenting dangerous and potentially fatal side effects in animal models when AAV-based gene therapy is delivered in extremely high doses. Putting an exclamation point on this warning, Wilson then resigned as a scientific adviser to Solid Biosciences, a startup that uses AAV.
Wilson’s research in pigs and monkeys does raise serious concerns about ultra-high-dose AAVs. But, there are some important caveats. For one, a substantial proportion of the gene therapies in development – including Luxturna – use far lower doses of AAV; those doses have been shown to be safe in trial after trial. The ultra-high doses are used only in treatments for specific diseases, such as Duchenne muscular dystrophy or spinal muscular atrophy. (In general, such high doses are needed only when the therapy has to be pushed into parts of the body it would not normally penetrate, such as into skeletal muscles or across the blood-brain barrier.)
Another key note: The high-dose human trials now underway have not led to the same toxic side effects that Wilson saw in pigs and monkeys. He recently told Forbes that the early data from such programs were “encouraging.”
Wilson added in the Forbes interview that overall, “the safety profile of AAV with respect to immune toxicity is remarkable” – and “qualitatively better” than other delivery platforms he’s tried.
That’s why he’s not calling for an abrupt halt to high-dose clinical programs. Instead, Wilson is urging his fellow researchers to be highly vigilant in looking for possible toxicities in preclinical research. He’s asking them to carefully weigh the risks and benefits before launching human trials. And, he’s advocating more research to investigate whether any potentially harmful side effects could be mitigated with a preventative course of immunomodulating drugs.
Wilson’s research raises important questions for the entire field. As the science continues to advance, we’re bound to learn more about the potential for both the progress and the limitations of gene therapies – and the vectors that deliver them into patients’ cells.