Clean genes

Twenty years on, James Wilson’s vision is redeemed.

aav_3-02017 probably will be the year in which gene therapies will be first approved by the Food and Drug Administration—a positive move in a year that’s not looking so positive overall.

These successes were built in part on experience from a tragic clinical failure back in 1999, with the death of a teenage volunteer in the far-too-aggressive early gene therapy trial spearheaded by James Wilson of the University of Pennsylvania.

“This event had far-reaching effects on the trajectory of gene therapy research and oversight of all clinical trials,” Wilson noted a decade later in a commentary on lessons learned.

“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,” he wrote. “The immunologic response that precipitated the lethal syndrome of systemic inflammation was unanticipated and not predicted based on the preclinical and clinical data available at the time. However, some of the problems in the design and conduct of the clinical trial that surfaced in the subsequent investigations were real and absolutely unacceptable and ultimately were my responsibility.”

Wilson lost his government research funding. But with initial backing from a former mentor at GlaxoSmithKline, he went back into the lab to develop more advanced gene therapy delivery systems,  “adeno-associated” virus (AAV) vectors, that are a cornerstone of many therapies now approaching approval.

“We characterized these vectors and started to distribute them to academic researchers,” Wilson told me last year for a story in Nature. “Over the next 10 to 15 years, these vectors have formed the basis for most of the clinical translation and most of the companies that have been founded.”

One of these companies is Spark Therapeutics, whose treatment for a rare genetic eye disease may be the first gene therapy to get FDA approval. Spark also is among several biotechs with candidates for treating hemophilia that appear both surprisingly effective and, so far, acceptably safe.

True, no one really knows if the effects of these new therapies will last a lifetime. Or exactly how payers will view their high prices.

“If we can deliver transformative therapies, we’ll see huge effects on the practice of medicine,” said Wilson, who is now leading the creation of a third generation of AAV vectors (above). “The concept is so fundamental: engineering a cell to modify expression of a gene to prevent, cure or treat a disease. This will only grow.”