As Judson observed, despite hundreds of millions of dollars lavished on hundreds of gene therapy trials involving thousands of patients and volunteers, “new hopes cyclically turned to ashes, dramatic claims to sad farce.”30 Gene therapy itself was on life support.
With some sober reflection, many of the setbacks could be understood. After all, viruses did not evolve simply to be used at our beck and call as delivery drones. As one gene therapy expert said: “We underestimated the fact that it took billions of years for the viruses to learn to live in us—and we were hoping to do it in a five-year grant cycle.”31 There was also the complication of our immune system, which is designed to combat foreign agents such as viruses. The human body isn’t going to automatically give billions of recombinant viruses a pass just because they mean well.
It has been a long haul back to respectability and success for gene augmentation therapy. The roller-coaster ride follows the Gartner Hype Cycle: the inflated expectations of the 1990s, the trough—or abyss—of disillusionment at the turn of the century; followed by the slope of enlightenment. What’s been holding up the field is not a lack of suitable targets—we have an encyclopedic catalogue of thousands of eligible Mendelian genetic diseases—but the capability of delivering the therapeutic gene safely and effectively. Researchers had to go back to the drawing board, focusing on viral delivery and safety. Two new candidates emerged as reliable, adaptable, and effective delivery vehicles for a swath of gene therapy (and genome editing) indications: adeno-associated viruses (AAV) and lentiviruses.
AAV was discovered by accident in the mid-1960s as a contaminant of an adenovirus preparation. The attraction of AAV comes from its barebones structure—it is the tiny house of viruses, a protein shell that can carry a small gene cargo. The virus is very safe—about 90 percent of humans have been exposed and infected by AAV without knowing it. Wilson’s group, clutching a financial lifeline from GlaxoSmithKline, got to work. There were only six known varieties when Guangping Gao in Wilson’s team set out.32 But at the end of 2001, he presented Wilson with a bounty of novel AAVs he had isolated from monkeys. More than one hundred forms of AAV are currently known. “Penn’s viral vector center became the Amazon of AAV,” observed science journalist Ryan Cross.33
Why so much interest in this tiny virus? AAV naturally carries just two genes, REP and CAP, which encode proteins that make up an icosahedral capsid coat. Fully clothed, the virus is just twenty-five nanometers in diameter, holding a payload of single-stranded DNA about 5,000 bases in length—enough for a small therapeutic gene. And unlike retroviruses, AAV does not integrate into the host genome; that means it will dilute out over time as the cells it infects divide.
Despite their popularity, there’s room for improvement, says UC Berkeley’s David Schaffer. “We need better viruses. Viruses did not evolve in nature to be used as human therapies.”34 Treating spinal muscular atrophy (SMA) patients, for example, has required the highest dose of AAV used in a human to date. Schaffer’s team is evolving in the lab the amino acids on the AAV surface to create novel vehicles with improved targeting properties to the appropriate cells, such as the retina.35 Jean Bennett was able to overcome the limitations of AAV2, which doesn’t travel through the vitreous of the eye, by delivering it directly through the retina. Schaffer’s group has evolved a new AAV that can penetrate the full surface of the retina by injecting into the vitreous.
Lentiviruses, the other emerging virus class, form a sub-family of retroviruses and includes HIV. The tenacity with which HIV can lurk in the T cells of a patient illustrates their potential value as a modified gene delivery vehicle. Lentiviruses can infect both dividing and non-dividing cells and have a cargo hold double that of AAV. The first clinical trial using a lentiviral vector was conducted in 2005.
A decade after Gelsinger’s death, an editorial in Nature signaled a renewed sense of optimism in gene therapy circles. “The pervading sense of disillusionment is misplaced,” Nature stated.36 It was time for researchers and biotech “to consider its successes with as much intensity as its setbacks.” Wilson reflected on the lessons he had learned. “With what I know now, I wouldn’t have proceeded with the study,” he said. “We were drawn into the simplicity of the concept. You just put the gene in.”37 Carl Zimmer penned a story for WIRED with a striking hero image of two viruses: on the left was the adenovirus that “laid waste” to Wilson’s career. On the right, the AAV, the bright new hope of gene therapy that could bring Wilson “redemption.”38
In 2015, Friedmann and Fischer were awarded the Japan Prize for their contributions to the gene therapy field. Friedmann opened his award lecture in Tokyo by showing a picture of the serpent-entwined Rod of Asclepius, the ancient Greek symbol of medicine. Next he substituted the snake with the double helix—the repository of all genetic information. “We would like to think that knowledge of this molecule is going to markedly change the way we understand disease and the way we treat disease,” he said.39 As an example, Friedmann paid tribute to a female physician in Philadelphia who was pioneering a method to deliver a gene therapy directly into the retina of patients with a rare genetic form of blindness. Those early results, Friedmann proclaimed, were of “biblical proportions.”
Indeed, they were little short of miraculous.
I. The virus was named after Richard Shope, a Rockefeller University pathologist who, studying a flu outbreak in pigs in 1918, helped prove that influenza was caused by a virus, not a bacterium. In 1933, Shope injected himself with the eponymous virus.
II. As I described in my first book, Breakthrough, King’s quest to isolate BRCA1 was thwarted by Myriad Genetics. Twenty years later, I served as the technical advisor for a film called Decoding Annie Parker, based on the true story of the first woman in North America to undergo BRCA1 genetic testing. Helen Hunt played Mary-Claire King. Sadly, few of my suggestions were incorporated—the writers told me we weren’t filming a Nova documentary. My name is buried at the end of the closing credits, right after Aaron Paul’s guitar coach.
CHAPTER 11 OVERNIGHT SUCCESS
The world got a prime time glimpse of the renaissance of gene therapy on a 2017 episode of the television show America’s Got Talent. Christian Guardino, a genial sixteen-year-old from Long Island, New York, stunned Simon Cowell and the other judges with his rendition of the Jackson 5 hit, “Who’s Lovin’ You.” While the audience cheered the teenager’s amazing voice, the bigger story was out of sight. As an infant, Guardino was diagnosed with a form of Leber’s congenital amaurosis (LCA type 2)—a genetic disorder that causes an inexorable degeneration of cells in the retina. A Fox News report made light of Guardino’s medical ordeal. “When Christian Guardino was young, he learned that he would lose his sight. Fortunately, thanks to some gene therapy, he later regained the gift of sight. In the interim, he turned to music and stuck with it.” The report irked geneticist Ricki Lewis, author of The Forever Fix. “Christian didn’t just order up gene therapy like a side of fries,” she grizzled.1