To appease the sticker shock over its Zolgensma pricing, Novartis executives came up with a lottery. In December 2019, the company announced it would offer one hundred free doses of Zolgensma annually—four names drawn every fortnight—for patients outside the United States. Winners must undergo testing for AAV9 antibodies before AveXis sends the magic dose to the relevant hospital. “Imagine parents putting a child in a draw every two weeks to see if their life can be saved,” sighed Lucy Frost, mother of an SMA child. “I think it could have been done much better.”36
The molecular arsenal to combat cancer and tackle genetic diseases is expanding far beyond gene therapy. Cell therapy, RNA interference, and phage therapy all show promise. Former President Jimmy Carter is the poster boy for CAR-T therapy. A pair of FDA approved drugs, Kymriah and Yescarta, have produced near-miraculous results in some patients, although the effects are short-lived in many others.
Recently, an ancient therapy dating back more than a century has returned to the headlines. Bacteria, as we have seen, evolved their CRISPR defense systems to nullify phage invasions. But in diseases caused by antibiotic-resistant bacteria, we can weaponize these phages to become a new form of precision medicine.
In 1915, physician Frederick Twort discovered a bacteria-killing extract that he said contained an “ultra-microscopic virus.”37 Around the same time, Félix d’Hérelle at the Pasteur Institute was studying dysentery among French cavalry when he noted the bacteria in one of his cultures “dissolved away like sugar in water.” He suspected an invisible microbe, “a virus parasitic on bacteria”38 and coined the phrase bacteriophage (from the Greek phagin, “to eat”). D’Hérelle later performed the first successful phage therapy experiment, treating dysentery patients with phage isolated from another patient’s stool samples. But the reaction of most of his peers ranged from indifference to scorn. D’Hérelle forged a collaboration with George Eliava in Tbilisi, the capital of the Republic of Georgia, who had independently discovered phages that kill cholera samples. Founded in 1923, the Eliava Institute in Tbilisi became the last refuge for decades for phage therapists.39
In September 2017, fifteen-year-old cystic fibrosis patient Isabelle Holdaway underwent a lung transplant at the Great Ormond Street Hospital in London. Although successful, pockets of antibiotic-resistant bacteria seized her liver and her surgical wound. Isabelle’s health deteriorated as bacterial nodules broke through her skin. Her doctor, Helen Spencer, feared the worst. Isabelle’s mother suggested a Hail Mary pass—phage therapy. The medical team contacted Graham Hatfull at the University of Pittsburgh, who had amassed a trove of 15,000 phage strains, housed in a pair of six-foot-tall freezers.40 Hatfull identified a trio of phages from his subzero stockpile, named Muddy (isolated from a rotting eggplant),V BPs (from a storm drain), and ZoeJ (in a soil sample).41 In June 2018, Isabelle received her first infusion of about one billion phages. Within six weeks, her liver infection had cleared up and the skin lesions were under control. A similarly miraculous outcome occurred in San Diego, when a phage cocktail saved the life of Tom Strathdee, who suffered a serious multidrug-resistant bacterial infection.
Gene therapy is on course to become a mainstream part of 21st-century medicine. Novartis bought facilities to manufacture the large quantities of engineered virus to deliver Zolgensma and other therapies—patients with a neuromuscular disorder require ten times more vector than needed for a localized disease in the eye. Sarepta Therapeutics licensed the rights to two other muscular dystrophy gene therapy programs developed by Mendell’s team. “Our goal is to make Columbus the center of the universe for gene therapy,” said Sarepta CEO Ed Kaye.42 Meanwhile, Amicus Therapeutics, led by CEO John Crowley (portrayed by Brendan Fraser in the Harrison Ford film Extraordinary Measures), licensed ten programs for lysosomal storage disorders. Spark Therapeutics is one of several companies developing a gene therapy for hemophilia. Fulvio Mavilio, an executive with Audentes Therapeutics, reported initial success of gene therapy for boys with the incurable disease X-linked myotubular myopathy (XLMTM). Children previously unable to sit up, let alone walk, can now take their first steps unaided, and speak after being taken off a ventilator.
Terry Flotte, the dean of the University of Massachusetts Medical School, is leading a trial for Tay-Sachs disease, which is most common in Ashkenazi Jews. Investigators used gene therapy to supply the missing enzyme in two children, injecting the virus into the brain either directly or via the spinal fluid. And in New York, Ron Crystal, another gene therapy veteran, is launching an ambitious trial to treat Alzheimer’s patients, building on trailblazing work by Allen Roses two decades ago. Roses discovered an association between a rare version of the apolipoprotein E gene (APOE4) and the risk of Alzheimer’s disease. Crystal’s strategy is to deliver a different form of ApoE, which in principle will mop up the harmful variant. “If you’re a mouse, we can cure you of your amyloid plaques,” Crystal tells me. In San Francisco, one of David Schaffer’s new-and-improved AAV vectors using direct evolution has been licensed by Adverum Biotechnologies for use in treating the wet form of age-related macular degeneration.
The renaissance of gene therapy was best illustrated in a 2019 cover story on Jim Wilson in Chemical & Engineering News on the twentieth anniversary of Jesse Gelsinger’s death. The cover headline said it alclass="underline" “The redemption of James Wilson.”43 His new operation, featuring a staff of two hundred working in multiple buildings at Penn, was more a production line than an academic lab. “Ten years ago, no one would touch Jim with a ten-foot pole. Now everyone is happy to work with Jim and gives him lots of money,” said one biotech CEO.44 Indeed, Wilson was finally able to commercialize the production of AAV vectors in a company, RegenXbio, which went public on the sixteenth anniversary of Gelsinger’s death. The image of a sharply dressed Wilson and the company executives laughing as they were showered in confetti at the Nasdaq exchange dismayed Paul Gelsinger. “It really was all about the money,” he said.
Despite this remarkable turnaround, gene augmentation is not a perfect therapy. The faulty gene still lurks in the patient’s cells. More importantly, despite their excellent overall safety profile, Wilson and others have sounded the alarm about safety concerns using AAV vectors at higher doses.45 In 2018, Wilson resigned as a scientific advisor to Solid Biosciences, because of concerns about toxicity linked to high AAV dosage. In June 2020, six months after its $3 billion acquisition by Japan’s Astellas Pharma, Audentes disclosed the deaths of two young boys with XLMTM receiving the highest dose of the AAV8 vector. The children died from sepsis, and while pre-existing liver conditions might have been a factor, the FDA halted the trial.46 The XLMTM tragedies are a humbling reminder that nature still has a say in what we can and can’t do. Nicole Paulk, a gene therapy expert at UCSF, says we have to design viruses better so such extreme doses aren’t necessary. (The boys who died in the trial received around four quadrillion—a million billion—viruses each.) “As scientists and clinicians,” Paulk says, “we owe it to these boys to make sure this doesn’t happen again.”47
So gene therapy’s renaissance is not yet complete. But that has not stopped the technology marching forward. What if we could build on the promise of the gene-editing technologies highlighted earlier and actually go into the cell to correct the corrupt code? What if we take our molecular scissors and repair some of the more than 75,000 mutations, deletions, and rearrangements that give rise to genetic diseases? What if, in the words of Chris Martin in fact, we could “fix you”—genetically speaking?