I. Gene therapies can be classified as in vivo or ex vivo. For in vivo, the therapy is administered directly into the patient’s body. For ex vivo, cells are removed from the body, treated in the lab, and then readministered.
II. The CRISPR Journal was launched in 2018, published by Mary Ann Liebert Inc., with Rodolphe Barrangou as chief editor.
III. There is good evidence to suggest that the SCD mutation has actually occurred spontaneously on four different occasions in different populations.
IV. Ingram’s given name was Werner Adolf Martin Immerwahr.
V. Scientists like to show off their warped sense of humor when it comes to naming genes in certain species (notably fruit flies) or, it turns out, newly discovered viruses. Examples (courtesy of Amanda Warr) include CaptnMurica, IceWarrior, Heffalump, PuppyEggo, BeeBee8, and Megatron. Rule #1 is literally: “Do not name your phage after Nicolas Cage.”
CHAPTER 12 FIX YOU
In April 2016, Sean Parker, the billionaire co-founder of Napster portrayed by Justin Timberlake in the film The Social Network, hosted a star-studded party at his $55 million Los Angeles home, which borders the Playboy Mansion. Among the celebrities in attendance were Tom Hanks, Peter Jackson, Sean Penn, “Mother of Dragons” Emilia Clarke, and Katy Perry. Musical performances included John Legend, the Red Hot Chili Peppers, and Lady Gaga slaying a rendition of “La Vie en Rose.”1 In the audience, Bradley Cooper was blown away, “like in that old Maxell cassette commercial,” he said. That performance clinched her starring role in Cooper’s remake of A Star is Born.
Parker was celebrating the launch of the Parker Institute for Cancer Immunotherapy (PICI), to which he personally pledged $250 million. The guest list also included medical talent from cancer centers in LA, San Francisco, New York, Philadelphia, and Houston. Two years after the launch party, PICI supported Carl June’s team at the University of Pennsylvania Abramson Cancer Center in treating the first cancer patients in a CRISPR trial.2 A Phase I trial is all about safety, but June is well aware that Chinese doctors are pushing ahead much faster. “We are at a dangerous point in losing our lead in biomedicine,” June told the Wall Street Journal.3
The SINATRA trialI is an extension of June’s pioneering work on CAR-T cells, arming the patient’s own T cells to hunt tumor cells. Cancer patients are alive today because of these first-generation immunotherapies, but there is room for improvement. June’s team performed three kinds of CRISPR gene edits: insertion of a gene into the patients’ T cells that codes for a protein engineered to detect cancer cells while simultaneously removing the gene that interferes with this process. The third edit removes a gene that marks the T cells as immune cells and thus prevents the cancer cells from disabling them. Once edited, the manipulated cells are re-administered to the patient.
June’s team published the initial results on three very ill patients who had endured multiple rounds of chemotherapy and bone marrow transplantation in February 2020.4 The CRISPR therapy appeared safe—no toxicity, no cytokine storms, no neurological toxicity. June was relieved that there had been no adverse immune responses given the bacterial origin of Cas9. And while there was a low level of chromosomal rearrangements, he said that was similar to what astronauts who have been in space a few months endure.5
The journal Science treated the report as another major milestone. The cover headline read: HUMAN CRISPR.
Genome editing offers two enticing benefits for patients: first, it strikes at the root cause of a disease by correcting the code, repairing the faulty DNA sequence. Conventional drugs typically treat symptoms, not the root cause of a disease. Traditional gene augmentation therapy (as discussed in the previous two chapters) might compensate for, but does not repair, the underlying mutation. Second, the fix should in principle last forever, a one-and-done repair rather than chronic disease management. Of course, the CRISPR machinery still has to be delivered to the right tissues, safely, without triggering the patient’s immune system or causing any collateral DNA damage. None of those issues has been completely resolved, but the precision and safety of CRISPR is improving all the time, as can be seen in some of the early results in clinical trials.
A decade ago, the prospect of a universal cure for sickle-cell disease (SCD) didn’t look hopeful. But now genome-editing strategies are showing promise, adding to various approaches—allogeneic stem cell transplant, gene therapy, derepressing γ-globin—discussed in the previous chapter, at least for patients in first-world countries.
In April 2019, Sangamo announced results for their first patient treated with an ex vivo gene-edited cell therapy, in which ZFNs disrupt the BCL11A enhancer in the patient’s hematopoietic stem cells to boost γ-globin production. “I could not have imagined HbF this high in my wildest dreams,” tweeted Sangamo alumnus Fyodor Urnov. “Thirty-one percent HbF is SPECTACULAR.” Meanwhile, studies by Merlin Crossley’s group in Sydney are developing an approach he calls “organic gene therapy,” using CRISPR-Cas9 to recapitulate specific HPFH mutations to boost HbF levels.6
Stanford’s Matthew Porteus has been on a quest to use genome editing in the clinic since the early 2000s.7 Using CRISPR-Cas9 to break the DNA before fixing the sequence, Porteus says, is like fixing the headlight on someone’s car by first busting the headlight with a hammer before repairing it. The goal is to ensure that about 20 percent of the stem cells repopulating the bone marrow are genetically fixed. That means harvesting some 500 million stem cells from any given patient. In a specialized facility, those cells are mixed with Cas9 and the AAV vector. The modified cells will be transplanted back into patients, after they have recovered from chemotherapy to make room for the modified stem cells. The biggest hurdle is to improve the efficiency of delivering the Cas nuclease into the appropriate cells.
“We’ll cure people who have sickle-cell disease, not because they have a genetic defect but because they’re human beings and deserve all the rights, responsibilities, and value we should confer on any human being,” Porteus says.8 He calls genome editing “an anti-eugenics program.” The eugenics movement in the 20th century was designed to improve the gene pool by sterilizing or eliminating people who had genetic defects. A consequence will be that the frequency of the SCD variant will increase in the population, because now “we’ll be taking people who normally die in childhood and allowing them to live to adulthood, have families.” But it’s a fair exchange, he says. “We should embrace this consequence.”
One of the patients in Porteus’s care is teenager David Sanchez, who charms with his eloquence and humor. “My blood just doesn’t like me very much, I guess,”9 he shrugs as he prepares for his monthly three-hour appointment with the apheresis machine, which replaces his warped erythrocytes with a fresh batch of healthy biconcave blood cells. His nurse likens David’s visit to booking an oil change for a car. David endures his share of debilitating pain episodes but he exhibits no self-pity, even after enduring brain surgery. “I’m not just going to not play basketball. You can’t not play basketball,” he says in the film Human Nature.