Danny Funt

The Wait Is (Maybe Nearly) Over

investigators at Sangamo have slowly been stocking freezers at their Bay Area headquarters with pairs of zinc fingers, the proteins that regulate gene expression. At one point, their technology was considered the cutting edge of genomic medicine, and Sangamo’s scientists were regarded as the best in the world at building it. Then simpler and more accessible gene-editing techniques came along, such as CRISPR, and many people dismissed Sangamo—as though it manufactured steam engines in an age of internal combustion. Still, the company’s 40 or so investigators continued to toil away at mastering zinc fingers and adding to their library, 1 pair after another.Sangamo’s president and CEO, Sandy Macrae, PhD, imagines an enormous checkerboard of all the different zinc finger combinations necessary to target particular nucleotides. After investing hundreds of millions of dollars to refine this technology, the company has a proprietary library that now includes about 3000 such pairs, allowing the rapid preparation of medicine that can manipulate an ultra-specific DNA sequence: Targeting efficiency has gone from 2% to above 99.5%, and treatment that once took several months to assemble can now be ready in fewer than 10 days. In short, Macrae explains, “we can now target any nucleotide in the genome.”At last, Sangamo is starting to take more of its medicine out of the freezer. The results of these early trials could help initiate the transformation in precision treatment—with wide-ranging implications for the cost of care—that the medical world has been waiting for.In the past 18 months, Sangamo has overhauled its leadership team and revitalized its mission, changing its name from Sangamo Biosciences to Sangamo Therapeutics and planning a corporate relocation from the East Bay to San Francisco’s biotech hub as it strives to cash in on years of research. When Macrae took over, he had photographs installed throughout the company’s headquarters of people with the rare diseases that these first clinical trials seek to treat. The point was to refocus on patients, and the results of that seem promising.In November, doctors in Oakland used Sangamo’s zinc finger nucleases to treat a man with the metabolic disease mucopolysaccharidosis type II (MPS II), or Hunter syndrome, the first person to receive treatment that edits genes within the body. With enzyme replacement therapy, the current treatment option, patients with MPS II require weekly transfusions. The patient in Oakland received a single 3-hour transfusion. If it works, he will produce the vital enzymes for the rest of his life.Some investigators at Sangamo have spent their entire careers pursuing that medicine. For them, “seeing this go literally from the bench to the bedside has really been a life’s work realized,” says Russell DeKelver, PhD, who began working as a research associate and is now the rare diseases team leader at Sangamo.Once the preeminent developer of gene-based medicine, Sangamo was overshadowed by the emergence of competitors, and biotech investors grew impatient with gene editing in general because of slowness in bringing it to market. If current trials are successful, Sangamo executives say, the medicine could be extended with relative ease to up to 1000 diseases that are also caused by a single gene mutation—they’ve already received $70 million up front from Pfizer to pursue such a treatment. The ultimate goal, however, is to be able to cure any genetic disease, permanently, at its source. Recent progress provides an infusion of optimism for genomic medicine and is no small triumph for a company seeking to reestablish itself at the forefront of its field.Near the New Year, a family that has 2 sons with hemophilia visited Sangamo headquarters to describe their experience with the disease and to learn about Sangamo’s treatment, which is also entering clinical trials. Macrae recalls a topic of discussion: “What does it mean to change someone who has hemophilia to someone who doesn’t have hemophilia, and how do they feel about that?”It’s a peculiar way of describing medicine, indicative of the fact that this treatment approach aspires to be, in the most literal sense, life-changing.tends to assume an intense gravity, and deservingly so, even if that kind of medicine has been almost entirely hypothetical. In his acclaimed 2016 book The Gene, the oncologist Siddhartha Mukherjee, MD, asks, “And what if we learned to change our genetic code intentionally? If such technologies were available, who would control them, and who would ensure their safety? Who would be the masters, and who the victims, of this technology?”It’s fitting, in a way, that his warning echoes a prayer before the Jewish Day of Atonement: “How many shall pass away, and how many shall be born? Who shall live, and who shall die?”Yet when asked to foresee the distant prospects of this medicine, Paul Harmatz, MD, betrays a polite frustration with that focus. Harmatz is a pediatric gastroenterologist at University of California, San Francisco, Benioff Children’s Hospital in Oakland, and he is most concerned about patients with metabolic diseases whom he has been treating for decades. As a principal investigator of the phase 1/2 clinical trials for Sangamo’s in vivo gene-editing treatment of Hunter syndrome, Harmatz describes this moment—cautiously—as “the forefront of a new paradigm in medicine.”One of Harmatz’s longtime patients, Brian Madeux, a 44-year-old from Arizona, lacked a gene that produces an enzyme responsible for breaking down toxic carbohydrates in cells throughout the body. One of about 100,000 people, primarily men, has this debilitating disease. Madeux has required 26 operations throughout his life for all sorts of ailments, the Associated Press reported. (However expensive a onetime gene-editing treatment may turn out to be, it waits to be seen how that compares with a lifetime of recurring care.)Under Harmatz’s supervision, Madeux received a transfusion with Sangamo’s medicine packaged in adeno-associated virus (AAV) vectors, a virus engineered to avoid bodily harm. The virus infects the albumin locus in the liver, where zinc fingers attach to a precise DNA sequence. A highly optimized nuclease makes a double-strand break, and the therapeutic genes are inserted. Billions of copies of this corrective gene are delivered, modifying less than 1% of the body’s vast surplus of albumin. As Sangamo’s chief medical officer, Edward Conner, PhD, puts it, “It’s almost like having a permanent transfusion pump based in the liver.”“This treatment isn’t actually treating anything,” Harmatz explains. “It’s setting up a factory in the liver to produce a lot of this enzyme over a long time period.” About 6 months after Madeux’s treatment, a liver biopsy will reveal whether the enzyme is being produced successfully.Doctors could, in theory, use that same process to implant corrective genes for any monogenic disease that involves a protein deficiency. Clinical trials are under way for MPS I, MPS II, and hemophilia B, with trials for Fabry disease forthcoming. There are altruistic reasons for focusing on ultrarare diseases but also practical ones: For novel technologies in particular, it’s extremely difficult to get FDA approval for diseases with huge patient populations, and those trials require elaborate designs to demonstrate efficacy. The MPS II phase 1/2 trials, by contrast, will treat up to 12 patients. These rare diseases have significant unmet need, largely because pharmaceutical and biotech companies don’t see the potential return on investment.“We’re just exponentially grateful to Sangamo, recognizing that MPS diseases are so small compared with diseases everybody knows about,” says Terri Klein, president and CEO of the National MPS Society. “Brian is very brave, not knowing what to expect. Someone has to be on that front line.”Indeed, the cutting edge brings risk. In 1999, 18-year-old Jesse Gelsinger died from complications after receiving gene therapy in a clinical trial at the University of Pennsylvania. An FDA investigation found several areas of negligence. Genomic medicine has advanced dramatically since then, but the lessons from that first “biotech death” are not forgotten.