This past year will be remembered for many things, many of them not good. But here’s at least one flicker of hope: 2017 may go down as the year gene therapy finally turned a corner. In late December, the Food and Drug Administration announced its approval of the third gene therapy since August. These three therapies—two for treating cancer and one for treating a form of congenital blindness—are the first of their kind to pass muster with the FDA. And with hundreds of clinical trials for other gene therapies underway, they won’t be the last. For decades, gene therapy was a pipe dream, symbolizing the unfulfilled promises of biomedical scientists who claimed that they could not just treat but actually cure disease by fixing genes. Those promises are finally beginning to be realized.
The logic behind gene therapy is simple. Many diseases are caused by a missing or defective gene; replace the broken gene with a working copy, and you cure the disease. But putting this logic into practice hasn’t been so easy. For more than a century, scientists have cataloged disease-causing defective genes. In 1902, British physician Archibald Garrod deduced that an inherited disease called alkaptonuria was caused by a mutation that breaks a specific, but then-unknown metabolic enzyme. Half a century later, biochemist Vernon Ingram was the first to pinpoint the exact molecular cause of a genetic disease, when he discovered the specific molecular defect in the hemoglobin protein of people afflicted by sickle-cell disease.
Finding such damaged genes, while not trivial, has however turned out to be much easier than fixing them.
As Ingram later wrote about his 1956 discovery: “Entirely different approaches were needed to find a therapy [for sickle cell disease]; that took a long time, because they were not based on the molecular biology.”
By the 1990s, scientists had developed the capability to make replacements for damaged genes, but they had no good way to deliver these replacements to the right cells inside a living patient. The most obvious delivery vehicles were viruses, since infiltrating cells is what viruses do best. But infecting a patient with a high dose of virus risks creating a toxic immune system response, which is what killed 18 year-old Jesse Gelsinger, a volunteer in a 1999 gene therapy trial. Gelsinger’s widely publicized death was a major setback for gene therapy because it took researchers by surprise and vividly demonstrated the serious risks of the approach.
In spite of this setback, scientists continued to pursue gene therapy because, ultimately, it is the only way to directly cure a genetic disease. All drugs and other non-gene therapy treatments are indirect because they don’t correct the underlying genetic cause. As a result, those who suffer from conditions like sickle-cell anemia and cystic fibrosis are dependent on a lifetime regimen of drugs—at least in the fortunate cases where effective drugs are available.
After nearly two decades of careful work, researchers are beginning to safely and reliably solve the problem of how to use viruses to deliver a replacement gene to a patient. The viruses are genetically altered so that they don’t replicate inside a patient’s body—meaning that, unlike the flu, these viruses can’t be spread from person to person. Luxturna, the latest gene therapy approved by the FDA, relies on such viruses to carry a replacement gene into the retinas of patients with a certain form of congenital blindness. In two small trials published in December, viruses successfully delivered gene therapy to the blood cells of patients suffering from the two major types of hemophilia. In a November study, a different virus—optimized to target the central nervous system—successfully delivered a replacement gene into cells of 15 children suffering from spinal muscular atrophy, a neurodegenerative disease that is almost always fatal by age two. At 20 months, all 15 children were doing well. And in a March report, yet another type of virus was used in gene therapy administered to a 13-year-old boy suffering from sickle-cell disease. Fifteen months after treatment, he was largely free of symptoms.