Gene Therapy Arrives

THE DNA DRUG REVOLUTION

After false starts, drugs that manipulate apply to employers with fewer than 15 employees and does not cover the code of life are finally changing lives insurance for long-term care, life or disability. It also does not apply to people employed and insured by the military’s Tricare system, such as By Jim Daley Rylan Gorby. When his son’s genome was sequenced, researchers also obtained permission to sequence Rylan’s genome, to determine if he The idea for gene therapy—a type of DNA-based medicine that was a carrier for the rare hemoglobin condition. Because it manifests inserts a healthy gene into cells to replace a mutated, disease- itself only in childhood, Gorby decided taking the test was worth the causing variant—was first published in 1972. After decades risk of possible discrimination. of disputed results, treatment failures and some deaths in Cost is another consideration. Clinical sequencing is still about experimental trials, the first gene therapy drug, for a type of skin $500 to $800, and interpretation can be upward of $1,000, according cancer, was approved in China in 2003. The rest of the world to Brigham and Women’s Green. For families who can’t afford health was not easily convinced of the benefits, however, and it was not insurance, this is out of reach. Some experts have also raised concerns until 2017 that the U.S. approved one of these medicines. Since that genetic testing could lead to a lot of follow-up testing with special- then, the pace of approvals has accelerated quickly. At least nine ists, which could overburden an already resource-strapped health care gene therapies have been approved for certain kinds of cancer, system. If sequencing turns out to save money in the long run, insur- some viral infections and a few inherited disorders. A related ance companies may cover it, but there’s no guarantee. drug type interferes with faulty genes by using stretches of DNA Yet another problem is that the majority of the sequencing to date or RNA to hinder their workings. After nearly half a century, the has been done in babies whose families are well-off and white, raising concept of genetic medicine has become a reality. concerns that this could become the province of only the privileged. And the racial homogeneity could skew the results: diseases more GENE INSERTION prevalent in Caucasian individuals could be overrepresented in test These treatments use a harmless virus to carry a good gene panels, whereas illnesses more common in racial minorities may be into cells, where the virus inserts it into the existing genome, underrepresented. (New medical data projects intend to address this canceling the effects of harmful mutations in another gene. disparity [see “All of Us,” on page S14].) GENDICINE: China’s its manufacturer declined THE U.C.S.F. NSIGHT PROJECT included a working group that investi- regulatory agency approved to renew its marketing gated some of these ethical and policy issues, which culminated in a the world’s first commercially authorization; Glybera is 2018 report by the Hastings Center, a bioethics nonprofit in Garrison, available gene therapy in no longer on the market. N.Y. The report concluded that newborn sequencing has many bene- 2003 to treat head and neck IMLYGIC: The drug was fits in helping diagnose sick babies and could expand the number of squamous cell carcinoma, a approved in China, the conditions that meet the stringent newborn screening criteria. But us- form of skin cancer. Gendicine U.S. and the E.U. to treat ing genome sequencing as a replacement for newborn screening is “at is a virus engineered to carry melanoma in patients who best premature,” the authors say, and direct-to-consumer sequencing a gene that has instructions for have recurring skin lesions should not be used for diagnosis or screening purposes. making a tumor-fighting pro following initial surgery. Barbara Koenig, a professor of medical anthropology and bioeth- tein. The virus introduces the Imlygic is a modified genetic ics at U.C.S.F. and one of the report’s co-authors, underscores the fact gene into tumor cells, causing therapy inserted directly into that sequencing, while promising, is not yet mature enough to be them to increase the expres tumors with a viral vector, routinely used to screen healthy children. “This is not a technology sion of tumor-suppressing where the gene replicates that’s ready for prime time for use in healthy infants,” Koenig says. genes and immune response and produces a protein Despite these concerns, the era of newborn sequencing is now factors.The drug is still that stimulates an immune upon us, and the practice will likely become more widespread as costs awaiting fda approval. response to kill cancer cells. come down and the results become more accurate and useful. In the GLYBERA: The first gene KYMRIAH: Developed for meantime, the risks and benefits of sequencing must be weighed on therapy to be approved in patients with B cell lympho an individual basis. Extremely sick newborns are a completely differ- the European Union treated blastic leukemia, a type of ent case from apparently healthy children of worried parents suscepti- lipoprotein lipase deficiency cancer that affects white blood ble to marketing from genetic-testing firms. (LPLD), a rare inherited cells in children and young For Mitchell Gorby, sequencing was certainly worth it. Two disorder that can cause adults, Kymriah was approved months after leaving the hospital, he is doing fine and has doubled his severe pancreatitis. The drug by the fda in 2017 and the weight. His parents are settling into their new routine, somewhat inserted the gene for lipopro E.U. in 2018. It works by sleep-deprived, but happy to be home with their healthy baby boy. tein lipase into muscle cells. introducing a new gene into But because LPLD occurs a patient’s own T cells that Tanya Lewis is an associate editor who covers health and medicine in so few patients, the drug enables them to find and kill at Scientific American. was unprofitable. By 2017 cancer cells.

LUXTURNA: The drug CAR-T cell therapy, uses GENE INTERFERENCE was approved by the fda a virus to insert a gene that This approach uses a synthetic strand of RNA or DNA in 2017 and in the E.U. in codes for proteins called (called an oligonucleotide) that, when introduced into 2018 to treat patients with chimeric antigen receptors a patient’s cell, can attach to a specific gene or its a rare form of inherited messenger molecules, effectively inactivating them. (CARs) into a patient’s blindness called biallelic Some treatments use an antisense method, named for T cells. When these cells RPE65 mutation-associated one DNA strand, and others rely on small interfering are reintroduced into the retinal dystrophy. The RNA strands, which stop instruction molecules that go disease affects between patient’s body, the CARs from the gene to the cell’s protein factories. 1,000 and 2,000 patients allow them to attach to in the U.S. who have a and kill cancer cells in DEFITELIO: This drug down production of— mutation in both copies the bloodstream. contains a mixture a protein that helps to of a particular gene, ZOLGENSMA: In May of single-strand produce low-density lipo RPE65. Luxturna delivers 2019 the fda approved oligonucleotides protein (LDL). Injected a normal copy of RPE65 Zolgensma for children obtained from the subcutaneously, this to patients’ retinal cells, younger than two years with intestinal mucosa of therapy is used to lower allowing them to make pigs. It was approved LDL levels in patients spinal muscular atrophy, a a protein necessary for (with limitations) in the who have dangerously neuromuscular disorder that converting light to electrical U.S. and the E.U. in high cholesterol. affects about one in 10,000 signals and restoring 2017 to treat severe MACUGEN: Age-related their vision. people worldwide. It is one cases of veno-occlus macular degeneration is STRIMVELIS: About 15 of the leading genetic ive disease, a disorder the leading cause of vision patients are diagnosed in causes of infant mortality. in which the small loss in people age 60 Europe every year with Zolgensma delivers a veins of the liver and older. It is caused by severe immunodeficiency healthy copy of the human become obstructed, deterioration of the center from a rare inherited SMN gene to a patient’s in patients who have of the retina due to leaking condition called adenosine motor neurons in received a bone mar- blood vessels. Approved deaminase deficiency row transplant. in the U.S., Macugen a single treatment. (ADA-SCID). These EXONDYS 51: In 2016 inhibits these blood ZYNTEGLO: Granted patients’ bodies cannot the fda granted approval vessels from growing approval in the E.U. in make the ADA enzyme, to Exondys 51 amid some under the retina, thus which is vital for healthy May 2019, Zynteglo controversy regarding treating the disorder. white blood cells. Strimvelis, treats a blood disorder its efficacy; two members SPINRAZA: With its fda approved in the E.U. in called beta thalassemia of the fda review panel approval in 2016, Spin 2016, works by introducing that reduces a patient’s resigned in protest of the raza became the first the gene responsible for ability to produce hemo decision. The therapy is gene-based therapy producing ADA into stem globin, the protein in red designed to treat a form for spinal muscular cells taken from the pa blood cells that contains of Duchenne muscular atrophy. The inherited tient’s own marrow. The dystrophy caused by disorder is caused by iron, leading to life- cells are then reintroduced mutations in the RNA that low levels of SMN, a threatening anemia. The into the patient’s blood codes for the protein that key protein for the main therapy has been approved stream, where they are helps to connect muscle tenance of motor transported to the bone for individuals12 years and fibers’ cytoskeletons to neurons. Spinraza binds marrow and begin older who require regular a surrounding matrix. to RNA from a “backup” producing normal white blood transfusions. It em Exondys 51 is effective gene called SMN2, blood cells that can ploys a virus to introduce in treating about converting that RNA produce ADA. healthy copies of the gene 13 percent of the into instructions for YESCARTA: Developed to for making hemoglobin Duchenne population. making fully functioning treat a cancer called large into stem cells taken from KYNAMRO: Approved SMN proteins. B cell lymphoma, Yescarta the patient.The cells are by the fda in in 2013, was approved by the fda Kynamro is designed to Jim Daley is a freelance then reintroduced into in 2017 and in the E.U. in inhibit—or effectively shut journalist based in Chicago. the bloodstream and 2018. It is in clinical trials transported to the bone in China. Large B cell lymphoma affects white marrow, where they blood cells called lympho begin producing healthy red cytes. The treatment, part of blood cells that can an approach known as manufacture hemoglobin.