For years, the term “designer babies” has been tossed around as people discussed the ability to manipulate the sex, eye color and even personality of their babies. While the technology to create the rumored “designer babies” is not quite there, gene therapy is a real possibility. Gene therapy is the administration of genetic material, often through viruses, to manipulate the expression of a gene product and alter the biological properties of living cells to treat and even cure genetic diseases. It has only recently begun to be realized to its full potential following the Food and Drug Administration’s (FDA) monumental first approval of gene therapy products in 2017.
Gene therapy aims to attack the root cause of many diseases by altering DNA rather than treating symptoms that result from a genetic mutation. On September 14, 1990, a 4-year-old girl became the first gene therapy patient to treat her adenosine deaminase (ADA) deficiency, a genetic disease that left her defenseless against infections (1). This milestone promised the beginning of groundbreaking treatments and cures of many illnesses, as it is estimated that 80 percent of an estimated 7,000 known rare diseases are based on genetic mutations. Yet, nearly thirty years later and despite public support for and strong scientific basis, the field of gene therapy has been beset with major clinical and public policy setbacks that have cast doubts on the efficiency of the field. In 1991, concerns about efficiency and safety prompted the Recombinant DNA Advisory Committee (RAC), a National Institute of Health (NIH) appointed panel, to shift its focus to examining potential risks of human gene therapy (2). And in 1999, the first death of a gene therapy patient, Jesse Gelsinger, set the field back several years as United States regulators put several key experiments on hold due to public backlash (3). The RAC would only select 20 percent of the hundreds of submitted protocols to be reviewed for board meetings, but ultimately, none were approved (2).
However, under Scott Gottlieb, the newly appointed FDA commissioner, the gene therapy field has been reinvigorated. In August 2017, the FDA approved the product Kymriah, making it the first gene therapy available in the United States. Kymriah is a genetically modified T-cell immunotherapy designed to treat pediatric and young adult patients with a form of acute lymphoblastic leukemia (ALL). Each year, 3,100 patients aged 20 or younger are diagnosed with ALL. Kymriah collects and sends a patient’s T-cells to a center where a new gene that codes for a chimeric antigen receptor (CAR), a protein that directs T-cells to target and kill leukemia cells that have CD19 antigens, markers for lymphocyte development, are inserted. Once the cells are modified, they are inserted back into the patient (4). According to Peter Marks, director of the FDA’s Center for Biologics Evaluation and Research, “Not only does Kymriah provide these patients [children and young adults] with a new treatment option where very limited options existed, but a treatment option that has shown promising remission and survival rates in clinical trials” (5). The treatment produced remission within three months in 83 percent of 63 pediatric and young adults, all of whom had failed to respond to standard treatments or had suffered relapses (5). Similarly, Dr. Renier J. Brentjens, of Memorial Sloan Kettering Cancer Center in New York and another leader in the treatment, admits, “Did I think it could work? Yes. We have cohorts of patients who would have been considered terminal who are now in durable and meaningful remissions with good quality of life for up to 5 years. So the enthusiasm for this technology is now quite high” (6).
Since then, the FDA has approved two other treatments, one of which, called Luxturna, is the first gene therapy approved for an inherited disease. Luxturna involves inserting a genetically modified virus into the eyes of patients born with retinal dystrophy, a rare condition that destroys cells in the retina. Treatment produced dramatic improvements in vision, such as restoring the ability of patients to see things they could never see before such as the stars, fireworks, and their parents’ faces” (5).
Concerns about the safety of some of the treatments and cost are still being addressed. Kymriah, for example, can cause acute side effects. The treatment can cause Cytokine Release Syndrome (CRS), which is a systemic response to the activation and proliferation of CAR T-cells and can cause high fever, drops in blood pressure, flu-like symptoms and neurological events, all of which can be life-threatening (4). Ironically, CRS is considered proof that the modified T-cells are working, and doctors have discovered that anti-inflammatory drugs such as tocilizumab are able to manage severe CRS (6). Another more recent side effect observed in some larger trials has been cerebral edema, or swelling in the brain. In fact, one company halted further development of their product after several patients died as a result of treatment-induced cerebral edema (6). While lifesaving, these drugs may cost “20 or 30 times the annual wages of the typical American” (5), with Luxturna costing about $475,000 per eye, or $850,000 total (5). The Institute for Clinical and Economic Review reports that Luxturna, in most cases, should cost about 50-75% less than the proposed price in order to be cost-effective, forcing Luxturna’s company to reevaluate payments and reimbursement plans with the government and private health insurers (7).
“We’re entering a new frontier in medical innovation with the ability to reprogram a patient’s own cells to attack a deadly cancer,” Gottlieb said. “New technologies such as gene and cell therapies hold out the potential to transform medicine and create an inflection point in our ability to treat and even cure many intractable illnesses” (4). In the coming years, the FDA will begin to revise the approval process with more efficient, modern parameters, including new clinical measures, to evaluate gene therapy products (4). This includes the over 700 gene therapy-related clinical trials that have been submitted to the FDA for approval. Dr. Stephan Grupp, a pediatrician at the Children’s Hospital of Philadelphia and a professor of pediatrics at the University of Pennsylvania’s Perelman School of Medicine, who led the global clinical trials for Kymriah, summarizes the recent developments, “This is just the tiniest little crack in the dam and we’re going to see a flood of this over the coming years” (8).
Edited by: Will Wick
Illustrated by: Avni Joshi