The National Institutes of Health (NIH) and the Food and Drug Administration (FDA) have played key roles in the emergence of safe and effective human gene therapies. Now, we are proposing new efforts to encourage further advances in this rapidly evolving field.
The potential to alter human genes directly was first recognized nearly 50 years ago, around the same time as initial groundbreaking advances were being made in recombinant DNA technology. After intense discussions regarding the ethical, legal, and social implications of this technology, conversations were initiated at the NIH that led to the establishment of the Recombinant DNA Advisory Committee (RAC) in 1974. The RAC’s mission was to advise the NIH director on research that used emerging technologies involving manipulation of nucleic acids — a mission that was eventually expanded to encompass the review and discussion of protocols for gene therapy in humans. In 1990, the FDA oversaw the first U.S. human gene-therapy trial, which involved pediatric patients with adenosine deaminase deficiency and was conducted at the NIH Clinical Center in Bethesda, Maryland.
Although no major safety concerns were initially reported, over the course of the 1990s it became evident that many questions regarding the safety and efficacy of gene therapy remained unanswered. These unknowns were brought into sharp focus in 1999 when Jesse Gelsinger died of a massive immune response during a safety trial of gene therapy for ornithine transcarbamylase deficiency.1 This tragic death led to closer scrutiny of the field, including a greater focus on open dialogue and increased regulatory oversight.
Since that time, a tremendous amount of scientific work related to gene therapy has been conducted with support from government agencies, academic institutions, and commercial sponsors. These efforts have increased understanding of the basic biology of the diseases being treated, the various methods used for gene delivery, and the potential adverse events that can be encountered. Progress has also been made in improving safety precautions, as well as gene-transfer efficiency and delivery.
As science advanced, along with the ability to apply these innovations, gene therapy has evolved from offering modest effects in early trials to producing measurable benefits in the clinic. In 2017, the FDA approved the first three gene-therapy products for use in the United States. Two are cell-based gene therapies — chimeric antigen receptor T-cells (CAR-T) — that have demonstrated remarkable efficacy against cancer in clinical trials.2 The third, which treats retinal dystrophy caused by RPE65 gene mutations, is the first approved gene-therapy product to be administered in vivo and the first to target a specific genetic condition. Given the field’s rapid evolution, and the fact that the FDA currently has more than 700 active investigational new drug applications for gene therapies, it seems reasonable to envision a day when gene therapy will be a mainstay of treatment for many diseases.
Though still more needs to be learned about the safety and efficacy of current technologies, many promising new approaches are on the horizon. For example, the advent of genome editing opens new possibilities for treating diseases that might be challenging or impossible to address with gene-transfer technologies. The capacity for editing genes using zinc finger nucleases (ZFNs), transcription activator–like effector nucleases (TALENs), and meganucleases has existed for decades. But the field made a quantum leap forward about 5 years ago with the discovery and development of the CRISPR (clustered regularly interspaced short palindromic repeats)-Cas9 gene-editing system.3 Already, researchers have announced the first in vivo clinical trial of genome editing to correct Hunter’s syndrome by means of ZFNs, and CRISPR-Cas9 and TALENs gene-editing approaches are being explored in the clinic for T-cell immunotherapy. Clinical trials for sickle cell disease are expected soon…
