Every cell in your body has a genome, a collection of over 20,000 genes that instruct the body to function properly. Genes are made up of smaller building blocks called DNA bases. With over three billion bases in the human genome, a natural outcome is mutations, when incorrect bases occur. Although many mutations are harmless, some impact important genes and cellular pathways, causing dysfunction and debilitating disease. Gene therapies target the root cause of these previously thought “incurable” diseases by fixing mutations in the affected cells.
Each gene therapy is tailored to the nature of the genetic disease, in terms of how best the genetic mutation can be corrected and which tissues are primarily affected. To reach the target cells, gene therapies can be delivered in vivo (inside the body), through injection into the bloodstream, or at a specific site, such as the muscle, retina, or cerebrospinal fluid. An example of an in vivo gene therapy is LUXTURNA. It delivers a functional version of the RPE65 gene to the eye. RPE65 is mutated in individuals that suffer from inherited retinal diseases, such as Leber congenital amaurosis and retinitis pigmentosa, causing progressive vision loss. This is an example of gene addition therapy which introduces new copies of genes to replace the function of the mutated ones. Other gene therapies can prevent the disease-causing genes from functioning, called gene silencing therapies, such as ONPATTRO. This is a treatment for patients with hereditary transthyretin-mediated amyloidosis, a disease caused by a mutation in the transthyretin gene, leading to nervous system dysfunction and heart failure. Transthyretin is primarily expressed in the liver, and the mutant produces misfolded proteins that clump together, forming aggregates that can build up in the heart and nerves. ONPATTRO is delivered into the bloodstream, where it makes it to the liver and blocks the mutated transthyretin gene from forming disease-causing protein aggregates.
However, in vivo gene therapies cannot feasibly treat all affected cells to restore their normal function, especially if the genetic disease affects multiple organs or the blood system. For blood cell disorders, it’s easiest to administer the treatment ex vivo (outside the body), before transferring the modified cells back to the patients. All blood cells come from bone marrow stem cells, and by isolating and modifying these stem cells directly, essentially all the derived blood cells will also possess the gene therapy. HEMGENIX is a gene therapy for patients with beta-thalassemia. Affected individuals have a mutation in their beta-globin gene and cannot produce functional hemoglobin, which is the component of red blood cells required to transport oxygen throughout the body. HEMGENIX inserts a functional copy of the beta-globin gene into the genome of the patient’s bone marrow stem cells. New red blood cells emerged from these modified stem cells will have a copy of the correct beta-globin gene, capable of producing functional hemoglobin. In addition, other ex vivo therapies can also engineer a patient’s immune cells to become better at recognizing and killing cancer cells. After almost 50 years of active research, we’re approaching the golden age of gene therapy, where thousands have been developed, and several are passing rigorous clinical trials to prove their safety and lasting therapeutic effects. Gene therapy has come a long way since its start in the 1970s, when scientists first began developing and optimizing ways to transfer functioning genes into cells as a therapeutic option. Unfortunately, initial attempts at human gene therapy in the 1990s were not completely effective and led to cancer or death in some participants. A clinical trial in 1999 recruited five infants with severe combined immune deficiency-X1 to participate, who would otherwise die from unresolved infections due to a dysfunctional immune system. The gene therapy was delivered into their blood stem cells ex vivo. However, nearly three years after the treatment, two patients developed leukemia, or cancer of the immune system. Upon analysis of their genomes, scientists found that the location where the therapeutic gene was inserted into the patients’ genomes activated a cancer-causing gene.
In 1999, a patient named Jesse Gelsinger participated in a gene therapy trial to treat his rare metabolic disorder. Within a day, Jesse had an intense inflammatory response followed by multi-organ failure, eventually being taken off life support five days later. The ensuing court cases revealed that 691 volunteers in various FDA gene therapy experiments had died or fallen ill in the seven years leading to Jesse’s death. In effect, clinical testing for gene therapies came to a halt. These events made it apparent that gene therapies would not truly be safe and effective for decades to come. Yet, through these trials and errors, scientists developed a better understanding of how our complex genomes are regulated and the relationships between genetic mutations and disease. Progress was also made on safer and more accurate methods of gene delivery, allowing clinical trials to resume using improved gene therapies. Notably, CRISPR-based gene editing tools were developed, which can change DNA bases at precise locations in the genome to correct genetic mutations. As some CRISPR-based clinical trials are currently undergoing clinical testing, the field should take caution from its past and be precautious when testing new therapies on patients.
The current landscape of gene therapy is a rapidly advancing field that stands to help millions of people with rare and debilitating monogenic diseases. Gene therapies, when implemented safely, alleviate their suffering and allow them to lead fulfilling lives. For many that would benefit from approved therapies, however, receiving treatment is still a distant reality. With gene therapy companies charging upwards of 1 million dollars for a single treatment, and bureaucratic delays in obtaining public healthcare coverage, patients with degenerative genetic diseases are still suffering. Further gene therapy research must reconcile safety above all else. Research into cost reduction and accessibility are critical next steps forward to implementing life-improving gene therapies for all those affected.