Cancer. Cardiovascular disease. HIV. Cystic Fibrosis. Hemophilia. Can you imagine a world in which these diseases could be controlled and potentially eradicated? Gene therapy is an innovative technique that creates a promising future for the cure of these devastatingly destructive diseases.
Gene therapy is a relatively new area of science, on the spectrum of scientific discovery, which classically involves using healthy genes to replace mutated genes that cause disease. A second method for gene therapy, non-classical gene therapy, focuses on inhibiting or repairing mutations. Gene therapy is used on two types of cells: germ cells and somatic cells. Germline gene therapy involves inserting healthy DNA fragments into germ cells (sperm and egg cells) so that a patient’s children do not inherit a targeted genetic defect, thereby eliminating the mutation in future generations. However, due to various ethical concerns (e.g. the children who would be affected by germline therapy cannot decide if they want the treatment), the U.S. government does not sponsor research on germline therapy. In contrast, somatic gene therapy receives federal funding because it does not prevent mutated genes from being passed to offspring, as it does not affect germ cells, but rather it targets somatic cells in the body such as cells from the bone marrow.
The concept of classical gene therapy appears very straightforward: simply insert a new gene to replace a mutated one. Unfortunately, the process is a bit more sophisticated. A functional DNA fragment is carried via a vector (e.g. virus or plasmid) which is either injected into the body area with the mutated cells, or is injected into cells that have been removed from the body and will then be transplanted back into the body after the injection. Classical gene therapy has recently been given recognition in the news for its success in treating Leber Congenital Amaurosis.
Leber Congenital Amaurosis (LCA) is a rare inherited retinal disease that affects approximately 2,000 people in the United States. A fully-functioning retina enables visual recognition by translating light into signals that are sent to the brain. However, individuals with LCA are born with a mutation in a gene which causes retinal dysfunction. There are several types of LCA so symptoms generally vary, but patients afflicted by LCA often have severe vision impairment from birth. Patients who are not completely blind are generally farsighted and have low visual acuity permitting them to perceive only general stimuli such as hand motions and bright lights. Surprisingly, people with LCA generally have seemingly normal eyes upon initial examination, hence the term amaurosis, meaning loss of vision without evident change to the eye. An electroretinogram, an eye test used to determine how the retina responds to light, or a genetic screen are needed for a more definitive diagnosis. Once a diagnosis has been made, treatment options primarily include low-visual aids or orientation and mobility training so those afflicted with this disease can learn to navigate independently. A new treatment option called Luxturna may become the first gene therapy treatment to target this inherited disease. The treatment involves injecting specially engineered viruses into the eye. The viruses carry a correct copy of the mutated gene to the retinal cells. Although the treatment does not restore 20/20 vision, patients who participated in the clinical trial reported life-altering improvements in visual acuity, perception of color, night vision, and their ability to navigate.
At this point you may be wondering why we do not see widespread benefits of gene therapy in many facets of medicine. First, gene therapy is still in the early stages of development. Although the use of functional DNA to modify genes was first suggested in 1970, nearly 20 years passed before gene therapy could be used on a patient - a four-year-old girl with a genetic disease that caused immunodeficiency and prohibited her body from fighting infection. The child showed significant improvement after the treatment and was eventually able to attend school without worrying about developing severe infections. The success of this treatment promoted additional gene therapy clinical trials in the 1990’s. Unfortunately, in 1999, a patient died while participating in a clinical trial for gene therapy. This publicized tragedy severely impacted the field as many gene therapy trials were put on hold while new regulations were put in place. Finally, in 2003 the dark cloud was lifted when the first gene therapy was approved to treat head and neck cancer in China. However, most of the research that has made it to clinical testing is ongoing and has not yet been granted FDA approval.
Although there seems to be astounding benefits to gene therapy, like many medical treatments there are risks. When researchers inject viruses that carry a functional copy of a mutated gene, there is the risk of severe autoimmune response, such as an infection, or even tumor generation if the newly implemented genes are inserted at the wrong location in the DNA. Therefore, you can probably understand why researchers spend countless hours creating an effective treatment that maximizes benefits and minimizes risks. Naturally, the FDA is also extremely careful in granting their approval. Finally, we do not see widespread impact of gene therapy because is it extremely cost prohibitive. For example, the new gene therapy treatment for LCA is estimated to cost nearly one million dollars. Prices for other gene therapy treatments are similarly high in cost.
Although the promise of gene therapy gives us hope for a future in which disease is more easily eradicated, there is still a lot of work to be done.