Gene Therapy: A New Frontier in Medical Innovation

It is no surprise that one of the most impactful health stories of 2023, as reported by Scientific American, is gene therapy, specifically the approval by the U.S. Food and Drug Administration (FDA) of a groundbreaking gene therapy treatment for sickle cell disease using a novel genome editing technology called CRISPR.

While the treatment highlighted in the Scientific American article is revolutionary in scope, the approval of a gene therapy product by the FDA is not unique. Over six years ago, the FDA granted approval in a landmark action to a gene therapy product. That product, Kymriah (tisagenlecleucel) from Novartis Pharmaceuticals Corporation, was approved to treat certain pediatric and young adult patients with an acute form of leukemia. At the time, then FDA Commissioner Scott Gottlieb, M.D. heralded this milestone event as “entering a new frontier in medical innovation with the ability to reprogram a patient’s own cells to attack a deadly cancer.” This statement is noteworthy given the setbacks and high-profile failures characteristic of gene therapy research less than twenty-five years ago.

Since the approval of Kymriah in 2017, FDA approvals of gene therapy products have skyrocketed. This past year, the FDA approved more gene therapies than the previous five years combined, and almost triple the number of clinical trials in gene therapy have been initiated compared to the same time frame in the previous year.

What is Gene Therapy?

What exactly is gene therapy? And why is it so promising, especially in the treatment of rare forms of cancer and other diseases?

Simply stated, gene therapy allows modern medicine to fight disease on the genetic level by altering or replacing adverse genetic material. Within the cells of our bodies, there are thousands of genes that provide information to produce specific proteins. Sometimes, a part or all of a gene may be missing or defective at birth. Other times, healthy genes may mutate over the course of our lives. In either case, the cause is usually a genetic defect. In gene therapy, a carrier or vector, usually a virus that has been modified to eliminate its harmful components, carries a healthy copy of the genetic material into the nucleus of the cell, where it replicates to replace defective genes, or “turn off” those genes causing the problem.

It is important to note that gene therapy is not exactly the same as immunotherapy. While both may be used to treat cancer and other diseases, they ultimately represent different approaches. Gene therapy entails the insertion of genes into cells to alter the genetic component of a person. Immunotherapy, in contrast, is a strategy aimed at improving or facilitating the body’s natural defenses, i.e., the treatment of disease by activating or suppressing the immune system. In most cases, immunotherapy treatment does not involve the alteration of genetic materials. For example, the vaccines developed to treat COVID-19 are a type of immunotherapy in that they do not alter a person’s genetic materials but instead work to trigger the body’s natural immune system to attack the coronavirus.

However, gene therapy and immunotherapy can intersect or work together for more effective treatments. For example, in CAR T-cell therapy, the cells in our body known as “T cells,“ which help orchestrate the immune response to kill other cells infected by pathogens, are altered in the laboratory. When reinserted back into the body, the altered T cells replicate and enhance the immune response. The first approved gene therapy product for pediatric treatment of leukemia reference above, Kymriah, is an example of such an approach.

Gene Therapy Treatment for Rare Diseases

Since the approval of Kymriah, scientists have employed gene therapy to address even rarer diseases, or to replace existing limited non-genetic therapies for certain diseases with more effective treatment modality using gene therapy. Two examples of recently approved gene therapy treatments for rare diseases are:

1. Skysona (elivaldogene autotemcel), developed by Bluebird bio, Inc. to slow the progression of neurologic dysfunction in boys 4-17 years of age with early, active cerebral adrenoleukodystrophy; and
2. Zynteglo (betibeglogene autotemcel) also developed by bluebird bio, Inc. to treat an inherited blood disorder.

One striking example of how gene therapy has been used to address previously untreatable conditions is the approval of Spark Therapeutics’ gene therapy product called Luxturna (voretigene neparvovecrzyl) to treat patients born with severe vision loss caused by certain retinal diseases that once led to total blindness. In developing this treatment, researchers programmed a harmless adeno-associated virus (AAV) to find retinal cells and insert a healthy version of the gene, which they then injected into the eye directly underneath the retina. Thus far, results have been remarkable. Some patients with severely impaired vision reported that, following injection with Luxturna, their vision was restored to the extent that they could even see stars in the night sky for the first time in their lives.

Initially scientists employed two fundamental approaches to gene therapy. One method was to draw blood from the patient, reprogram cells within the laboratory, and then reinject those cells into the person’s body. The other approach was to deliver gene treatments directly into the body, usually to more accessible areas such as the eye, as was the case with Luxturna.

Gene Editing and the Future of Gene Therapy

More recently, scientists have developed increasingly sophisticated gene therapy techniques. This is at the heart of the Scientific American articles referenced earlier reporting on the approval of Casgevy (exagamglogene autotemcel), developed by Vertex Pharmaceuticals, as the first approved, CRISPR-based treatment for sickle cell disease. In Casgevy, scientists used a type of genome editing technology in the laboratory to modify a patient’s blood stem cells in targeted areas. The modified blood stem cells are then transplanted back into the patient where they attach and multiply within the bone marrow and increase the production of fetal hemoglobin, a type of hemoglobin that facilitates oxygen delivery. In patients with sickle cell disease, increased levels of this fetal hemoglobin prevent the sickling of red blood cells, thereby treating the disease on the cellular level.

The use of this new gene editing technology to treat a painful, life-threatening disease attacking a vulnerable population demonstrates the promise of gene therapy. Yet, despite the encouraging results, scientists are proceeding with caution. For example, while 29 of the 52 clinical trial patients injected with the CAR T cell treatment known as Kymriah went into sustained remission, the therapy is not without risk. CAR T cell therapy can cause severe side effects, including cytokine release syndrome, a dangerous inflammatory response that ranges from mild flulike symptoms to organ failure, and even death. Further study is necessary to determine the long-term effects associated with gene therapy treatment. In addition, the high cost of gene therapy presents its own challenges, particularly in the rare disease space where the patient population is limited.

As predicted by former FDA Commissioner Gottlieb, gene therapy has indeed opened a “new frontier in medical innovation.” But it is not without its challenges. In upcoming articles, we will explore these challenges, as well as some of the regulatory and manufacturing hurdles to the widespread commercialization of gene therapy technology.

Authored by Maria-Cristina Smith, AVP, Products & Professional Liability Specialist.