Gene therapy modifies or manipulates a person’s genetic material to treat or potentially cure a disease. This approach introduces, replaces, or alters a gene within a patient’s cells to correct the underlying cause of a disorder. For a gene therapy to be approved, it must successfully pass rigorous safety and efficacy trials, demonstrating consistent therapeutic benefit. Authorization from major regulatory bodies like the U.S. Food and Drug Administration (FDA) or the European Medicines Agency (EMA) signifies that the treatment has met stringent standards, moving it into clinical use.
How Gene Therapy Works
The fundamental mechanism of gene therapy involves delivering a functional copy of a gene to a patient’s cells to compensate for a faulty, disease-causing gene or to introduce a new therapeutic function. Many genetic diseases stem from a single defective gene that fails to produce a necessary protein, and the therapy seeks to restore that function. Therapeutic genes are packaged inside a delivery vehicle called a vector, which acts as a microscopic transport system to ferry the genetic material into the target cells.
Most currently approved therapies utilize modified viruses as vectors because of their natural ability to efficiently enter human cells. Adeno-associated viruses (AAVs) are frequently used, as they generally do not cause disease and are effective at delivering genes to non-dividing cells, such as those found in the eye, liver, and central nervous system. AAVs typically deliver the new gene as an episome, a circular piece of DNA that resides in the nucleus but does not integrate into the host cell’s chromosomes, allowing for long-term protein production.
Lentiviruses, a type of retrovirus, are another common vector, modified to remove their ability to cause illness. Unlike AAVs, lentiviral vectors are engineered to integrate their genetic payload directly into the host cell’s genome. This ensures the therapeutic gene is copied every time the cell divides, making it useful for ex vivo therapies involving rapidly dividing cells, such as blood stem cells. The choice between AAV and lentiviral vectors depends on the target tissue, the size of the gene being delivered, and whether the target cells are dividing or non-dividing.
Current Approved Treatments and Conditions
The list of approved gene therapies continues to expand, offering one-time treatment options for inherited disorders and cancers. One early example of an approved in vivo gene therapy is voretigene neparvovec (Luxturna), which treats Leber congenital amaurosis caused by mutations in the RPE65 gene. This therapy is delivered via a single injection directly into the retina. Another significant approval is onasemnogene abeparvovec (Zolgensma), which treats spinal muscular atrophy (SMA) caused by a defect in the SMN1 gene.
Zolgensma uses an AAV vector to deliver a functional copy of the SMN1 gene to motor neurons via a single intravenous infusion. Etranacogene dezaparvovec (Hemgenix) received approval for hemophilia B, a bleeding disorder caused by a deficiency in coagulation factor IX. This therapy also uses an AAV vector, targeting the liver to produce the missing clotting factor after a single infusion.
A major class of approved gene therapies involves chimeric antigen receptor (CAR) T-cell treatments for certain blood cancers, such as leukemias and lymphomas. These therapies modify a patient’s own immune cells ex vivo, genetically altering the T-cells to recognize and attack specific proteins found on cancer cells. Recently, cell-based gene therapies for sickle cell disease and beta thalassemia, such as exagamglogene autotemcel (Casgevy), utilize CRISPR gene-editing technology to correct the genetic defect in the patient’s blood stem cells.
Distinction Between In Vivo and Ex Vivo Therapies
Approved gene therapies are distinguished by whether the modification occurs in vivo or ex vivo. In vivo therapies involve administering the vector containing the therapeutic gene directly into the patient’s body, where the genetic material finds its way to the target cells. This approach is typically favored for tissues difficult to access outside the body or for systemic delivery, such as the liver or the eye.
In vivo examples include Luxturna, where the vector is injected directly into the subretinal space, and Zolgensma, delivered intravenously to target motor neurons. These methods streamline the process by avoiding the need for cell harvesting and reinfusion.
In contrast, ex vivo therapies require the patient’s cells to be removed from the body, genetically modified, and then returned to the patient. This method is often used when the target cells, like hematopoietic stem cells or T-cells, are easily accessible or when the modification process requires strict control. CAR T-cell therapies are the most prominent examples of ex vivo treatments, where a patient’s T-cells are engineered with a new receptor and expanded before being reinfused to fight cancer.
The Unique Financial Landscape of Gene Therapies
The approval of gene therapies has introduced financial challenges due to their high cost and one-time administration model. These treatments offer the potential for a long-term cure but carry price tags reaching millions of dollars per patient, with some exceeding $3 million. These costs reflect the decades of research, complex manufacturing processes, and the relatively small patient populations for many rare genetic diseases.
The immense upfront cost burdens insurance payers, challenging traditional reimbursement models designed for chronic, recurring treatments. Payers face a large budget impact when a small number of patients require these expensive therapies within a single budget cycle. This has spurred the development of innovative payment models, such as outcomes-based agreements, where payments are tied to the treatment’s successful performance over time.
A major hurdle is “patient portability,” where a patient may switch insurance providers shortly after receiving the therapy. The initial payer bears the entire cost, while subsequent payers benefit from the long-term savings of avoided chronic care expenses. To improve patient access, novel strategies like installment plans or risk-sharing pools are being explored by commercial and government payers, including the Centers for Medicare and Medicaid Services (CMS).