Cell and gene therapies (CGTs) are fundamentally changing the landscape of medicine by offering treatments that target the root cause of diseases rather than just managing symptoms. These advanced therapies utilize the building blocks of life—genes and cells—to provide a lasting or permanent therapeutic effect. By introducing corrected genetic instructions or specialized, therapeutic cells, CGTs aim to reprogram the body to fight illness from within. This approach offers a new paradigm for complex and inherited disorders.
Defining Cell and Gene Therapies
Cell and gene therapies are distinct but often overlapping modalities, each utilizing biological components for therapeutic effect. Gene therapy focuses on modifying, replacing, or inactivating genetic material inside a patient’s cells to treat a condition at its molecular origin. This often involves introducing a new, functional copy of a gene to compensate for a faulty one. Manipulation of genetic material can occur either in vivo (directly inside the body) or ex vivo (where cells are modified in a laboratory before being returned to the patient).
Cell therapy involves introducing, modifying, or replacing entire cells to restore normal function or use them to carry a therapy. These therapeutic cells can be sourced from the patient (autologous) or from a healthy donor (allogeneic). Stem cell transplants, which replace damaged blood-forming cells, are a long-standing example of cell therapy.
The two modalities often converge in gene-modified cell therapy, exemplified by the engineering of immune cells. This involves extracting a patient’s cells and using gene therapy techniques to alter their genetic makeup. The reprogrammed cells are then cultivated and multiplied in the lab before being infused back into the patient.
The Mechanisms of Genetic Repair
The scientific power of these therapies lies in their ability to manipulate molecular mechanisms within the cell with precision. Gene editing techniques, such as CRISPR/Cas9, allow scientists to make targeted modifications to the DNA sequence itself. This system uses a synthetic guide RNA molecule to direct the Cas9 enzyme to a specific location in the genome, where the enzyme then acts as molecular scissors to create a double-strand break in the DNA.
Once the DNA is cut, the cell attempts to repair the damage using its natural mechanisms. Scientists can exploit the error-prone Non-Homologous End Joining (NHEJ) pathway to intentionally disrupt or “knock out” a disease-causing gene. Alternatively, supplying a corrected DNA template encourages the cell to use the Homology-Directed Repair (HDR) pathway for precise gene replacement.
For gene-modified cell therapies, such as CAR T-cell therapy, the mechanism involves programming the immune system to recognize and attack specific targets. T-cells are extracted and genetically engineered to express a Chimeric Antigen Receptor (CAR) on their surface. This receptor allows the T-cell to bind to a specific antigen found on the surface of cancer cells, such as the CD19 antigen in certain leukemias and lymphomas.
The delivery of genetic material relies on specialized carriers called vectors. Viral vectors, often derived from adeno-associated viruses (AAVs) or lentiviruses, are the most common delivery vehicles. Scientists modify these viruses by removing disease-causing genes and replacing them with the therapeutic genetic material, ensuring the vector can deliver its cargo without causing illness.
Clinical Applications and Successes
Cell and gene therapies have demonstrated utility across a spectrum of diseases. The earliest applications have been in treating monogenic disorders, which are caused by a mutation in a single gene. For instance, a gene therapy for Spinal Muscular Atrophy (SMA) uses a vector to deliver a functional copy of the SMN1 gene, addressing the root cause of the disorder with a single intravenous infusion.
In inherited retinal diseases, a gene therapy has been approved to treat a form of blindness caused by mutations in the RPE65 gene. The treatment involves injecting the therapeutic vector directly into the subretinal space. Gene therapies are also showing promising results for blood disorders like hemophilia and sickle cell disease, where they aim to restore the production of functional clotting factors or corrected hemoglobin.
The field of oncology utilizes CAR T-cell therapy, a powerful form of gene-modified cell therapy. Several CAR T-cell products have been approved to treat specific hematologic malignancies, including B-cell acute lymphoblastic leukemia and various types of lymphoma. These therapies have provided durable remissions for patients who had exhausted all other treatment options.
The Patient Journey
The process of receiving a cell or gene therapy differs significantly from a conventional treatment schedule. The first phase involves extensive screening to confirm the patient’s eligibility, which includes genetic testing and a thorough assessment of their overall health. Once approved, the patient begins the cell collection phase, which, for autologous CAR T-cell therapy, is called leukapheresis.
During leukapheresis, the patient’s blood is circulated through a specialized machine that separates and collects the white blood cells, including the T-cells. These collected cells are then cryopreserved and shipped to a specialized manufacturing facility where the genetic modification takes place. The ex vivo manufacturing process, which involves reprogramming the cells to become the therapeutic product, can take several weeks to complete.
While the patient awaits the final therapeutic product, they often undergo a short course of preparatory chemotherapy, known as lymphodepletion. This step temporarily reduces the number of existing immune cells in the patient’s body. This creates a more favorable environment for the modified cells to expand and persist upon infusion.
The final administration of the therapy is a straightforward, one-time process, typically delivered through an intravenous infusion. Following the infusion, patients require intensive monitoring for several weeks to manage potential side effects, such as a systemic inflammatory response known as cytokine release syndrome.