Gene therapy offers a novel approach to treating diseases at their genetic origin by introducing new genetic material into a patient’s cells. This field targets the root cause of many inherited conditions, holding the potential for lasting therapeutic benefits. The adeno-associated virus (AAV) is a promising tool within this domain. AAV-based therapies deliver therapeutic genes efficiently and safely, offering new hope for individuals with previously untreatable genetic disorders.
The AAV Vector Delivery System
Adeno-associated virus (AAV) is a small, non-pathogenic virus, meaning it does not typically cause disease in humans. This makes it an appealing starting point for gene delivery vehicles. In its native form, AAV possesses a small, single-stranded DNA genome encased within a protein shell known as a capsid.
Scientists engineer AAV into a “vector” by modifying its genetic makeup. The viral genes responsible for replication are removed from the AAV genome. This ensures the modified virus cannot replicate within the patient’s body, enhancing its safety. The therapeutic gene, which contains instructions for producing a beneficial protein, is inserted into the AAV’s DNA. The resulting recombinant AAV (rAAV) is a harmless delivery vehicle carrying a specific genetic payload.
AAV is a preferred choice for gene therapy due to several advantages. It efficiently delivers genes to target cells and provides long-lasting therapeutic effects, especially in non-dividing cells. Its ability to target specific cell types, known as tropism, can be controlled by selecting different AAV serotypes or modifying the capsid structure. AAV generally elicits a low immune response in humans, which aids its clinical applicability.
Mechanism of Gene Delivery and Correction
Once administered, the engineered AAV vector navigates to specific target cells, depending on the AAV serotype chosen. Upon encountering the target cell, the AAV vector attaches to the cell surface and is internalized, typically through endocytosis.
Inside the cell, the AAV vector travels towards the nucleus. The capsid uncoats, releasing the single-stranded DNA genome. This genetic material then enters the nucleus.
Within the nucleus, the single-stranded DNA is converted into a double-stranded form. This functional genetic code does not typically integrate into the host cell’s chromosomes. Instead, it forms an episome, a stable, circular piece of DNA that resides alongside the cell’s own genetic material. This episomal DNA acts as a template, providing the cell with instructions to produce the missing or faulty protein. The cell’s machinery then manufactures the therapeutic protein, which can restore normal cellular function or compensate for the genetic mutation.
Therapeutic Applications and Approved Treatments
AAV gene therapy primarily treats monogenic disorders, which are conditions caused by a mutation in a single gene. By introducing a functional copy of the faulty gene, these therapies aim to restore normal protein production and alleviate disease symptoms. This approach directly addresses the genetic cause of the disorder.
Several AAV gene therapies have received regulatory approval. Zolgensma (onasemnogene abeparvovec) is an approved therapy for spinal muscular atrophy (SMA), a severe neuromuscular disorder caused by an SMN1 gene mutation. This therapy delivers a functional copy of the SMN1 gene to motor neuron cells, enabling them to produce the survival motor neuron (SMN) protein.
Luxturna (voretigene neparvovec) is approved for a specific form of inherited retinal dystrophy caused by RPE65 gene mutations. This therapy delivers a working copy of the RPE65 gene directly to retinal cells, allowing them to produce the protein necessary for the visual cycle. These treatments exemplify how AAV vectors can precisely deliver genes to correct genetic deficiencies, improving patient outcomes.
The Treatment Process and Safety Profile
AAV gene therapy is typically administered as a one-time treatment, often through a single intravenous infusion, depending on the therapy and target cells. For therapies targeting specific organs like the eye, administration might involve a direct injection. After administration, patients are monitored to assess the therapy’s effects and any potential responses.
While AAV is generally considered a safe vector, the body can still mount an immune response to the viral capsid. This immune reaction is a natural defense mechanism against foreign substances. To manage this, patients may receive immunosuppressive medications around the time of treatment to reduce the likelihood and severity of an immune response.
Potential side effects include elevated liver enzyme levels, which may indicate liver inflammation. Patients are closely monitored for these and other potential reactions through blood tests and clinical evaluations for several weeks or months following treatment. Monitoring protocols ensure any adverse events are detected and managed promptly.