Adeno-associated virus type 2 (AAV2) is a member of the parvovirus family. Unlike many other viruses, AAV2 is naturally occurring in humans and does not cause disease. This non-pathogenic characteristic makes it a subject of interest in biological research. Its properties position AAV2 as a tool for medical applications, particularly in gene therapy.
Understanding AAV2
AAV2 is a small, non-enveloped virus. Its genetic material consists of a linear single-stranded DNA genome, about 4.7 kilobases in size, encased within a protein shell known as a capsid. This capsid is composed of three viral proteins: VP1, VP2, and VP3. The compact size and structural simplicity of AAV2 allow it to penetrate various tissues and cells.
In its natural life cycle, wild-type AAV2 is a dependovirus, meaning it cannot replicate on its own. It requires a “helper” virus, such as adenovirus or herpes simplex virus, to complete its replication cycle. Without a helper virus, AAV2 can establish a latent infection, persisting as an inactive genome in the cell nucleus. This dependency on a helper virus contributes to its non-pathogenic nature in humans.
AAV2 possesses several attributes that make it well-suited for gene therapy. It can infect a broad spectrum of cell types, including both dividing and non-dividing cells, which is valuable for targeting various tissues. The virus exhibits notable stability, maintaining its integrity even in dry conditions. AAV2 elicits a milder immune response compared to many other viral vectors.
AAV2 as a Gene Therapy Vector
The transformation of AAV2 into a gene therapy vector involves molecular engineering. The virus’s native genes, responsible for its replication and capsid formation, are removed from its genome. These viral genes are then replaced with a therapeutic gene and regulatory elements. The only remaining viral sequences are the inverted terminal repeats (ITRs) at each end of the genome, which are necessary for gene packaging.
Once modified, this recombinant AAV2 (rAAV2) vector acts as a delivery vehicle, transporting the therapeutic genetic material into target human cells. The rAAV2 particle enters the cell and travels to the nucleus. Inside the nucleus, the delivered single-stranded DNA genome converts into a double-stranded form and typically forms episomal structures.
The ability of rAAV2 to persist primarily as episomes in the nucleus, rather than integrating into the host cell’s genome, is a safety feature. This reduces the risk of insertional mutagenesis. This episomal persistence allows for long-term gene expression, particularly in non-dividing or slowly dividing cells. The sustained production of the therapeutic protein from these episomal genomes can provide lasting therapeutic effects.
Therapeutic Applications
AAV2’s broad tropism makes it suitable for treating a variety of diseases. Its ability to transduce various tissues, including the central nervous system, liver, muscle, and retinal cells, has led to its extensive use in clinical trials. This versatility has opened avenues for addressing numerous genetic disorders.
One success with an AAV2-based therapy is for Leber congenital amaurosis. Luxturna, an AAV2 vector encoding the RPE65 gene, was approved for this condition. AAV2’s tropism for retinal cells makes it a choice for ocular gene therapy.
AAV2 has also shown promise in neurological disorders. AAV2 can be used for certain neurological applications, often requiring direct administration to the affected area. AAV2 demonstrates tropism for skeletal muscle, making it relevant for some muscle-related conditions.
Safety and Immune Considerations
The use of AAV2 in gene therapy involves considerations, particularly regarding the body’s immune response. The human immune system can recognize the AAV2 capsid as foreign, leading to the production of antibodies. A portion of the population may have pre-existing antibodies against AAV2 due to prior natural exposure to wild-type AAVs. These pre-existing neutralizing antibodies can bind to the AAV2 vector, preventing it from effectively delivering its therapeutic gene to target cells.
The immune response can also involve cellular immunity, where T cells recognize and target cells that have been transduced by the AAV2 vector. This can lead to the loss of gene expression and adverse reactions. For patients with pre-existing antibodies, approaches include capsid modifications to evade antibody recognition or the use of immunosuppressive drugs to dampen the immune response.
Beyond immune responses, other safety considerations include off-target effects, where the vector might deliver the gene to unintended cells, or dose-related issues. Higher doses can increase the likelihood of immune activation or other adverse events.
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