Gene therapy treats diseases by addressing their underlying genetic causes. This field involves introducing new genetic material into a patient’s cells to correct faulty genes or provide instructions for producing therapeutic proteins. Viruses, naturally evolved to deliver genetic information, are modified to serve as efficient vehicles for this genetic cargo. These modified viruses carry beneficial genes into specific cells to restore normal function.
Understanding AAV5
AAV5 stands for Adeno-Associated Virus serotype 5, a specific variant of adeno-associated viruses. AAVs are small, non-enveloped viruses identified in 1965. They belong to the Dependovirus genus, requiring a “helper” virus like an adenovirus or herpesvirus to replicate in human cells.
AAVs are not known to cause disease in humans, making them appealing for therapeutic applications. For gene therapy, AAV5 is engineered by removing its viral genes and replacing them with the desired therapeutic gene. This modification ensures the virus cannot replicate on its own, enhancing its safety for gene delivery.
Why AAV5 is a Preferred Vector
AAV5 is a preferred choice for gene therapy. It has relatively low immunogenicity, meaning it provokes a weaker immune response compared to other viral delivery systems. This reduced immune activation can lead to a more sustained therapeutic effect and fewer adverse reactions.
AAV5 exhibits broad tropism, infecting a wide array of cell types, including those in the retina, brain, and airways. This versatility allows its use for diverse genetic disorders affecting different tissues. For example, AAV5 efficiently transduces photoreceptor cells in the retina and various neural cell types in the brain. Its capsid, the protein shell surrounding the genetic material, determines this tropism; AAV5’s capsid structure differs from other AAV serotypes like AAV2, enabling it to transduce cells AAV2 cannot.
How AAV5 Delivers Genetic Material
AAV5 delivers genetic material into target cells through a specific sequence of events. The AAV5 particle first binds to specific receptors on the target cell’s surface, such as sialic acid and platelet-derived growth factor receptors (PDGFR) α and β. This binding initiates the virus’s internalization into the cell through endocytosis.
Once inside, the AAV5 particle escapes the endosome into the cytoplasm. From there, the AAV5 capsid, containing the therapeutic gene, travels to the cell’s nucleus. The capsid enters the nucleus, uncoats, and releases its single-stranded DNA genome. This DNA is converted into a stable double-stranded form, persisting as an episome (a separate, non-integrated DNA molecule) within the nucleus. The therapeutic gene is then transcribed and translated into the desired protein, providing a new therapeutic function without integrating into the host cell’s DNA.
Therapeutic Applications of AAV5
AAV5-based gene therapies are explored for various conditions, with some already approved or in advanced clinical trials. Its ability to deliver genes to specific tissues makes it suitable for eye diseases, such as inherited retinal disorders. AAV5 has demonstrated high transduction efficiency for retinal cells, particularly photoreceptor cells.
Beyond ocular conditions, AAV5 is also investigated for central nervous system (CNS) disorders and muscle conditions. Research shows AAV5’s ability to transduce various neural cell types in the brain, including Purkinje cells and other neurons. For neuromuscular diseases, AAVs are considered effective gene transfer vectors due to their safety and efficiency.
Safety Profile and Considerations
AAV5 gene therapy exhibits a favorable safety profile due to its non-pathogenic nature and inability to replicate independently in human cells. However, the body can still recognize the AAV capsid as foreign, potentially triggering an immune response. This response can be immediate or delayed.
Immediate reactions, occurring within hours, might include mild flu-like symptoms or a temporary decrease in platelet count. Delayed responses, appearing around a month after administration, might involve inflammation. To manage these potential immune reactions, immunosuppressive regimens, often involving corticosteroids, are commonly used for a limited period. These therapies are administered under strict medical supervision, with careful monitoring for adverse effects.