Adeno-associated virus (AAV) has emerged as a tool in the field of gene therapy. This small virus acts as a delivery vehicle, transporting genetic material into cells. Understanding how AAV targets certain cells or tissues is fundamental for developing effective and safe therapeutic strategies. This specificity dictates where the therapeutic gene will be delivered.
Understanding AAV Tropism
Adeno-associated virus is a small, non-pathogenic virus, meaning it does not cause disease in humans. In biology, “tropism” refers to the ability of a virus to infect particular cell types or tissues within a host. AAV tropism describes the natural preference of different AAV serotypes to infect certain cells or tissues. This specificity is important for its application in gene therapy, as it determines where a therapeutic gene will be delivered. Each of the numerous AAV serotypes possesses a distinct pattern of tissue infection.
The natural tropism of AAV serotypes is an important factor in designing gene therapies. It allows researchers to select an AAV variant that naturally targets the specific cells affected by a disease. This targeted delivery helps ensure the therapeutic gene reaches its intended location, which is important for the treatment’s success. Without this natural preference, delivering genes accurately to diseased cells would be more challenging.
How AAV Achieves Cell Targeting
The ability of AAV to target specific cells is determined by its outer protein shell, known as the capsid. This capsid is composed of viral proteins that assemble to form its structure. Specific protein regions on the capsid surface interact with receptor molecules located on the surface of target cells. This binding interaction is the first step in the virus’s entry into a cell.
Different AAV serotypes bind to various cellular receptors, often cell surface glycans. Following this attachment, additional co-receptors facilitate the virus’s entry into the cell through a process called endocytosis [1, 2, 3, 5 (ResearchGate)]. Once inside the cell, the virus travels to the nucleus, where its genetic material is released and expressed [3, 5 (ResearchGate)].
Engineering AAV for Targeted Therapies
Scientists manipulate AAV tropism to enhance its therapeutic use and overcome limitations of natural serotypes [1 (ASGCT), 5 (AAVnerGene)]. Capsid engineering involves modifying the proteins that make up the AAV capsid, particularly within regions responsible for tropism and immune recognition [4 (Expanding Patient Access), 5 (AAVnerGene)]. These modifications alter the virus’s interaction with cellular receptors.
Directed evolution is another method, where large libraries of AAV variants are generated and selected for desired properties, such as enhanced targeting or reduced off-target effects [2 (Synthetic AAV Capsids), 3 (Optimizing AAV Capsids)]. This approach involves various molecular techniques. Rational design leverages structural and functional insights, allowing strategic modifications to improve tissue specificity and reduce immune system recognition [5 (AAVnerGene)]. The goal of these engineering efforts is to achieve more precise delivery, minimize unintended effects on healthy tissues, and potentially bypass pre-existing immunity in patients [4 (Expanding Patient Access)].
AAV Tropism in Medical Applications
The inherent or engineered tropism of AAV is leveraged in various gene therapy applications for precise delivery of therapeutic genes. For instance, AAV2 has natural tropism towards retinal cells, neurons, and skeletal muscles. This tropism makes it a suitable vector for treating inherited retinal diseases, exemplified by Luxturna, an AAV2-based therapy approved for inherited blindness [4 (Characteristics)].
AAV9 demonstrates an ability to cross the blood-brain barrier, making it valuable for delivering genes to the central nervous system [1 (Various AAV Serotypes), 4 (Characteristics)]. Zolgensma, an AAV9-based therapy, is used to treat spinal muscular atrophy by delivering a functional gene to motor neurons in the spinal cord [1 (Various AAV Serotypes), 3 (Various AAV Serotypes)]. Additionally, AAV5 is utilized for liver-directed therapies, such as Hemgenix and Roctavian, which treat hemophilia B and A by delivering genes for clotting factors to hepatocytes [1 (Various AAV Serotypes), 3 (Various AAV Serotypes)]. These examples highlight how tailored AAV tropism enables the delivery of therapeutic genes to the intended cells for specific conditions.