The Road to Transforming Medicine Through AAVs
Adeno-associated virus (AAV) continues to lead the way in gene therapy research. Discover its evolution since the 1960s and its growing role in transforming treatments for both rare and common diseases.
Adeno-associated virus (AAV) has emerged as a key vector in gene therapy due to its strong safety profile, ability to drive long-term transgene expression, and capacity to transduce both dividing and non-dividing cells. First identified in the 1960s as a contaminant in adenovirus preparations, AAV gained increasing scientific interest over the following decades.
During the 1980s and early 1990s, studies demonstrated that AAV vectors could enable stable gene expression across various animal models, including primates, while maintaining a favourable safety profile. The first human clinical trial utilizing an AAV vector was conducted in 1996 for cystic fibrosis. In the late 1990s and early 2000s, early clinical trials primarily targeted monogenic disorders, such as hemophilia and muscular dystrophy, providing crucial proof-of-concept data on AAV-mediated gene delivery. While these initial trials produced mixed results, they set the foundation for future developments.
A breakthrough occurred in 2008 when an AAV vector was successfully used to treat Leber’s congenital amaurosis (LCA), a genetic disorder causing blindness. Subretinal administration of an AAV vector carrying the RPE65 gene demonstrated an acceptable safety profile and led to measurable improvements in retinal function. This milestone paved the way for regulatory approvals of AAV-based therapies. In 2012, Glybera, an AAV1-based gene therapy for lipoprotein lipase deficiency, became the first AAV gene therapy to receive regulatory approval in Europe. However, it was later withdrawn due to high costs and limited market demand.
Advances in AAV vector engineering, including the development of novel serotypes with enhanced tissue tropism, optimized vector design, and improved production methodologies, significantly expanded its therapeutic potential. The first FDA-approved AAV-based gene therapy, Luxturna® (2017), demonstrated clinical efficacy in treating inherited retinal dystrophy, setting the stage for further approvals. To date, eight AAV-based gene therapies have been approved by the FDA, with more expected in the future.
The Future of AAV in Gene Therapy
AAV remains at the forefront of gene therapy research, with ongoing efforts focused on overcoming current challenges such as immune responses, delivery efficiency, and vector manufacturing constraints while expanding its therapeutic applications.
A key area of advancement is vector engineering, where novel AAV capsid variants are being developed to enhance tissue targeting, improve transduction efficiency, and evade pre-existing neutralizing antibodies. Techniques like directed evolution and rational design are enabling the creation of next-generation AAV serotypes with optimized properties for both systemic and targeted delivery.
Another critical focus is immune evasion, as pre-existing immunity continues to be a major obstacle in AAV-based therapies. Current strategies include capsid modifications (e.g., synthetic coatings to reduce immune recognition), immune-modulatory treatments (e.g., immunosuppressive drugs), and plasmapheresis to lower circulating neutralizing antibodies. Additionally, reducing the AAV dose through the use of highly efficient gene regulatory elements—such as strong promoters or enhancers—and delivering vectors via less immunogenic routes (e.g., intrathecal or subretinal injection) can help minimize immune detection.
Scaling up manufacturing and reducing costs are essential for the future success of AAV therapies. Advances in production techniques, including suspension cell culture, improved purification methods, and enhanced vector yield, are being developed to meet the growing clinical and commercial demand.
Beyond rare monogenic disorders, AAV is also being explored for more complex diseases, such as neurodegenerative diseases (e.g., Parkinson’s and Alzheimer’s), metabolic disorders, and cardiovascular diseases. Additionally, in vivo genome editing using AAV-based CRISPR/Cas9 systems holds promise for achieving permanent genetic corrections.
Regulatory developments and long-term safety studies will be crucial in shaping the future of AAV gene therapy. Data from ongoing clinical trials and real-world patient experiences will provide insights into treatment durability, efficacy, and potential risks, ultimately influencing future guidelines and approval processes.
Overall, AAV gene therapy is expected to become more precise, efficient, and widely applicable, addressing current limitations while transforming the treatment landscape for both rare and common diseases.
Interested in learning more about AAVs?
The Road To Even Safer AAV Gene Therapies
Although AAVs are among the safest gene therapy vectors, they do pose a few risks that can still be reduced.
