AAV9

AAV9, or adeno-associated virus serotype 9, is a non-pathogenic, replication-defective DNA virus from the parvoviridae family. It is commonly engineered as a gene-therapy vector due to its ability to package modest sized transgenes (about 4.7 kilobases) and to deliver genes to a variety of tissues.

AAV9 is known for broad tissue tropism, including skeletal and cardiac muscle, liver, and the central nervous system. Systemic delivery of AAV9 vectors can result in widespread transduction, particularly in neonatal or developing animals; this tropism makes AAV9 a popular choice for diseases requiring widespread expression. Tissue tropism and transduction efficiency can vary across species.

In vector design, the transgene cassette is flanked by inverted terminal repeats and packaged inside an AAV9 capsid; production typically uses helper plasmids in cell culture (HEK293 or similar) to generate recombinant AAV9 particles.

Clinical use: The best-known example is Zolgensma, an AAV9-based gene therapy that delivers the SMN1 gene to treat spinal muscular atrophy in children; approved by major regulators in 2019. AAV9 vectors are also under investigation for other neuromuscular and genetic disorders.

Safety and limitations: AAV vectors generally remain episomal; risk of insertional mutagenesis is low. Pre-existing neutralizing antibodies to AAV9 can limit efficacy or prevent re-administration. High systemic doses raise concerns about liver toxicity and immune responses; long-term expression and biodistribution are ongoing areas of study.

Research context: AAV9 is a common backbone for gene-therapy research and has spawned numerous clinical trials. Variants and engineering efforts aim to alter tissue specificity or enhance blood-brain barrier penetration, with mixed success in humans compared to animal models.