Adeno‑associated virus 9 (AAV9) is a naturally occurring serotype first isolated from a human sample in 2004. It is a small non‑enveloped parvovirus with a single‑stranded DNA genome of about 4.7 kb packaged within a 25 nm icosahedral capsid. AAV9 uses terminal N‑linked galactose as its primary cell receptor and can also engage a putative integrin and the laminin receptor as co‑receptors. Like other adeno‑associated viruses, AAV9 depends on helper viruses such as adenovirus or herpesvirus for productive replication.
Explanation
Following its identification in 2004, AAV9 was classified as a new serotype distinct from previously known AAVs but phylogenetically related to clades containing AAV7 and AAV8. Its genome comprises inverted terminal repeats flanking two open reading frames encoding replication and capsid proteins. Capsid proteins of recombinant AAV9 undergo extensive post‑translational modifications—including ubiquitination, phosphorylation, SUMOylation and glycosylation—that influence vector production and tropism. AAV9 binds terminal β‑galactose residues on glycans as its primary receptor and is proposed to interact with an integrin and the laminin receptor as co‑receptors; purification can be achieved via ion‑exchange or sucrose gradient centrifugation. The ability of AAV9 to cross endothelial barriers distinguishes it from most other serotypes: systemic administration in rodents and non‑human primates results in widespread transduction of both neuronal and non‑neuronal cells across the central nervous system, including astrocytes. AAV9 vectors also efficiently transduce cardiac and skeletal muscle, liver, pancreas, retina, renal tubular epithelium, testicular Leydig cells and respiratory epithelia. These properties make it one of the most versatile and efficient AAV serotypes for gene delivery.
Applications in gene therapy
AAV9 has been translated into clinical practice because of its broad tropism and ability to cross the blood–brain barrier. Onasemnogene abeparvovec, marketed as Zolgensma, uses an AAV9 vector to deliver a functional copy of the SMN1 gene for treatment of spinal muscular atrophy. Phase 1 and phase 3 trials showed that a single intravenous administration of the therapy improved motor function in infants with SMA; the product was approved in the United States in 2019 and subsequently in Japan and the European Union. AAV9 vectors are also under investigation for the treatment of lysosomal storage disorders, amyotrophic lateral sclerosis, Duchenne muscular dystrophy and heart failure. Preclinical studies have demonstrated that AAV9‑mediated gene transfer can correct enzyme deficiencies in metabolic diseases, restore cardiac function after myocardial infarction and deliver therapeutic genes to retinal and renal tissues. Despite its efficiency, clinicians monitor for hepatotoxicity and immune responses associated with systemic AAV9 administration.
AAV9 is notable for its ability to transduce a wide array of tissues after systemic delivery, including the central nervous system, muscle, liver and lung. Its use in Zolgensma has validated the clinical potential of this serotype, and ongoing trials continue to explore its application in neuromuscular, metabolic and cardiovascular diseases.
Related Terms: Adeno Associated Virus 8, Adeno Associated Virus 7, Adeno Associated Virus 6, Adeno Associated Virus 2, Parvovirus 4