Adeno-Associated Virus Vectors

Adeno-associated virus, or AAV, is a small, non-enveloped virus with a single-stranded DNA genome that requires a helper virus for productive replication. In gene therapy, engineered recombinant AAV vectors carry a therapeutic gene while lacking the viral genes needed for replication.

Why AAV is a useful delivery vehicle

• Wild-type AAV is not known to cause human disease, giving the vector a favourable starting safety profile.
• Different AAV capsids show preferences for different tissues, allowing vector selection or engineering for organs such as the liver, muscle, eye and nervous system.
• AAV can transduce both dividing and non-dividing cells, which is important for treating long-lived tissues.
• Its DNA generally persists as episomal forms outside chromosomes, supporting potentially long-term expression in non-dividing cells while reducing, but not eliminating, insertional risks.
• Compared with some viral vectors, AAV usually provokes less inflammation and does not replicate after delivery when properly engineered.

How the vector delivers a therapeutic gene

Most viral coding sequences are removed and replaced with a therapeutic expression cassette, while the inverted terminal repeats needed for genome packaging and persistence are retained. After the capsid enters a target cell, the vector genome reaches the nucleus, becomes transcriptionally active and directs production of the therapeutic product.

Important limitations

• AAV has a small packaging capacity of about 4.7 kilobases, including the therapeutic gene and regulatory elements.
• Pre-existing antibodies can neutralise the capsid, while immune responses after treatment may restrict repeat dosing.
• High systemic doses may cause serious immune or organ toxicities, so tissue targeting, dose selection and manufacturing quality are critical.
• Expression may decline in rapidly dividing tissues because episomal vector genomes are diluted during cell division.

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