AAV vectors: The Rubik's cube of human gene therapy

Defective genes account for X80% of the total of more than 7,000 diseases known to date. Gene therapy brings the promise of a one-time treatment option that will fix the errors in patient genetic coding. Recombinant viruses are highly efficient vehi-cles for in vivo gene delivery. Adeno-associated virus (AAV) vectors offer unique advantages, such as tissue tropism, speci-ficity in transduction, eliciting of a relatively low immune re-sponses, no incorporation into the host chromosome, and long-lasting delivered gene expression, making them the most popular viral gene delivery system in clinical trials, with three AAV-based gene therapy drugs already approved by the US Food and Drug Administration (FDA) or European Medicines Agency (EMA). Despite the success of AAV vectors, their usage in particular scenarios is still limited due to remaining chal-lenges, such as poor transduction efficiency in certain tissues, low organ specificity, pre-existing humoral immunity to AAV capsids, and vector dose-dependent toxicity in patients. In the present review, we address the different approaches to improve AAV vectors for gene therapy with a focus on AAV capsid selection and engineering, strategies to overcome anti-AAV immune response, and vector genome design, ending with a glimpse at vector production methods and the current state of recombinant AAV (rAAV) at the clinical level.

Automated summary

Defective genes account for X80% of known diseases. Gene therapy offers a one-time treatment option for fixing genetic errors. Adeno-associated virus (AAV) vectors are efficient for in vivo gene delivery but face challenges. This review discusses approaches to improve AAV vectors for gene therapy.