Systemic delivery of adeno-associated viral vectors

•Only intravascular delivery can truly change the course of systemic diseases.•AAV has the capacity to escape from the blood and lead to bodywide gene transfer.•Systemic AAV therapy has been achieved in rodents and large mammals.•Molecular engineering can lead to new AAV capsids for enhanced systemic delivery.

For diseases like muscular dystrophy, an effective gene therapy requires bodywide correction. Systemic viral vector delivery has been attempted since early 1990s. Yet a true success was not achieved until mid-2000 when adeno-associated virus (AAV) serotype-6, 8 and 9 were found to result in global muscle transduction in rodents following intravenous injection. The simplicity of the technique immediately attracts attention. Marvelous whole body amelioration has been achieved in rodent models of many diseases. Scale-up in large mammals also shows promising results. Importantly, the first systemic AAV-9 therapy was initiated in patients in April 2014. Recent studies have now begun to reveal molecular underpinnings of systemic AAV delivery and to engineer new AAV capsids with superior properties for systemic gene therapy.