AAV Is Now a Medicine: We Had Better Get This Right

What do Ken Berns, Nick Muzyczka, Barrie Carter, Jim Wilson, Mark Kay, Kathy High, Arun Srivastava, Chuck Venditti, Mark Sands, Gundi Ertl, Rob Kotin, Richard Snyder, and Chris Mueller have in common? Answer: They are all among the contributors to this month's special issue of Human Gene Therapy, entitled “Controversies in AAV Gene Therapy: Not All Black and White.” Why have we assembled such a constellation of stars from the AAV universe for this issue? Answer: An adeno-associated virus (AAV) vector is now an approved therapy in the European Union, and others are soon to be approved in the United States.

Quite simply, AAV gene therapy is becoming, and indeed already is, a part of the armamentarium of medicine after a half century of vector discovery and development, combined scientific breakthroughs and medical achievements. ^1,2

As our guest co-editors, Drs. Berns and Muzyczka, point out, the study of AAV has already spanned nearly 55 years in an article entitled “AAV: An Overview of Unanswered Questions” in this issue. As a virus, one marvels at how AAV accomplishes both life-long latency and rapid replication with such a small and elegantly simple genome. As a vector, AAV has proven to have just the right combination of long-term persistence of expression and lack of pathogenicity to be useful as a gene-therapy platform for genetic diseases. And yet, as the overview of this issue by our two guest co-editors points out, a number of key issues continue to perplex investigators and generate controversy for the field. These include aspects of AAV persistence, the potential risk of insertional mutagenesis and carcinogenesis, and the potential for immune responses to both transgene products and AAV capsid epitopes.

The concept of this special issue is to provide specialized reviews by authorities in the field on both sides of each of these crucial issues. In addition, we will look to the future as clinical grade production matures and AAV is used as a platform to deliver newer genetic intervention technologies (including RNAi and genome-editing constructs) based on recently discovered molecular mechanisms. We owe a great debt of gratitude to all of the contributors for their insightful comments and strong evidence-based arguments. Our hope is that by providing the arguments and citing the data on each side of each topic, this special issue will help to crystallize questions for future study of this vector system. The ultimate goal is to reveal the crucial aspects of the vector–host interaction that will be necessary for understanding and predicting the utility and safety of AAV vectors as they come into frequent clinical use for disorders of the retina, central nervous system, liver, muscle, and other organs. As we enter the clinical era, using AAV vectors to treat patients with genetic disorders that are life threatening and vision threatening, the stakes are too high to get this wrong.