Adeno‐associated Viral Vectors in Gene Therapy

Abstract Recombinant vectors based on a nonpathogenic human parvovirus, the adeno‐associated virus (AAV), have gained attention as a potentially safe and useful alternative to the more commonly used retroviral and adenoviral vectors. The past decade has witnessed the use of AAV vectors in the potential gene therapy of an ever‐increasing number of human diseases. The safety of AAV vectors in 165 Phase I/II and 1 Phase III clinical trials in humans to date and clinical efficacy in at least 8 human diseases have now been well documented. The availability of a vast repertoire of AAV serotype vectors, both naturally occurring and genetically engineered, and the availability of promising results with animal models of human diseases provide further impetus to the optimism that their use in the potential gene therapy of a wide variety of human diseases, both genetic and acquired, will continue in the foreseeable future. Key Concepts The first‐generation recombinant AAV vectors have shown efficacy in a number of Phase I/II clinical trials targeting various human diseases. The host immune response to AAV vectors, especially at high doses, remains a challenging problem. The presence of preexisting antibodies to AAV is also a challenge as a significant proportion of the human population is sero‐positive for one or more of the AAV serotypes. The next‐generation AAV vectors have been developed that promise to circumvent most, if not all, of the problems associated with the first generation of AAV vectors. The next generation of AAV vectors, which are more efficacious at lower doses, are likely to prove safe and effective in the potential gene therapy of a wide variety of human diseases in the not‐too‐distant future.