**AAV Biology, Infectivity and Therapeutic Use from Bench to Clinic**

Melisa A. Vance, Angela Mitchell and Richard J. Samulski

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/61988

#### **Abstract**

Adeno-associated virus (AAV) has been isolated from numerous vertebrate species since 1966. Besides its wide and promiscuous tropism, AAV infection does not re‐ sult in considerable toxicity or pathogenicity and is capable of achieving adequate and long-term levels of gene transfer, especially following generation of the AAV recombinant variant: rAAV. Due to these properties, rAAV has gained special at‐ tention as a viral vector for gene therapy in the last decade. Currently, there are 130 clinical trials taking place worldwide for several diseases testing the safety and effi‐ cacy profiles of rAAV. During preclinical and clinical studies, several challenges have arisen in terms of reaching the full therapeutic potential of rAAV, such as effi‐ cient delivery of the virus in a targeted and specific manner to a desired tissue. Im‐ portantly, the development of immune responses towards the viral capsids poses an obstacle to rAAV applicability in the clinical setting. Numerous approaches have been developed in order to tailor an optimized therapeutic virus for treating specif‐ ic diseases, including the use of different AAV serotypes or the creation of recombi‐ nant capsid variants with distinctive transduction and immunological profiles. This chapter reviews current information on rAAV clinical trials and the potential for combining rAAV platform with other technologies, such as induced pluripotent cells and gene editing.

**Keywords:** Adeno-associated virus, Gene therapy, Clinical trials

### **1. Introduction**

Gene therapy is currently one of the most promising technologies for the treatment and/or cure of several genetic diseases. Furthermore, it has the potential to battle inherited disorders as

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well as acquired diseases. By inducing modification of the gene pool, gene therapy aims to permanently and non-invasively treat the disease. Among the gene modifications that the therapy allows, a gene could be added, by direct introduction of a gene copy, silenced, by administering shRNA or siRNA, or removed, by the ZFN technology. Therefore, the spectrum of diseases that could potentially benefit from this technology is expanding.

Even though the idea of gene transfer has been pursued for decades using an array of diverse delivery approaches, several setbacks hampered its success for some time. In 1999, the death of Jesse Gelsinger after receiving an adenoviral-based gene therapy for the treatment of severe combined immunodeficiency disorder forced the halt on gene therapy progress [1]. Following this tragic incident, a more serious regulatory scrutiny was established and the use of alter‐ native viral and nonviral vectors was investigated. Among viral platforms for gene delivery, adeno-associated virus (AAV) emerged in 1965 and has attracted much attention since then because the virus is not pathogenic, does not induce significant immune response and/or toxicity to humans while it allows long-term transgene expression.
