Aav-Based Targeting Gene Therapy (Report‪)‬

INTRODUCTION AAV has been considered as a safe vector for gene transfer and has been involved in many clinical trials to treat metabolic abnormalities, hemophilia disease, Parkinson's disease and cystic fibrosis. AAV vectors have following advantages in gene therapy studies. (1) AAV vector is able to site specifically integrate into the host genome. Site specific integration of AAV doesn't activate the possible oncogenes and the inserted gene can be maintained for a relatively long-term in host cell genome and stably expressed in vivo [55,71,128]. Furthermore, selective genomic integration can be achieved via genetic modified AAV vectors [126]. (2) AAV capsids endure capsid modification and serotype swapping, which allows the AAV-mediated cell targeting delivery based on virus-host interaction. (3) AAV vectors show wide host spectrum and high infectivity for dividing and non-dividing cells. (4) AAV vectors also have advantages for solid cancers' application due to its small size, because of its high penetrability through the tumor stroma compared to other viral vectors. (5) AAV vector is low immunogenic. Most of the AAV serotypes are isolated from human; therefore immune response against the vector is relatively low and re-administration is possible due to low in vivo neutralizing antibody. However, AAV vector caused immune response was discovered in vivo by several groups. Heparin binding directed activation of cytotoxic T cells against AAV2 capsid, but not AAV8, was determined, which partially explained the liver toxicity in AAV2, not AAV8 mediated hemophilia treatment [15,102,53]. Moreover, Wang et al observed AAV2 induced in vivo capsid-specific cytotoxic T cells, but not AAV7 or AAV8. This CTL exerted the functional cytolytic effect on capsid-peptide loaded target cells, but not AAV2 vector-transduced hepatocytes [111]. Similarly, AAV2 capsid-specific cytotoxic T cells only eliminate AAV2 vector transduced cells co-expressing AAV2 capsid in vivo. Li further pointed out that additional modification to AAV vectors may be required for further study for elicitation of cellular immune response [16]. (6) AAV vector is reported to be non-pathogenic. AAV2 have been reported to be associated with certain pathogenic processes without causing obvious severe diseases [64,83]. Some recent studies, however, have shown hepatocarcinoma induced in AAV-injected mice due to insertion with 6-kilobase region of chromosome 12 [26]. The mechanism and cause for this phenomenon certainly requires further investigation.