Advances of AAV vectors
The AAV based gene delivery systems are more attractive compared to other vectors. More benefits were discovered using AAV vectors such as more safety due to the lack of pathogenicity, more varied host and cell-type tropisms, long-term gene expression, ability to transfect both dividing and nondividing cells, absence of enormous immune response. Furthermore, the discovery of more novel AAV serotypes will further extend the scope of application of an AAV based gene delivery system.
However several problems about this gene delivery system should be addressed. Firstly, the effective packaging capacity of AAV is limited to 4.1–4.9 kb [27], which restricts the transduction of larger genes. Secondly, antibody neutralization rises because of prior exposure of human beings with multiple AAV serotypes [28]. Thirdly, challenges with high-efficient transduction to specific cell populations remain in an AAV mediated gene delivery system. Since these problems influenced the extended application of AAV based gene therapy, a variety of attempts to improve this vector have been carried out. Self-complementary AAV (scAAV) vectors can fold into double-stranded DNA (dsDNA) without DNA synthesis or base-pairing between multiple vector genomes [29] bypassing the conversion to dsDNA. Naturally, these vectors are more sufficient to transgene expression than normal AAV vectors. The clinical application of AAV vector was slowed down due to the limitation of the packaging capacity of rAAV. Cotransduction of dual AAV vectors seems to be an alternative to solve this problem. Transgene expression cassettes are split into two, and each is packaged into an AAV vector. Then expression of full-length transgene is obtained via homologous recombination or viral inverted terminal repeat mediated recombination. Since low levels of pre-existing neutralizing antibodies significantly reduced the efficacy of therapeutic AAV gene delivery, modification of AAV capsid involved in interactions with host immunity has been a good idea to escape neutralization. Directed selection of AAV variants, “shielding” polymers, site-directed mutagenesis and directed evolution of AAV capsid made the neutralization escape of AAV based delivery system feasible [30].
Advances of AAV vectorsThe AAV based gene delivery systems are more attractive compared to other vectors. More benefits were discovered using AAV vectors such as more safety due to the lack of pathogenicity, more varied host and cell-type tropisms, long-term gene expression, ability to transfect both dividing and nondividing cells, absence of enormous immune response. Furthermore, the discovery of more novel AAV serotypes will further extend the scope of application of an AAV based gene delivery system.However several problems about this gene delivery system should be addressed. Firstly, the effective packaging capacity of AAV is limited to 4.1–4.9 kb [27], which restricts the transduction of larger genes. Secondly, antibody neutralization rises because of prior exposure of human beings with multiple AAV serotypes [28]. Thirdly, challenges with high-efficient transduction to specific cell populations remain in an AAV mediated gene delivery system. Since these problems influenced the extended application of AAV based gene therapy, a variety of attempts to improve this vector have been carried out. Self-complementary AAV (scAAV) vectors can fold into double-stranded DNA (dsDNA) without DNA synthesis or base-pairing between multiple vector genomes [29] bypassing the conversion to dsDNA. Naturally, these vectors are more sufficient to transgene expression than normal AAV vectors. The clinical application of AAV vector was slowed down due to the limitation of the packaging capacity of rAAV. Cotransduction of dual AAV vectors seems to be an alternative to solve this problem. Transgene expression cassettes are split into two, and each is packaged into an AAV vector. Then expression of full-length transgene is obtained via homologous recombination or viral inverted terminal repeat mediated recombination. Since low levels of pre-existing neutralizing antibodies significantly reduced the efficacy of therapeutic AAV gene delivery, modification of AAV capsid involved in interactions with host immunity has been a good idea to escape neutralization. Directed selection of AAV variants, “shielding” polymers, site-directed mutagenesis and directed evolution of AAV capsid made the neutralization escape of AAV based delivery system feasible [30].
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