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Over the past decades, numerous AAV serotypes have been identified with variable tropism. To date, 12 AAV serotypes and over 100 AAV variants have been isolated from adenovirus stocks or human/nonhuman primate tissues. Among them, AAV2, AAV3, AAV5, AAV6 were discovered in human cells, while AAV1, AAV4, AAV7, AAV8, AAV9, AAV10 (AAVrh10), AAV11, AAV12 in nonhuman primate samples . Genome divergence among different serotypes is most concentrated on hypervariable regions (HVRs) of virus capsid, which might determine their tissue tropism. Besides virus capsid, tissue tropisms of AAV vectors are also influenced by cell surface receptors, cellular uptake, intracellular processing, nuclear delivery of the vector genome, uncoating, and second-strand DNA conversion . To effectively enable the transduction of tissues or limit AAV tropism to specific tissues in vivo, researchers have developed a number of mosaic AAV vectors or chimeric AAV vectors by engineering custom-designed AAV capsids to carry out gene therapy [43,44].
a)AAV Serotype 2 (AAV2)
AAV Serotype 2 (AAV2) is the first isolate of AAVs and also the best studied AAV serotype, which stands for natural tropism towards skeletal muscles , neurons , vascular smooth muscle cells , and hepatocytes . AAV2 possesses three receptors, among which heparan sulfate proteoglycan (HSPG) functions as a primary receptor to scavenge AAV particles and impair the infection efficiency , while aVβ5 integrin and fibroblast growth factor receptor 1 (FGFR-1) enable AAV to enter the cell by receptor-mediated endocytosis as co-receptors [50-52]. In possession of great gene therapy potentials, AAV2 has been used for cancer treatments, such as ovarian carcinoma (OvCa) without any effect on healthy cells currently .
b)AAV Serotype 8 (AAV8) and AAV Serotype 9 (AAV9)
In addition to AAV2, the most widely used AAV serotypes are AAV Serotype 8 (AAV8) and AAV Serotype 9 (AAV9). AAV8 is a robust vector for gene delivery to liver and a promising research tool for delivering genes to various target organs with higher efficiency than most other serotypes. As demonstrated, efficient transduction of liver, skeletal muscle and heart can be detected after systemic injection of AAV8 . More importantly, a single tail vein injection of AAV8 was as efficient as portal vein injection at any dose and a high dose of AAV8 transduced skeletal muscle throughout the body, including the diaphragm, the entire cardiac muscle, and the pancreas, smooth muscle, and brain at substantial levels . Compared with AAV2, AAV9 displays a similar profile with widely disseminated transduction, just with much more efficient . Additionally, the ability of AAV9 to bypass the blood-brain barrier (BBB) enables intravascular administration as a non-invasive delivery route to achieve widespread CNS gene expression. What’s more, AAV9 intravenous gene delivery has already shown promising results for several diseases in animal models, including lysosomal storage disorders and motor neuron diseases, opening the way to the first clinical trial in the field .
c)Other AAV serotypes
Today, 12 AAV serotypes have been designed as gene delivery vectors. It might be difficult to interpret AAV serotype tissue tropism due to interstudy variations in vector titers and doses, promoters, and transgenes. A general hierarchy of transduction efficiency in major tissues and cell types has been established at table 1 and table 2. For instance, AAV2 can moderately transduce several tissue types, including central nervous system, liver, muscle, and lung. Similarly, within the CNS, AAV1 and AAV5 show higher transduction frequencies than AAV2 in all injected regions [58,59], while AAV4 just appears to transduce specific cell types, such as the astrocytes and ependyma in the subventricular zone . In skeletal muscle cells, AAV1, AAV6 and AAV7 are reported to present a very high transduction rate [56,61-63], while AAV8 exhibits transduction ability with super efficiency not only in hepatocytes but also in other organs [44,61,64]. In addition to skeletal muscle cells, AAV6 has been also reported to mediate more efficient transduction of airway epithelial cells in mouse lungs compared to that of AAV2 , which may supply AAV6 with more significant advantages over AAV2 for gene therapy of lung diseases like cystic fibrosis considering the lower immunogenicity of AAV6 than of AAV2 [44,61].
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