From the Cover: Recombinant adeno-associated virus type 2, 4, and 5 vectors: Transduction of variant cell types and regions in the mammalian central nervous system

Abstract

Recombinant adeno-associated virus vectors based on serotype 2 (rAAV2) can direct transgene expression in the central nervous system (CNS), but it is not known how other rAAV serotypes perform as CNS gene transfer vectors. Serotypes 4 and 5 are distinct from rAAV2 and from each other in their capsid regions, suggesting that they may direct binding and entry into different cell types. In this study, we examined the tropisms and transduction efficiencies of ␤-galactosidase-encoding vectors made from rAAV4 and rAAV5 compared with similarly designed rAAV2-based vectors. Injection of rAAV5 ␤-galactosidase (␤gal) or rAAV4␤gal into the lateral ventricle resulted in stable transduction of ependymal cells, with approximately 10-fold more positive cells than in mice injected with rAAV2␤gal. Major differences between the three vectors were revealed upon striatal injections. Intrastriatal injection of rAAV4␤gal resulted again in striking ependyma-specific expression of transgene, with a notable absence of transduced cells in the parenchyma. rAAV2␤gal and rAAV5␤gal intrastriatal injections led to ␤-gal-positive parenchymal cells, but, unlike rAAV2␤gal, rAAV5␤gal transduced both neurons and astrocytes. The number of transgene-positive cells in rAAV5␤gal-injected brains was 130 and 5,000 times higher than in rAAV2␤gal-injected brains at 3 and 15 wk, respectively. Moreover, transgene-positive cells were widely dispersed throughout the injected hemisphere in rAAV5␤gal-transduced animals. Together, our data provide in vivo support for earlier in vitro work, suggesting that rAAV4 and rAAV5 gain cell entry by means of receptors distinct from rAAV2. These differences could be exploited to improve gene therapy for CNS disorders.

Viral vectors as tools to model and treat neurodegenerative disorders

“…Attachment of AAV5 to cells on the other hand depends on a-2,3/2,6-N-linked sialic acid [54], and the platelet-derived growth factor receptor (PDGFR-α) has been identified as a receptor [55]. The AAV5 serotype leads to higher transduction efficiency and larger diffusion in the brain compared with AAV2 [56].…”

Viral vectors for therapy of neurologic diseases

“…It is currently the most frequently used viral vector for central nervous system (CNS) clinical trials (Table 2), and will thus largely be the focus of this review. AAV vectors are close to the ideal CNS gene therapy vector as they: a) can mediate gene transfer to both mitotic and post-mitotic cells, albeit the transgene is lost over time in dividing cells; b) are neurotropic after direct infusion into brain parenchyma (Davidson et al, 2000); c) can exist stably in an episomal state with a low rate of genomic integration (McCarty et al, 2004); d) exhibit no pathogenicity or cytotoxicity; e) have very mild immunogenicity, mostly humoral (Bessis et al, 2004); and f) can be manufactured at high titers (10 13 –10 14 particles per mL, depending on the production method) and at high purity (Xiao et al, 1999; Urabe et al, 2002). AAV vectors have been shown to mediate stable transgene expression in the human brain for >10 years (Leone et al, 2012).…”

Successful Gene Transfer Using Adeno-Associated Virus Vectors into the Kidney: Comparison among Adeno-Associated Virus Serotype 1–5 Vectors in vitro and in vivo

“…The distinct AAV serotypes were shown to have different tropisms for the cells and tissue. For instance, the AAV serotype 1 vectors could efficiently transduce the skeletal muscles [16], whereas AAV serotype 5 vectors could efficiently transduce liver [17]and central nervous system [18]. Although these differences in the tropism might be due to the receptors and processes during AAV transduction, the precise mechanisms are unknown.…”