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In an effort to reconstitute putative ancestors of current AAV serotypes (see Zinn et al., 2015) that help to better understand the structure-function relationship (and thereby improve transduction efficiency and specificity, alter tropism, and reduce immunogenicity), nine functional putative ancestral AAVs were generated.
Among those nine, Anc80 (the most distal evolutionary node of the putative dendrogram) was identified as the predicted ancestor of AAV serotypes 1, 2, 3, 6, 7, 8, 9 and rh10, excluding 4 and 5. The uncertainty provided by the maximum likelihood (ML) ancestral sequence reconstruction (ASR) method was captured in an Anc80 variant library (Anc80L). Members of this library were evaluated for their ability to yield high titer infectious AAV‐like particles. The 65th clone from that screen, Anc80L65, underwent extensive characterization and revealed a potent gene therapy vehicle with broad and unique properties in murine and nonhuman primate liver as well as muscle and retina targeting in mouse. Anc80L65 also transduces inner and outer hair cells in murine cochlea (see Landegger et al., 2017), in mouse kidney cells, and kidney mesenchymal cells in human kidney organoids (see Ikeda et al., 2018).
Furthermore, single-stranded (ss) AAV-Anc80L65 vectors were demonstrated to efficiently transduce mostly astrocytes and a wide range of neuronal subpopulations after intravenous, intracerebroventricular or intraparenchymal injections in the murine brain (see Hudry et al., 2018). Notably, AAV-Anc80L65 vectors may transduce an even larger brain area after intraparenchymal injections when compared to AAV-9 vectors.
As a first step towards the evaluation of the transduction efficiencies and profiles of this new "old" AAV vector capsid, the VVF has produced three reporter ssAAV-Anc80L65 vectors that are available through the viral vector repository:
