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A - Viral Vector Development -> AAV Vectors – Virology and Vectorology, Vectorology, and Engineering

331: Evolving Nephrotropic AAV Variants Using Ex Vivo NHP Kidney Perfusion and Human Kidney Organoids

Type: Oral Abstract Session

Presentation Details
Session Title: AAV Development for Eye, Muscle, Kidney and CNS
Location: Concourse Hall 150 & 151
Start Time: 5/20/2023 9:08
End Time: 5/20/2023 9:25

Kidney diseases are estimated to affect 37 million people in the US, with nearly 810K Americans living with kidney failure - underscoring the crucial need for effective kidney gene delivery vehicles. Building on previously reported success in engineering cross-species compatible AAV (ccAAV) capsids, we adapted our structure-guided approach to evolve new variants in human kidney organoids. In addition, we developed an ex vivo rhesus macaque kidney perfusion using both ureteral and arterial routes to cycle AAV capsid libraries. By employing evolution schemes across different kidney systems (intravenous in mice and pigs, human organoid cultures and ex vivo organ perfusion), we discovered multiple new AAV variants. Notably, the ureteral and arterial perfusions yielded distinct capsid sequences, highlighting the importance of route of vector administration. High capsid protein sequence convergence was also observed in the case of several variants enriched from different approaches. Two novel AAV variants, AAV.k20 and AAV.k13, displayed robust transduction efficiency in murine kidneys following IV administration. Both variants revealed higher transgene expression compared to AAV9 and AAV.cc47, in particular, within the proximal tubules as indicated by immune-colocalization with lotus tetragonolobus lectin (LTL) staining. We also observed robust transgene expression using AAV.k20 and AAV.k13 vectors in human kidney organoids, corroborating murine data. The approach described here can also potentially be extended to ex vivo human kidney perfusion. Nephrotropic AAV variants represent promising delivery vehicles for therapeutic kidney gene transfer applications.

Alan Rosales1, Leo O. Blondel2, Qimeng Gao2, Andrew S. Barbas2, Aravind Asokan3

1Biomedical Engineering, Duke University, Durham, NC,2Surgery, Duke University, Durham, NC,3Duke University, Durham, NC
 A. Rosales: None.

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