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Abstract: FR-PO407

Comprehensive Characterization of 47 Adeno-Associated Virus Serotypes and Mutants for Renal Gene Transfer

Session Information

Category: Genetic Diseases of the Kidneys

  • 1102 Genetic Diseases of the Kidneys: Non-Cystic

Authors

  • Furusho, Taisuke, Oregon Health & Science University, Portland, Oregon, United States
  • Galbraith-Liss, Mia S., Oregon Health & Science University, Portland, Oregon, United States
  • Sairavi, Anusha, Oregon Health & Science University, Portland, Oregon, United States
  • Nakai, Hiroyuki, Oregon Health & Science University, Portland, Oregon, United States
Background

With the advent of the NGS-based clinical diagnostics, a number of genetic causes have been identified in CKD whose etiology was previously unknown. Such increasing knowledge about genetic etiology of CKD and the relatively high prevalence of monogenic kidney diseases in both pediatric and adult CKD patients have made CKD an attractive target for AAV vector-mediated in vivo gene therapy. However, gene delivery to the kidney has been challenging and there has been no study that compared renal transduction efficiencies of many AAV serotype and mutant capsid-derived vectors in a head-to-head setting. In addition, route of administration (ROA)-dependent differences in renal transduction profiles among different AAV capsids have yet to be investigated. Thus, the development of AAV vector-mediated renal gene therapy has been impeded so far.

Methods

We comprehensively characterized renal transduction profiles of 47 different AAV capsids (serotypes and mutants) following vector administration in mice using two ROAs (intravenous injection, IV; and renal vein injection, RV). To this end, we employed AAV DNA/RNA Barcode-Seq, an NGS-based high-throughput method. A barcoded AAV vector library was administered into C57BL/6J mice via IV or RV, kidneys were harvested 6 weeks post-injection, and transduction efficiency of each AAV capsid for each ROA was assessed by Barcode-Seq. Select AAV capsids were then individually vectorized and validated in mice.

Results

AAV9 showed the highest renal transduction by IV among the 47 AAV capsids but AAV9 was outperformed by a set of AAV capsids including AAVmt when administered by RV. AAVmt was found to transduce the kidney >30 times better than AAV9. AAV9 transduced only mesangial cells and interstitial cells and transduction patterns by IV and RV remained the same. In contrast, AAVmt transduced only mesangial cells by IV while cortical renal tubule epithelial cells, mostly proximal tubules, were efficiently transduced by RV.

Conclusion

Our high-throughput approach using Barcode-Seq identified AAV capsid - ROA combinations that can mediate renal transduction at levels that were not attainable by previous approaches. In addition, our study underscores the importance of carefully selecting AAV capsid and ROA as a combination depending on target cells of interest.

Funding

  • NIDDK Support