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. 2024 Aug 15;134(17):e174722.
doi: 10.1172/JCI174722.

Adeno-associated virus-based gene therapy treats inflammatory kidney disease in mice

Guochao Wu  1   2 , Shuya Liu  1   2 , Julia Hagenstein  1   2 , Malik Alawi  3 , Felicitas E Hengel  1   2 , Melanie Schaper  1   2 , Nuray Akyüz  4 , Zhouning Liao  1   2 , Nicola Wanner  1   2 , Nicola M Tomas  1   2 , Antonio Virgilio Failla  5 , Judith Dierlamm  4 , Jakob Körbelin  4 , Shun Lu  1   2 , Tobias B Huber  1   2
Affiliations

Adeno-associated virus-based gene therapy treats inflammatory kidney disease in mice

Guochao Wu et al. J Clin Invest. .

Abstract

Adeno-associated virus (AAV) is a promising in vivo gene delivery platform showing advantages in delivering therapeutic molecules to difficult or undruggable cells. However, natural AAV serotypes have insufficient transduction specificity and efficiency in kidney cells. Here, we developed an evolution-directed selection protocol for renal glomeruli and identified what we believe to be a new vector termed AAV2-GEC that specifically and efficiently targets the glomerular endothelial cells (GEC) after systemic administration and maintains robust GEC tropism in healthy and diseased rodents. AAV2-GEC-mediated delivery of IdeS, a bacterial antibody-cleaving proteinase, provided sustained clearance of kidney-bound antibodies and successfully treated antiglomerular basement membrane glomerulonephritis in mice. Taken together, this study showcases the potential of AAV as a gene delivery platform for challenging cell types. The development of AAV2-GEC and its successful application in the treatment of antibody-mediated kidney disease represents a significant step forward and opens up promising avenues for kidney medicine.

Keywords: Autoimmune diseases; Endothelial cells; Gene therapy; Nephrology; Therapeutics.

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Figures

Figure 1
Figure 1. In vivo selection of the AAV2 peptide display library identified capsids enriched in renal glomeruli.
(A) Schematic overview of in vivo selection in the murine kidney. (B) Pie charts demonstrating the distribution of peptide variants in each selection round. The frequency of particular peptide inserts was determined by NGS. “Others” indicates the occurrence of peptide variants ranked below the “top 100 peptides” in the total pool. (C) Heatmap demonstrating the top 10 peptide variants enriched in the glomerulus ranked by C scores. The combined C score (by multiplying GS and E) described the peptide performance regarding specificity (GS score) and efficacy (E score) with an ideal value of 1. (D) Quantification of vector genome distribution by qPCR. The number of vector genomes was quantified and normalized to vector copy numbers per diploid genome (vg/dg). Values are mean + SD. Significance was determined by 1-way ANOVA with Dunnett’s test, ****P < 0.0001 in all comparisons (glomeruli versus other organs).
Figure 2
Figure 2. AAV2-GEC specifically transduced the GEC.
(A) Representative overview images of AAV2-GEC and AAV2-WT mediated GFP expression in kidneys from C57BL/6J. Original magnification x10. (B) AAV2-GEC mediated GFP expression was detected in the GEC marked by anti-CD31 antibody. Mesangial cells were marked by anti-PDGFRB antibody. Podocytes were marked by anti-WT1 antibody. Nuclei were counterstained with DAPI. Scale bars: 25 μm.
Figure 3
Figure 3. AAV2-GEC maintained robust tropism in BTBRob/ob and Nphs1ΔiPod mice.
(A) Representative overview images of AAV2-GEC–mediated GFP expression in kidneys from BTBR ob/ob mice. Original magnification x10. (B) GFP expression was detected in the GEC marked by anti-CD31 antibody. (C) Representative overview images of AAV2-GEC mediated GFP expression in kidneys from Nphs1ΔiPod mice. Original magnification x10. (D) GFP expression was detected in the GEC marked by anti-CD31 antibody. Nuclei were counterstained with DAPI. Scale bars (B and D): 25 μm.
Figure 4
Figure 4. AAV2-GEC maintained robust tropism in Balb/c mice and SD rats.
(A) Representative overview images of AAV2-GEC mediated GFP expression in kidneys from Balb/c mice. (B) GFP expression was detected in the GEC marked by anti-CD31 antibody. (C) Representative overview images of AAV2-GEC mediated GFP expression in kidneys from SD rats. (D) GFP expression was detected in the GEC marked by anti–RECA-1 antibody. Nuclei were counterstained with DAPI. Scale bars (B and D): 25 μm. Original magnification: x20 (A) and x10 (C).
Figure 5
Figure 5. AAV2-GEC delivery of IdeS successfully treated anti-GBM glomerulonephritis.
(A) Schematic of the prophylactic intervention protocol. C57BL/6J mice were divided into control (AAV2-GEC-GFP) and treatment (AAV2-GEC-IdeS) groups. n = 10 per each group. (B) UACR was measured at 0, 1, 3, and 7 days. (C) Representative images showing remaining sheep IgG Fc and the deposition of C1q in kidneys at 7 days. Scale bars: 100 μm. (D) Schematic of the therapeutic intervention protocol. C57BL/6J mice were divided into control (AAV2-GEC-GFP) and treatment (AAV2-GEC-IdeS) groups. n = 6 per each group. (E) UACR was measured at 0, 1, 4, 8, 15, and 22 days. (F) Representative images showing remaining sheep IgG Fc and the deposition of C1q in kidneys at 22 days. Nuclei were counterstained with DAPI. Values are mean ± SEM. Significance: 2-way ANOVA with repeated measures, *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001; only statistically significant comparisons are shown.
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