A Novel Glomerular Endothelium-Targeting Adeno-Associated Virus (AAV) Delivers Bacterial Proteinase to Treat Glomerulonephritis
- Bioengineering, Augmented Intelligence, Digital Health, and Data Science
November 04, 2023 | Location: Room 108, Pennsylvania Convention Center
Abstract Time: 05:06 PM - 05:15 PM
- 400 Bioengineering
- Liu, Shuya, III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Wu, Guochao, III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Körbelin, Jakob, Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Lu, Shun, III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Huber, Tobias B., III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
The breakdown of glomerular filtration barrier (GFB) is relevant to the pathogenesis of most kidney diseases. Targeting the GFB by conventional drugs is challenging due to the lack of cell-targeting specificity, which consequently compromises the therapy efficacy. Adeno-associated virus (AAV) as a promising in vivo gene delivery platform shows the advantage in delivering therapeutic molecules to those difficult or non-druggable cells. However, natural AAV serotypes have insufficient targeting specificity and transduction efficiency in kidney cells, thus approaches to broaden the tropism of AAV and screenings for kidney-specific AAV vectors are particularly needed. In this study, we aimed to discover new AAV vectors targeting the renal glomerulus.
We developed a selection protocol specifically for kidneys and screened a random AAV2 display peptide library in vivo. Integrative experimental and bioinformatics workflows were conducted to identify the most promising AAV vectors enriched in renal glomeruli. The targeting specificity and transduction efficiency of the selected AAV were evaluated in vivo under both physiological and pathological conditions.
We identified a new AAV vector termed AAV2-GEC, which specifically and efficiently targeted the glomerular endothelial cells (GEC) after systemic administration. AAV2-GEC exhibited robust GEC tropism in C57BL/6J, Balb/c mice and Sprague Dawley rats, as well as in disease models causing GEC damage. The potential of AAV2-GEC for kidney-targeting therapy was evaluated by delivering a bacterial cysteine proteinase originally purified from Streptococcus pyogenes (IdeS) to the GEC. IdeS, also known as imlifidase, is an antibody-cleaving enzyme used in the clinic to eliminate pathogenic IgG. We showed that AAV2-GEC-IdeS transduction efficiently produced IdeS in GEC, which provided sustained clearance of kidney-bound IgG and successfully prevented the progression of anti-glomerular basement membrane glomerulonephritis.
This study establishes an AAV in vivo screening approach for renal glomeruli. It identifies a novel GEC-targeting AAV vector with robust tropism maintained cross species in both physiological and pathological settings. The identification of AAV-GEC demonstrates the feasibility of future GFB-targeting strategies for novel kidney therapies.
- Government Support – Non-U.S.