Gene transfer for kidney disease is challenging. To address this, a team used “context-dependent selection of AAV capsids.” They found that local delivery of AAV-KP1, but not AAV9, via the renal vein or pelvis effectively transduces proximal tubules with minimal off-target liver transduction. Meanwhile, systemic AAV9, but not AAV-KP1, enhances proximal tubule and podocyte transduction in chronic kidney disease.
These differences are partly due to the AAVs’ varying pharmacokinetics, the researchers found. The team was from Oregon Health & Science University School of Medicine.
They conducted a barcode-seq-based comparison of 47 AAV capsids administered through different routes in mice, followed by individual validation. Besides the key delivery differences for AVVs, they found that renal pelvis injection overcomes pre-existing immunity, leading to robust and exclusive proximal tubule transduction, in non-human primates (NHPs). In addition, they highlight drastic differences in renal transduction profiles between mice and NHPs.
The paper appeared in Nature Communications. The lead author is Taisuke Furusho, of the department of molecular and medical genetics, Oregon Health & Science University School of Medicine.
AAV vector-mediated in vivo gene therapy has shown success in treating many genetic diseases, including cancers, types of cardiovascular disease, eye disease and more. With recent remarkable progress in the understanding of the genetic etiology of kidney diseases, the success of AAV vector-mediated gene therapy seems poised to treat these conditions too. For renal gene transfer, renal vein injection, and renal pelvis injection are the two common studied local routes of administration. However, in contrast to other organs, AAV vector-mediated gene delivery to the kidney remains a challenge.
In this study, the Oregon team assessed renal transduction efficiencies of various AAV capsids in mice by IV, RV, and RP injections using AAV Barcode-Seq, followed by individual capsid validation in mice and non-human primates (NHPs). Six capsids, including AAV-KP1, showed remarkably enhanced renal transduction via RV and RP routes in mice, and RP injection overcame pre-existing anti-AAV neutralizing antibodies in NHPs.
To validate the AAV Barcode-Seq data, they individually packaged the AAV-CAG-tdTomato genome with AAV9 and AAV-KP1 capsids and produced AAV9-CAG-tdTomato and AAV-KP1-CAG-tdTomato vectors. Each of the two vectors was injected into eight-week-old C57BL/6 J male mice by IV, RV, or RP injection.
Vector genome copy numbers in the kidney were comparable between the AAV9-injected and AAV-KP1-injected mice in the IV group, while there were 35 times and 23 times more vector genomes in the AAV-KP1-injected mice than the AAV9-injected mice following RV and RP injections, respectively. Vector genome copy numbers in the AAV9-injected animals were not different between the IV, RV and RP groups, which, the authors write, “demonstrates that there is no advantage of local administration over systemic administration when AAV9 capsid is used.”
The study also revealed marked differences in renal transduction profiles between healthy and diseased kidneys and distinct renal transduction pathways in mice and NHPs. These observations emphasize the importance of the optimal selection of both the AAV capsid and the route of administration, considering the host and its disease conditions.
The researchers write, “This study provides mechanistic insights and underscores importance of context-dependent selection of AAV capsids to overcome challenges in gene delivery to the kidney.”
