Comparison of Gene Delivery to the Kidney by Adenovirus, Adeno-Associated Virus, and Lentiviral Vectors After Intravenous and Direct Kidney Injections

Abstract

There are many kidney diseases that might be addressed by gene therapy. However, gene delivery to kidney cells is inefficient. This is due, in part, to the fact that the kidney excludes molecules above 50 kDa and that most gene delivery vectors are megaDaltons in mass. We compared the ability of adenoassociated virus (AAV), adenovirus (Ad), and lentiviral (LV) vectors to deliver genes to renal cells. When vectors were delivered by the intravenous (IV) route in mice, weak luciferase activity was observed in the kidney with substantially more in the liver. When gene delivery was observed in the kidney, expression was primarily in the glomerulus. To avoid these limitations, vectors were injected directly into the kidney by retrograde ureteral (RU) and subcapsular (SC) injections in mice. Small AAV vectors transduced the kidney, but also leaked from the organ and mediated higher levels of transduction in off-target tissues. Comparison of AAV2, 6.2, 8, and rh10 vectors by direct kidney injection demonstrated highest delivery by AAV6.2 and 8. Larger Ad and LV vectors transduced kidney cells and mediated less off-target tissue transduction. These data demonstrate the utility of direct kidney injections to circumvent the kidney size exclusion barrier. They also identify the effects of vector size on on-target and off-target transduction. This lays the foundation for the use of different vector platforms for gene therapy of diverse kidney diseases.

Doxorubicin Improves Cancer Cell Targeting by Filamentous Phage Gene Delivery Vectors

“…Gene therapy has been attempted against cancer for the past 28 years, with more than 67% of clinical trials of gene therapy designed to treat cancer patients [ 1 ]. However, progress has been hindered, mostly by a lack of tumor-selective gene delivery vectors efficient via clinical systemic routes and by problems with repeated vector administrations [ 2 , 3 ]. Currently, the most common vectors are eukaryotic viruses, because they can enter cells and deliver genes as part of the natural infection process.…”

Fibrosis regression is induced by AdhMMP8 in a murine model of chronic kidney injury

“…Several publications provide a comprehensive overview of recent progresses using viral vectors for direct gene transfer to the kidney. Different strategies have been developed to demonstrate viral vector transduction in all types of cells within the kidney, including the glomeruli, tubular epithelial cells in the cortex and medulla, and interstitial cells [ 22 , 23 ]. Important to state, is the fact that in this work, total renal expression of hMMP8 was the primary aim of AdMMP8 administration, regardless of the type of a specific protein-expressing cell.…”

Oligonucleotide-Based Therapies for Renal Diseases

“…Podocytes within the glomerulus create slit diaphragms with diameters of only 10 nm. Results from a number of studies targeting the renal tubules via renal artery injection suggest that this glomerular filtration barrier can be temporarily disrupted by controlled hydrodynamic-pressure upon injection, potentially allowing the administration of large bioconjugates and nanoparticles [ 118 ]; (2) retrograde renal vein administration, predominantly targeting the renal tubules through the basolateral domain. Similar to what occurs in the renal artery, increased localized pressure in the renal capillaries creates transient pores on cell membranes, resulting in nucleic acid extravasation [ 18 , 22 , 61 ]; (3) retrograde ureteral administration, targeting the tubular epithelium; (4) intraparenchymal administration.…”

“…Although viral vectors are excluded by the glomerular filtration barrier, even those based on adeno-associated virus (AAV), which have the smallest capsid diameters (25 nm), the use of direct routes of administration has successfully achieved renal transduction [ 118 , 120 , 121 ]. This indicates the feasibility of using viral vectors and similar large-sized nanoparticles to deliver oligonucleotides.…”

“…The same strategies employed for their use in gene therapy can be adapted here, including the possibility of a rational design and modification of the viral particles to improve renal tropism [ 123 ], or kidney-specific promoters that increase specificity and expression in renal cells [ 124 ]. As previously mentioned, this strategy has already been successfully tested for gene therapy purposes [ 118 , 119 ].…”