Adeno-Associated Virus Gene Transfer into Renal Cells: Potential for in vivo Gene Delivery

Abstract

The human parvovirus adeno-associated virus (AAV), type 2, has a number of features that make it an attractive choice as a vector for gene delivery to the kidney. AAV vectors permit long-term gene expression in vivo by integration into the host genome, have potential for site-specific integration on chromosome 19, do not express viral genes or generate a cellular immune response, and demonstrate enhancement of gene expression by chemotherapeutic agents that are approved for use in vivo. These properties confer advantages to AAV over other viral and nonviral methods for gene transfer. Preliminary experiments in our laboratory suggest that AAV is able to transfer genes to both renal cells in culture and the kidney in vivo. Thus, AAV has the potential to be an important gene transfer vector for the kidney in vivo.

Systemic administration of naked DNA with targeting specificity to mammalian kidneys

“…It was demonstrated that delivery via renal artery perfusion resulted in gene expression predominantly in the renal cortex; in comparison, retrograde infusion via the ureter resulted in strong expression mainly in papillary tubular cells. [41][42][43] Recently, Gusella et al 44 studied the transduction of kidney in mice after delivery of lentiviral vectors by various routes of administration. After parenchymal or ureteral infusion, expression of the transgene was localized to the outer medulla and corticomedullary junction.…”

“…Retroviral vectors direct gene expression predominantly in the outer medulla, 40 while adenoviruses could direct gene expression in either the outer medulla or inner medulla through different injection routes. [41][42][43] Renal arterial perfusion generated highest gene expression mainly in the outer medulla, while the highest gene expression is usually found in the papilla through retrograde infusion via the ureter. [41][42][43] In contrast, nonviral vectors consistently produce high gene expression either in the cortex or in the outer medulla and almost no expression could be detected in the inner medulla.…”

“…[41][42][43] Renal arterial perfusion generated highest gene expression mainly in the outer medulla, while the highest gene expression is usually found in the papilla through retrograde infusion via the ureter. [41][42][43] In contrast, nonviral vectors consistently produce high gene expression either in the cortex or in the outer medulla and almost no expression could be detected in the inner medulla. 46 Lai et al 46 demonstrated a prolonged systemic gene expression in the kidney after intravenous delivery of DNA-liposome complex in mice.…”

Adeno-associated virus mediated endostatin gene therapy in combination with topoisomerase inhibitor effectively controls liver tumor in mouse model

“…Moreover, besides being difficulty to be purified, endostatin has a short half-life in vivo. In order to circumvent the obstacle presented by the pharmacokinetics of endostatin, delivery of the gene cassettes encoding endostatin has been attempted [11][12][13][14][15][16][17][18][19] . Recombinant adeno-associated virus (rAAV) vector is a good candidate for antiangiogenesis-based cancer gene therapy [20] .…”

Genetic targeting of the renin-angiotensin system for long-term control of hypertension

“…Although its site of integration is known, the recombinant adeno-associated virus looses this property. Even though expression is longer than with the adenovirus, there are some limitations with this vector system mainly because it is difficult to produce large quantities of the virus, and it has a limited capacity for inserting the transgene [40][41][42]. Finally, lentiviral vectors can infect nondividing cells with high efficiency and can be produced with high titer.…”