Pseudo-hydrodynamic Delivery of Helper-dependent Adenoviral Vectors into Non-human Primates for Liver-directed Gene Therapy

Abstract

Helper-dependent adenoviral vectors (HDAds) are attractive for liver-directed gene therapy because they can mediate long-term, high-level transgene expression without chronic toxicity. However, systemic delivery requires high vector doses for efficient hepatic transduction, resulting in dose-dependent acute toxicity. Clearly, strategies to improve hepatic transduction with low vector doses are needed. In this regard, we have previously shown that hydrodynamic injection of helper-dependent adenoviral vectors into mice results in increased hepatic transduction, reduced systemic vector dissemination, and reduced pro-inflammatory cytokines compared with conventional injection and thus has the potential to improve dramatically the therapeutic index of helper-dependent adenoviral vectors. Unfortunately, the rapid, large-volume injection used in this method cannot be applied to larger animals. Therefore, we have developed a novel balloon occlusion catheter-based method to mimic hydrodynamic injection of helper-dependent adenoviral vectors into non-human primates that does not require rapid, large-volume injection. Using a low, clinically relevant vector dose, this minimally invasive method results in high-efficiency hepatic transduction with minimal toxicity and stable long-term transgene expression for at least 413 days.

Progress and prospects: gene therapy for genetic diseases with helper-dependent adenoviral vectors

“…However, considering its tremendous potential, a minimally invasive method to mimic hydrodynamic injection but without rapid, large volume injection was developed using balloon occlusion catheters to achieve preferential hepatic delivery of the HDAd (Figure 2). 38 In this method, hepatic venous outflow is occluded using two balloon occlusion catheters percutaneously placed in the inferior vena cava, above and below the hepatic veins in nonhuman primates ( Figure 2). As blood entering the liver from the hepatic artery and portal vein remains unobstructed, an increase in intrahepatic pressure is achieved, mimicking the high pressures achieved by systemic hydrodynamic injection in the mice.…”

“…This pseudo-hydrodynamic injection method resulted in high-efficiency hepatic transduction with minimal toxicity and stable, long-term transgene expression for at least 413 days. 38 Further improvements in balloon catheter delivery of HDAd preferentially into the liver to enhance safety and efficacy have recently been reported. 39 Other potential strategies for overcoming the activation of the innate immune response include masking of the virion capsid by polyethylene glycol (PEG).…”

Management of malignant pleural effusion by suicide gene therapy in advanced stage lung cancer: a case series and literature review

“…63 Several efforts have been made towards diminishing the immune response. These strategies include modification of viral capsids, 64 covalent conjugation of polyethleneglycol to Ad vectors, 65--68 hydrodynamic injections toward local delivery of low-vector doses directly into the liver, 69 pretreatment with gulucocortocoid, use of lipid bilayer envelopes and preventing binding to the CAR (coxsackie B and adenovirus receptor) receptor by masking the adenoviral fiber knob. 70--72 However, recent data suggest that combination of immunotherapy with chemotherapy can overcome the inability to give multiple doses, resulting the boosting of the initial vaccination of the adenovirus.…”

Advances in Gene Delivery Systems

“…[168] Because of its simplicity, high efficiency and reproducibility, hydrodynamic gene delivery has been utilized for the delivery of DNA, small interfering RNA, proteins, small compounds and even viral vectors. [171][172][173][174][175][176][177][178][179] This technique has been widely used for gene therapy studies, gene knockdown, functional analysis of genetic elements and for establishing a disease model in animals. [171,176,180] In an attempt to apply this simple procedure of gene delivery to the clinic, efforts have been made to reduce the total injection volume.…”

“…Similar studies have been reported by several groups using pigs as an animal model. [172,[182][183][184] A computercontrolled injection device has been developed for hydrodynamic gene delivery in large animals. [185] Using this system, Suda and colleagues [185] have reported safe and efficient gene delivery in pig liver, kidney and muscle.…”