Gene Therapy in In Vivo Isolated Perfusion Models

Abstract

Locoregional administration of a genetic construct by means of in vivo, in situ isolated perfusion (IP) of a target organ or extremity is a method that may increase in vivo efficacy. Vascular isolation and perfusion minimizes systemic exposure and thereby reduces unwanted side effects. Isolated hepatic perfusion (IHP) is the most extensively studied IP model, especially in gene therapy protocols for inborn errors of metabolism. To achieve stable transduction most frequently retroviruses are used in IHP. IHP is combined with hepatectomy or vascular ligation of liver lobes to induce liver regeneration increasing transduction efficacy. When adenoviruses are used in IHP high transduction percentages of hepatocytes can be achieved without significant toxicity. In tumor models adenoviral IHP has been performed, but has not been very successful up till now. Isolated limb perfusion (ILP) is a promising treatment modality in pre-clinical cancer gene therapy studies. After ILP a homogeneous distribution of transduced cells was demonstrated especially at the viable rim of the tumor and around tumor associated vessels. Moreover complete tumor responses have been observed. Isolated pulmonary perfusion (IPP) results in selective expression in the perfused lung and the duration of expression is longer than after systemic administration. In rats a significant decrease of tumor nodules upon IPP can be achieved. Furthermore other less studied perfusion models are discussed: isolated kidney perfusion (IKP), isolated spleen perfusion (ISP) and isolated cardiac perfusion (ICP). IP is a methodology that delivers vectors highly selectively, with a long exposure time and high concentrations at the target side. This results in higher transduction rates and thereby may improve therapeutic effects.

Modified in vivo lung perfusion allows for prolonged perfusion without acute lung injury

“…29 IVLP with a safe extended perfusion time may also open up opportunities for other localized therapies that require a longer exposure window such as gene therapy. 30 In conclusion, this modified IVLP technique can be performed safely, without evidence of acute lung injury. Studies on the use of chemotherapy using the strategy described here need to be performed.…”

Modified In Vivo Lung Perfusion for Local Chemotherapy: A Preclinical Study With Doxorubicin

“…We recognize that the optimal duration of IVLP requires further study and that the extent of the IVLP studied here (4 hours) may seem long for clinical application. However, long-term IVLP may be needed for treatments that require longer exposure, such as gene therapy [26]. Second, we were able to safely achieve flows of 450 to 550 mL/min (with PA pressure ranging from 10-15 mm Hg).…”

Gene Therapy for Acute Liver Failure

“…In addition, this technique also induces long-lasting gene expression reaching therapeutic level [101][102][103] and to efficiently deliver large intact bacterial artificial chromosome (BAC) DNA (150 kb) into the liver [104], justifying its translation to humans. Recently, several groups have developed novel methods with balloon-induced occlusion to achieve more lobe-specific gene delivery, leading to long-term therapeutic effects in animal models [98,103,105]. In individual clinical cases, HBGT has shown great promise in delivering therapeutic genes, such as p53 to patients with hepatocellular carcinoma (HCC) and achieved complete tumor regression for at least 12 months [106].…”