In humans, treatment for inborn errors of liver metabolism has focused on dietary, drug, and cell therapies. However, significant morbidity and mortality still remain and alternative and/or adjunctive strategies are needed. It has been 15 years since human gene therapy trials were initiated for genetic diseases. While significant progress has been made in the preclinical arena in a variety of disease models, sustained effect in humans has still eluded the field of inborn errors of liver metabolism. At this time, achievement of clinical efficacy in different animal models has been reported with multiple gene transfer technologies. Current efforts are aimed at fully understanding host-vector interactions, and how manipulation of these interactions can help us to increase the therapeutic index of any specific therapy. As with any therapy, it will be the balance of this index and the disease natural history which will determine the future of clinical studies and their outcomes.
"To overcome the drawbacks related to shortage of donors, mortality and morbidity related to the transplantation procedures, and risks of lifelong immunosuppression, alternative therapies are highly needed. The small percentage of hepatocytes required for phenotypic correction (Fox et al., 1998; Brunetti-Pierri and Lee, 2005), the availability of a spontaneous animal model (e.g., the Gunn rat), and the ease of biological assessment of therapeutic efficiency make Crigler–Najjar syndrome a paradigm for gene therapy of inherited liver diseases. Therefore, during the past two decades, several studies have documented proof of principles of gene therapy for Crigler–Najjar syndrome in the Gunn rat using various vectors, such as viral vectors based on retrovirus (Nguyen et al., 2007), lentivirus (van der Wegen et al., 2006; Schmitt et al., 2010), recombinant SV40 virus (Sauter et al., 2000), Ad and HDAd (Askari et al., 1996; Toietta et al., 2005; Dimmock et al., 2011; Pastore et al., 2013), AAV (Seppen et al., 2006), and naked plasmid DNA (Danko et al., 2004; Jia and Danko, 2005). "
[Show abstract][Hide abstract] ABSTRACT: Helper-dependent adenoviral vectors (HDAd) are attractive vectors for liver-directed gene therapy because they can drive sustained high levels of transgene expression without chronic toxicity. However, high vector doses are required to achieve efficient hepatic transduction by systemic delivery due to a nonlinear dose response. Unfortunately, such high doses result in systemic vector dissemination and dose-dependent acute toxicity with potential lethal consequences. We have previously shown in nonhuman primates that delivery of HDAd in surgically isolated livers resulted in a significantly higher hepatic transduction with reduced systemic vector dissemination compared to intravenous delivery liver and multi-year transgene expression. Encouraged by these data, we have now employed a surgical vector delivery method in the Gunn rat, an animal model for Crigler-Najjar syndrome. Following vector delivery into the surgically-isolated liver, we showed phenotypic correction at the low and clinically relevant vector dose of 1x1011 vp/kg. Correction of hyperbilirubinemia and increased glucuronidation of bilirubin in bile was achieved for up to 1 year after vector administration. Surgical delivery of the vector was well tolerated without signs of acute or chronic toxicity. This method of delivery could thereby be a safer alternative compared to liver transplantation for long-term treatment of Crigler-Najjar syndrome type I.
"Consistent with a previous study (Crettaz et al., 2006), we found that compared with the same dose of vector injected intravenously, direct intrahepatic injections resulted in reduced secretion of serum IL-6 and no reduction of platelet counts. After intravenous administration, Ad vectors disseminate systemically into multiple organs, and particularly in the spleen (Zhang et al., 2001; Brunetti-Pierri et al., 2005b). Vector systemic dissemination contributes to activation of the inflammatory response (Brunetti-Pierri et al., 2005b). "
[Show abstract][Hide abstract] ABSTRACT: Crigler-Najjar syndrome type I is due to mutations of the uridine diphospho-glucuronosyl transferase 1A1 (UGT1A1) gene resulting in life-threatening increase of serum bilirubin. Life-long correction of hyperbilirubinemia was previously shown with intravenous injection of high doses of a helper-dependent adenoviral (HDAd) vector expressing UGT1A1 in the Gunn rat, the animal model of Crigler-Najjar syndrome. However, such high vector doses can activate an acute and potentially lethal inflammatory response with elevated serum interleukin-6 (IL-6). To overcome this obstacle, we investigated safety and efficacy of direct injections of low HDAd doses delivered directly into the liver parenchyma of Gunn rats. Direct hepatic injections performed by either laparotomy or by ultrasound-guided percutaneous injections were compared to the same doses given by intravenous injections. A greater reduction of hyperbilirubinemia and increased conjugated bilirubin in bile were achieved with 1x1011vp/kg by direct liver injections compared to intravenous injections. In sharp contrast to intravenous injections, direct hepatic injections did not raise serum IL-6 neither resulted in thrombocytopenia. In conclusion, ultrasound-guided percutaneous injection of HDAd vectors into liver parenchyma resulted in improved hepatocyte transduction and reduced toxicity compared to systemic injections and is clinically attractive for liver-directed gene therapy of Crigler-Najjar syndrome.
[Show abstract][Hide abstract] ABSTRACT: Gene therapy for inherited disorders might cause an immune response to the therapeutic protein. A solution would be to introduce the gene in the fetal or neonatal period, which should lead to tolerization. Lentiviral vectors mediate long-term gene expression, and are well suited for gene therapy early in development. A model for fetal or neonatal gene therapy is the inherited disorder of bilirubin metabolism, Crigler-Najjar disease (CN). The absence of bilirubin UDP-glucoronyltransferase (UGT1A1) activity in CN patients causes high serum levels of unconjugated bilirubin and brain damage in infancy. CN is attractive for the development of gene therapy because the mutant Gunn rat closely mimics the human disease. Injection of UGT1A1 lentiviral vectors corrected the hyperbilirubinemia for more than a year in rats injected as fetuses and for up to 18 weeks in rats injected the day of birth. UGT1A1 gene transfer was confirmed by the presence of bilirubin glucuronides in bile. All animals injected with UGT1A1 lentiviral vectors developed antibodies to UGT1A1. Animals injected with green fluorescent protein (GFP) lentiviral vectors did not develop antibodies to GFP. Our results indicate that fetal and neonatal gene therapy with immunogenic proteins such as UGT1A1 does not necessarily lead to tolerization.
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