Gene therapy for inborn errors of liver metabolism.
ABSTRACT 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.
SourceAvailable from: Pasquale Piccolo[Show abstract] [Hide abstract]
ABSTRACT: Helper-dependent adenoviral (HDAd) vectors that are devoid of all viral coding sequences are promising non-integrating vectors for gene therapy because they efficiently transduce a variety of cell types in vivo, have a large cloning capacity, and drive long-term transgene expression without chronic toxicity. The main obstacle preventing clinical applications of HDAd vectors is the host innate inflammatory response against the vector capsid proteins that occurs shortly after intravascular vector administration and result in acute toxicity, the severity of which is dose dependent. Intense efforts have been focused on elucidating adenoviral vector–host interactions and the factors involved in the acute toxicity. This review focuses on the recent acquisition of data on such interactions and on strategies investigated to improve the therapeutic index of HDAd vectors.04/2014; 2(2):132-148. DOI:10.3390/biomedicines2020132
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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.Human Gene Therapy Methods 08/2013; DOI:10.1089/hgtb.2013.108 · 1.64 Impact Factor
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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.Human Gene Therapy Methods 03/2014; DOI:10.1089/hgtb.2013.236 · 1.64 Impact Factor