Improved efficacy and reduced toxicity by ultrasound-guided intrahepatic injections of helper-dependent adenoviral vector in Gunn rats
Abstract
Crigler-Najjar syndrome type I is caused by mutations of the uridine diphospho-glucuronosy] transferase lAI (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 cxpressing UGT1A1 in the Gunn rat, the animal model of Crigler-Najjar syndrome.
I lowever, 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 ultrasound-guided percutaneous injections were compared with the same doses given by intravenous injections. A greater reduction of hyperbilirubinemia and inereased conjugated bilirubin in hile were achieved with 1 x 1011 vp/kg by direct liver injections compared with intravenous injections In sharp contrasl to intravenous injections, direct hepatic injections neither raised serum IL-6 nor resulted in thrombocytopenia.
In eonclusion, ultrasound-guided percutaneous injection of HDAd vectors into liver parenchyma resulted in im proved hepatocyte transduction and reduced toxicity compared with systemic injections and is clinically at tractive for liver-directed gene therapy of Crigler-Najjar syndrome.