Neonatal intravenous injection of a gammaretroviral vector has a low incidence of tumor induction in mice.

Neonatal intravenous injection of gammaretroviral vectors (gamma-RVs) with an intact long terminal repeat (LTR) and an internal liver promoter can result in long-term expression in liver cells and correction of mucopolysaccharidosis. Some expression also occurs in blood cells and brain, which likely derives from the LTR, and may contribute to clinical efficacy. The goal of this project was to determine whether neonatal gene therapy with an LTR-intact gamma-RV would induce tumors in mice. Fifty-one normal newborn C57BL/6 mice were injected intravenously at 10(10) transducing units/kg with a gamma-RV expressing canine beta-glucuronidase (GUSB) cDNA. This resulted in transduction of 23 +/- 9% of hepatocytes as determined by histochemical staining, and 0.24 +/- 0.20 copy of gamma-RV DNA per cell in liver as determined by real-time polymerase chain reaction. Serum GUSB activity was stable for 1.75 years after transduction at 705 +/- 119 units/ml. Ninety-six percent of mice survived for the duration of evaluation, which was similar to the survival rate for 65 control mice that were not injected with gamma-RV. One gamma-RV-treated mouse (2%) developed a small (diameter, 2 mm) liver adenoma, which was similar to the frequency of liver adenomas (2%) or hepatocellular carcinoma (2%) in untreated mice. Although 22% of gamma-RV-treated mice developed hematopoietic tumors, none contained high gamma-RV DNA copy numbers, and the frequency was similar to that in the control group (22%). We conclude that neonatal intravenous injection of an LTR-intact gamma-RV does not have a high risk of inducing cancer in mice.