Somatic gene therapy for phenylketonuria and other hepatic deficiencies

Summary Gene therapy is the delivery of genetic material to specific cell types of an organism to alter its physiology or function. This technology is being explored as a means of treating diseases caused by deficiencies of hepatic gene products. The two diseases being used as models for hepatic gene therapy are classical phenylketonuria (PKU) and haemophilia B. Vectors derived from adenoviruses can be used to completely correct these diseases in animal models. The phenotypic correction generated in these studies is transient, and cannot be duplicated by vector readministration. The transient nature of transgene expression results from the destruction of the virally-transduced cells by a cellular immune response directed against the late viral gene products that are also expressed in the target cells. The inability to repeatedly administer virus is caused by a humoral immune response directed against viral proteins present at the time of infusion. If the host immune response is suppressed, transgene expression can persist for 6 months or more. These findings suggest that host immunomodulation in combination with further modification of the adenoviral vector to reduce or eliminate late viral gene expression may permit long-term expression of potentially therapeutic gene products in mammalian liver.