Retroviral vectors for liver-directed gene therapy

Retroviruses are popular gene therapy vectors because they stably integrate the DNA copy of their genome into the host chromosome during their replica tion cycle. The widely used murine retroviral vector systems have two compo nents: the transfer vector for the transgene carries all the cis-acting ele ments necessary for the replication and efficient integration of the viral DNA; and the packaging cell line produces all the trans-acting proteins nec essary for both structural and catalytic functions of the virus. Advances i n design of retroviral vectors have re suited in greater degree of biosafet y, expanded host range, and increased stability of the virus particles. Ret roviral vectors have been widely used in the ex vivo gene therapy protocols to correct the liver diseases in a wide variety of species. In a limited n umber of applications, in vivo gene therapy has been achieved after the liv er cells have been stimulated to regenerate. One major limitation of murine retroviral vectors is their inability to infect nondividing cells. This pr oblem has been overcome by deriving vectors from lentiviruses (a class of r etroviruses) that have the ability to infect both dividing and nondividing cells. The lentiviral vectors are derived from human immunodeficiency virus type 1 (HIV-1). Initial studies using lentiviral vectors for gene delivery to the liver in vivo show promising results. A highly crippled version of lentivirus has been generated by using producer cells in which the trans-ac ting components are expressed by several different coding elements and vect ors that incorporate features of self-inactivation. These improvements shou ld ensure biosafety of lentiviruses and make them useful in efficient deliv ery of therapeutic genes to nondividing differentiated tissues such as the liver.