Compositions and Methods for Tissue Specific Targeting

Inventors: Inder Verma, Brian Spencer, Robert Marr
Potential Uses: Lentiviral vectors, Gene Therapy
Lentiviral targeting vectors capable of being targeted to any desired cell or tissue that contains an identifying cell surface marker.

Therapies for certain diseases will require gene delivery to a specific tissue or organ, e.g. diabetes (pancreas), cystic fibrosis (lung), hemophilia (liver or hematopoetic stem cells), hypercholesteremia (liver). Although tissue specific promoters can be used to restrict expression of the gene to a tissue, many of these promoters appear to allow limited gene expression in other tissues while others restrict gene expression to a short time frame after gene delivery. Furthermore, many tissues and cells will still be infected with the virus if the transgene is not expressed. Salk scientists have developed a novel approach to selectively and rationally target the lentiviral vector to tissues or organs based on receptor expression. This invention is directed to lentiviral targeting vectors that are capable of being targeted to essentially any desired cell or tissue that contains an identifying cell surface marker. These lentiviral vectors separate the cell binding and attachment functions from the membrane fusion functions of a lentiviral envelope polypeptide. Accordingly, the vectors are advantageous in that the infection specificity and the transduction activities constitute modular components of the viral vector. By separating these activities into targeting and fusogenic polypeptides, the inherent constraints associated with linked activities when modification is necessary or desired are circumvented because each activity can be separately manipulated. This approach may be useful for directing gene therapy treatment to specific tissues and organs. In addition, gene delivery to the whole brain to treat global neuronal degenerative disorders could best be accomplished by targeting the viral vector for transport across the blood brain barrier and thus widespread distribution over the whole brain.