The Salk Institute for Biological Studies

Inder M Verma

Ronald M Wisdom

Jong-Young J Yen

Brian Spencer

Frederic D Bushman

Mark R Hansen

Robert Marr

Philippe A Gallay

Tal Kafri

Daniel Claude St Louis

Luigi Naldini

Mark Schmitt

Didier Trono

Nikunj V Somia

Keith A Cauley

This disclosure provides lentiviral vectors containing an attachment incompetent fusogenic polypeptide and a heterologous targeting polypeptide. Also provided are lentiviral packaging constructs, lentiviral packaging systems, and lentiviral gene delivery systems. Finally, methods of transducing a cell and methods of targeting a gene to a cell or tissue using the disclosed lentiviral vectors and systems are also provided.

Compositions and methods for tissue specific targeting of lentivirus vectors

The present invention is a somatic cell gene therapy method that is especially useful for the treatment of certain diseases that are caused by gene defects. According to the invention, fibroblast cells are transduced so that they express a &ldquo;replacement&rdquo; gene of interest. These transduced fibroblasts are preferably fixed in vitro in an extracellular matrix, and then implanted in the loose connective tissue of the skin of an individual or animal to be treated. Because the fibroblasts are implanted in a highly vascularized compartment of the skin i.e., loose connective tissue of the dermis, the transduced cells, and thus their &ldquo;replacement&rdquo; gene products, have direct access to the circulatory system. As a result the needed replacement gene products can easily and efficiently be distributed to other parts of the body. When the gene therapy is no longer needed, the implanted fibroblasts can be conveniently removed.

Somatic cell gene therapy

A substantially purified lifeguard (LFG) polypeptide is provided. The polypeptide includes an amino acid sequence as set forth in SEQ ID NO:2, or a conservative variant thereof. An isolated polynucleotide is provided that encodes an amino acid sequence as set forth in SEQ ID NO:2, or a conservative variant thereof. An antibody is provided that binds to a polypeptide having an amino acid sequence as set forth in SEQ ID NO:2. A method is provided for identifying a compound which affects a function a polypeptide as set forth in SEQ ID NO:2, or a conservative variant thereof, or affects the expression of a polynucleotide comprising a sequence as set forth in SEQ ID NO:1. A method is provided for treating a subject with a disorder associated with decreased or increased Fas-mediated cell death. A method is provided for treating a patient having or at risk of having a disorder associated with increased Fas-mediated cell death.

Lifeguard (LFG) polynucleotides and polypeptides and methods of use thereof

In accordance with the present invention, there is provided a novel analytical method for identifying compounds which induce and/or inhibit signal transduction in cells. The invention method enables rapid testing of a variety of compounds to determine if they exert an influence on signal transduction. The invention assay can be carried out using unmodified cells and/or cell lines, avoiding the need for extensive preparation prior to analysis.

Functional assays for the identification of ligands which modulate signal transduction

The present invention provides packaging cell lines and recombinant lentiviral or retroviral particles produced therefrom, particularly pseudotyped retroviral particles. The packaging cell lines of the invention are produced by inducibly expressing an envelope protein by methods described herein. Also described is a screening assay for compounds that affect integration of viral nucleic acid into target (e.g., host) nucleic acid. Such compounds are identified based on their effect on viral integrase.

Retroviral packaging cell line

A recombinant retrovirus capable of infecting a non-dividing cell and a method of producing such a virus is provided. The recombinant retrovirus is preferably of lentivirus origin and is useful for the treatment of a variety of disorders including neurological disorders and disorders of other non-dividing cells.

Vector and method of use for nucleic acid delivery to non-dividing cells

The present invention provides a transrepressing protein of the Fos proto-oncogene family. The protein, FosB2, is characterized by having a leucine zipper domain and forming a heterodimer with a Jun related protein. This heterodimer is capable of binding to an AP-1 site and suppressing transcriptional transactivation of a promoter containing the AP-1 site.

Transdominant negative proto-oncogene

The present invention provides polynucleotide and polypeptide sequences for a trans-repressing protein of the Fos proto-oncogene family, where the polypeptide is characterized by having a leucine zipper domain and forming a heterodimer with a Jun related protein. This heterodimer is capable of biding to an AP-1 site and suppressing transcriptional transactivation of a promoter containing the AP-1 site.

Growing community of inventors

Solana Beach, CA, United States of America

Inder M Verma