Endothelial cell tropic compositions and methods of making and u

Details Endothelial cell tropic compositions and methods of making and u Endothelial cell tropic compositions and methods of making and u

1996-05-30

1998-04-07

Zitomer, Stephanie W.

Chemistry: molecular biology and microbiology

Micro-organism, tissue cell culture or enzyme using process...

Recombinant dna technique included in method of making a...

4351723, 4353201, C12P 2102, C12P 1563, C12P 1585

Patent

active

057363609

DESCRIPTION:

BRIEF SUMMARY
FIELD OF THE INVENTION

The present invention relates to genetic regulatory sequences that direct vessel endothelial cell specific expression of genes, chimeric genes comprising the regulatory sequence linked to coding sequences and to methods of producing proteins in endothelial cells using the chimeric genes.


BACKGROUND OF THE INVENTION

Advances in molecular biology over the past few decades have created new technologies for combating human disease. In particular, the transduction of foreign genes into somatic cells, or gene therapy, has shown great promise as a powerful clinical tool. Gene therapy has been used experimentally to correct disorders such as ADA deficiency and new trials are underway for treating other genetic diseases such as cystic fibrosis and muscular dystrophy. Most gene therapy studies to date have focused on correcting single gene defects by introducing the wild type gene into somatic cells. The product of the newly transduced gene then restores the normal phenotype. Other recent application include targeting tumor cells with neo-antigens for enhanced recognition by the immune system. Additionally, biologically active proteins may be delivered to an individual by the introduction and expression of foreign genes encoding such proteins.
Many studies have used bone marrow or bone marrow derived cells as targets for gene therapy. However, there has been a recent surge of interest in using other cell types, particularly endothelial cells. Endothelial cells represent an ideal target for gene therapy in many diseases. Endothelial cells are particularly useful in the treatment of hematological and vascular disorders as well as any disease that requires the systemic deliver of therapeutic factors.
Broader applicability of gene therapy has been hindered due to technical limitations. Most studies thus performed have been so using infected tissue ex vivo and then reconstituting the host with the genetically altered cells. While this practice is acceptable for tissues that can be harvested and re-implanted with relative ease, many desired target cells do not fall into this category. For this reason, the search for and/or creation of vectors that are expressed by specific tissues is an area of intense research interest. There is a need for regulatory elements which can be used to direct expression of foreign genes and endothelial cells. There is a need to create tissue specific vectors for in vivo gene therapy. There is a need to provide gene therapy constructs with regulatory elements that will direct tissue specific expression of the foreign genes.


SUMMARY OF THE INVENTION

The present invention relates to isolated nucleic acid molecules that comprise a modified Murine Leukemia Virus Long Terminal Repeat which comprises SEQ ID NO:4. In some embodiments, such nucleic acid molecules may comprise SEQ ID NO:3, SEQ ID NO:2 or SEQ ID NO:1.
The present invention relates to isolated nucleic acid molecules that comprise a modified Murine Leukemia Virus Long Terminal Repeat which comprises SEQ ID NO:4 and is operably linked to a nucleotide sequence that encodes a non-Murine Leukemia Virus. In some embodiments, such nucleic acid molecules may comprise SEQ ID NO:3, SEQ ID NO:2 or SEQ ID NO:1. In some embodiments, the non-Murine Leukemia Virus protein is a human protein, such as for example Factor VII protein, Factor IX protein, von Willdebrand factor, complement proteins, insulin, cytokines, tissue plasminogen activator, alpha-L-iduronidase, iduronate sulfatase, heparin, N-sulfatase and alpha 1 antitrypsin.
The present invention relates to isolated nucleic acid molecules that comprise a modified Murine Leukemia Virus Long Terminal Repeat which: a) comprises SEQ ID NO:4, SEQ ID NO:3, SEQ ID NO:2 or SEQ ID NO:1; b) is operably linked to a nucleotide sequence that encodes a non-Murine Leukemia Virus and c) is encapsulated within a liposome or a viral coat. The viral coat may be that of an infectious, replicating viral particle such as a retrovirus or a viral coat of an infectious, non-replicating viral pa

REFERENCES:
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