Drug – bio-affecting and body treating compositions – Whole live micro-organism – cell – or virus containing – Genetically modified micro-organism – cell – or virus
Reexamination Certificate
2001-11-01
2004-09-21
Guzo, David (Department: 1636)
Drug, bio-affecting and body treating compositions
Whole live micro-organism, cell, or virus containing
Genetically modified micro-organism, cell, or virus
C435S456000, C435S320100, C536S023100
Reexamination Certificate
active
06793918
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates generally to gene therapy, more specifically, to virus-mediated and other forms of gene therapy. More particularly, the invention relates to adenovirus-mediated delivery of genes useful in the promotion of angiogenesis.
Angiogenesis is the formation of new capillary blood vessels by a process of sprouting from pre-existing vessels, and occurs during development as well as in a number of physiological and pathological processes. Angiogenesis is a physiologically complex process involving proliferation of endothelial cells, degradation of extracellular matrix, branching of vessels and subsequent cell adhesion events. In the adult, angiogenesis is tightly controlled and limited under normal circumstances to the female reproductive system. Angiogenesis can, however, be switched on in response to tissue damage. Solid tumors are also able to induce angiogenesis in surrounding tissue, thus sustaining tumor growth and facilitating the formation of metastases (Folkman, J., Nature Med. 1:27-31, (1995)). The molecular mechanisms underlying the complex angiogenic processes are far from being understood. A similar although far less well studied process also occurs in the lymphatic system, and is sometimes referred to as lymphangiogenesis.
Angiogenesis begins with localized breakdown of the basement membrane of the parent vessel, which is followed by the migration and outgrowth of endothelial cells into the surrounding extracellular matrix, resulting in the formation of a capillary sprout. A lumen is subsequently formed, and constitutes an essential element in functional sprout formation. Sprout maturation is completed after reconstitution of the basement membrane.
Alterations in at least three endothelial cell functions occur during this series of events: 1) modulation of interactions with the extracellular matrix, which requires alterations in cell-matrix contacts and the production of matrix-degrading proteolytic enzymes (plasminogen activators (PAs) and matrix metalloproteinases); 2) an initial increase and subsequent decrease in locomotion (migration), which allows the cells to translocate towards the angiogenic stimulus and to stop once they reach their destination; 3) an increase in proliferation, which provides new cells for the growing and elongating vessel, and a subsequent return to the quiescent state once the vessel is formed.
Together, these cellular functions contribute to the process of capillary morphogenesis, i.e. the formation of three-dimensional patent or open tube-like structures. Many newly formed capillaries subsequently undergo a process of vessel wall maturation (i.e. formation of a smooth muscle cell-rich media and an adventitia, while others undergo regression (i.e. in the absence of blood flow) [see Pepper et al.,
Enzyme Protein,
49:138-162 (1996); Risau,
Nature
386:671-674 (1997)].
With the exception of angiogenesis which occurs in response to tissue injury or in female reproductive organs, endothelial cell turnover in the healthy adult organism is very low. The maintenance of endothelial quiescence is thought to be due to the presence of endogenous negative regulators, since positive regulators are frequently detected in adult tissues in which there is apparently no angiogenesis. The converse is also true, namely that positive and negative regulators often co-exist in tissues in which endothelial cell turnover is increased. This has lead to the notion of the “angiogenic switch”, in which endothelial activation status is determined by a balance between positive and negative regulators.
In activated (angiogenic) endothelium, positive regulators predominate, whereas endothelial quiescence is achieved and maintained by the dominance of negative regulators [Hanahan et al.,
Cell,
86:353-364 (1996)]. Used initially in the context of tumor progression to describe the passage from the prevascular to the vascular phase, the notion of the “switch” can also be applied in the context of developmental, physiological as well as pathological angiogenesis. Although it still remains to be definitively demonstrated in vivo, the current working hypothesis is that the “switch” involves the induction of a positive regulator and/or the loss of a negative regulator.
Because of the crucial role of angiogenesis in so many physiological and pathological processes, factors involved in the control of angiogenesis have been intensively investigated. A number of growth factors have been shown to be involved in the regulation of angiogenesis; these include fibroblast growth factors (FGFs), platelet-derived growth factors (PDGFs), transforming growth factor alpha (TGF-alpha), and hepatocyte growth factor (HGF). See for example Folkman et al.,
J. Biol. Chem.,
267:10931-10934 (1992) for a review.
It has been suggested that a particular family of endothelial cell-specific growth factors, the vascular endothelial growth factors (VEGFs), and their corresponding receptors is primarily responsible for stimulation of endothelial cell growth and differentiation, and for certain functions of the differentiated cells. These factors are members of the PDGF/VEGF family, and appear to act primarily via endothelial receptor tyrosine kinases (RTKs). The PDGF/VEGF family of growth factors belongs to the cystine-knot superfamily of growth factors, which also includes the neurotrophins and transforming growth factor-&bgr;.
Eight different proteins have been identified in the PDGF/VEGF family, namely two PDGFs (A and B), VEGF-A and five members that are closely related to VEGF-A. The five members closely related to VEGF-A are: VEGF-B, described in International Patent Application PCT/US96/02957 (WO 96/26736) and in U.S. Pat. Nos. 5,840,693 and 5,607,918 by Ludwig Institute for Cancer Research and The University of Helsinki; VEGF-C or VEGF2, described in Joukov et al.,
EMBO J.
15:290-298 (1996), Lee et al.,
Proc. Natl. Acad. Sci. USA
93:1988-1992 (1996), and U.S. Pat. Nos. 5,932,540 and 5,935,540 by Human Genome Sciences, Inc; VEGF-D, described in International Patent Application No. PCT/US97/14696 (WO 98/07832), and Achen et al.,
Proc. Natl. Acad. Sci. USA
95:548-553 (1998); the placenta growth factor (PlGF), described in Maglione et al.,
Proc. Natl. Acad. Sci. USA
88:9267-9271 (1991); and VEGF3, described in International Patent Application No. PCT/US95/07283 (WO 96/39421) by Human Genome Sciences, Inc.
Each VEGF family member has between 30% and 45% amino acid sequence identity with VEGF-A in their VEGF homology domain (VHD). This VHD contains the eight conserved cysteine residues which form the cystine-knot motif. In their active, physiological state, the proteins are dimers. Functional characteristics of the VEGF family include varying degrees of mitogenicity for endothelial cells and related cell types, induction of vascular permeability and angiogenic and lymphangiogenic properties.
Vascular endothelial growth factor (VEGF-A) is a homodimeric glycoprotein that has been isolated from several sources. VEGF-A shows highly specific mitogenic activity for endothelial cells. VEGF-A has important regulatory functions in the formation of new blood vessels during embryonic vasculogenesis and in angiogenesis during adult life (Carmeliet et al.,
Nature,
380: 435-439, (1996); Ferrara et al.,
Nature,
380: 439-442, (1996); reviewed in Ferrara and Davis-Smyth,
Endocrine Rev.,
18: 4-25, (1997)). The significance of the role played by VEGF-A has been demonstrated in studies showing that inactivation of a single VEGF-A allele results in embryonic lethality due to failed development of the vasculature (Carmeliet et al.,
Nature,
380: 435-439, (1996); Ferrara et al.,
Nature,
380: 439-442, (1996)). The isolation and properties of VEGF-A have been reviewed; see Ferrara et al.,
J. Cellular Biochem.,
47: 211-218, (1991) and Connolly,
J. Cellular Biochem.,
47:219-223, (1991).
In addition VEGF-A has strong chemoattractant activity towards monocytes, can induce the plasminogen activator and the plasminogen activator inhibitor
Alitalo Kari
Bergsten Erika
Branellec Didier
Enholm Berndt
Eriksson Ulf
Guzo David
Ludwig Institute for Cancer Research
Nguyen Quang
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