Inhibition of an FGF-binding protein using ribozymes

Details Inhibition of an FGF-binding protein using ribozymes Inhibition of an FGF-binding protein using ribozymes

1998-09-25

2001-06-12

Schwartzman, Robert A. (Department: 1635)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C435S006120, C435S091310, C435S325000, C435S375000, C536S023100, C536S023200, C536S024500

Reexamination Certificate

active

06245748

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to use of ribozymes for inhibition of fibroblast growth factor binding protein (FGF-BP). The increase of FGF-BP is accompanied by various pathological changes, including the disease phenomena seen in autoimmune disease, e.g., multiple sclerosis and in growth and metastatic spread of cancer.
BACKGROUND OF THE INVENTION
Fibroblast growth factor (FGF) is a potentially active growth factor found in large amounts in the nervous system and, to a somewhat lesser extent, in the rest of the body. Because of the blood-brain barrier, the two reservoirs, including the components such as the FGF and FGF-binding protein, remain separated. However, in certain instances of infection or trauma there is cross-over between the two reservoirs.
Tumor growth and, ultimately, metastasis is a complex process regulated in part by factors controlling cellular proliferation and death as well as tumor angiogenesis. The driving factors which regulate angiogenesis and tumor growth need to be understood to control the process of growth in malignancies. It is known that tumor cells and their normal stroma express a multitude of candidate angiogenic factors. Very few specific inhibitors have been generated to assess which of these gene products are only innocent bystanders and which contribute significantly to tumor angiogenesis and metastasis.
Developmental expression of the retinoid-regulated FGF-BP gene is prominent in the skin and intestine during the perinatal phase and is down-modulated in the adult. The gene is, however, up-regulated in various cancers such as carcinogen-induced skin tumor, in squamous cell carcinoma, in breast cancers and in some colon cancer cell lines and tumor samples. FGF-BP is also up-regulated in autoimmune responses of the nervous system such as in the case of multiple sclerosis.
Tumor-angiogenesis, a process whereby factors stimulating the ingrowth of blood vessels into the tumor are secreted into the local tumor milieu by cancer and stroma cells, also plays a critical role by regulating the balance between cell proliferation and cell death and by providing a route for distant spread. Both clinical and laboratory evidence suggest that spread of malignant cells from a localized tumor is directly related to the number of microvessels in the primary tumor. Of the multitude of factors secreted by tumor and stroma cells which are potentially angiogenic, two have been confirmed as angiogenic factors which are rate-limiting in in vivo tumor models. The importance of one of these, vascular endothelial growth factor/vascular permeability factors (VEGF/VPF), was previously demonstrated through functional knockout through use of blocking antibodies. A critical role for the other factor, pleotrophin (PTN), has been shown in angiogenesis and metastasis associated with melanoma using a hammerhead-ribozyme PTN mRNA depletion strategy.
SUMMARY OF THE INVENTION
It has now been discovered that increased expression of a secreted FGF-binding protein (FGF-BP) occurs in certain autoimmune and malignant disease conditions. It is found, for example, that tumor secretions of FGF-BP results in mobilization and activation of locally-stored FGFs that can serve as an angiogenic switch molecule. Furthermore, it has been found that in an animal model of multiple sclerosis (MS), the exacerbation of the disease is accompanied by increased FGF-BP. Using ribozymes, it is possible to cause cleavage of the FGF-BP mRNA. Hence, administration of ribozymes which cleave the FGF-BP mRNA in sufficient amounts to inhibit disease processes triggered by FGF-BP is appropriate.


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