Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
2000-10-05
2003-11-18
Yucel, Remy (Department: 1636)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S021800, C514S899000, C530S350000
Reexamination Certificate
active
06649588
ABSTRACT:
BACKGROUND OF THE INVENTION
Transforming growth factor-beta (TGF-&bgr;) is a pleiotropic peptide that controls proliferation and differentiation of many cell types, and modulates the coagulation process. Many cells synthesize TGF-&bgr;, and almost all of them have specific receptors for this peptide.
The activities of TGF-&bgr; are well documented. TGF-&bgr; inhibits the growth of epithelial cells (Böttinger et al., 1997; Hall et al., 1996; Kornmann, 1999; Morton and Barrack, 1995; and Mur et al., 1998), but promotes the proliferation of fibroblasts (Bettinger et al., 1996; Clark et al., 1997; and Franzen and Dahlquist, 1994) and the deposition of collagen (Bettinger et al., 1996; and Han, 1999). In particular, TGF-p has been implicated in various forms of fibrosis, including: normal wound healing and scar formation (Choi et al., 1996; Lin et al., 1995; Liu et al., 1995; Messadi, 1998; O'Kane and Ferguson, 1997; and Stelnicki et al., 1998); the formation of keloid (Lee, 1999; Tredget et al., 1998; Younai et al., 1994; and Zhang et al., 1995); radiation-induced fibrosis (Randall and Coggle, 1996); fibromatosis (Berndt et al., 1995; and Zamora et al., 1994); hypertrophic burn scars (Polo et al., 1997; and Zhang et al., 1995); pulmonary fibrosis (Khalil et al., 1996; Martinet et al., 1996; Specks et al., 1995; Vaillant et al., 1996; and Yoshida and Hayashi, 1996), including that associated with radiation (Yi et al., 1996), drugs (Coker et al., 1997; and Zhang et al., 1996), and transplantation (El-Gamel et al., 1998); the healing of the myocardial infarct (Hao et al., 1999); fibrosis associated with autoimmune disorders such as scieroderma (Querfeld et al., 1999); and sarcoidosis (Salez et al., 1998).
In view of the wide-ranging activities of TGF-&bgr;, it is clear that overactivity of TGF-&bgr; is implicated in the conditions of fibrosis, defects in cell proliferation, and coagulation defects. Thus, a factor which inhibits the activity of TGF-&bgr; would be extremely useful in treating those conditions associated with the overactivity of TGF-&bgr;. However, there are currently no known effective inhibitors of TGF-&bgr;.
Recently, a new member of the TGF-&bgr; superfamily, lefty-1, was recognized for its distinct asymmetric expression in gastrulating mouse embryos (Meno et al., 1996; and Oulad-Abdelghani et al., 1998). Lefty-A is the human homologue of lefty-1. Lefty-A is also known as endometrial bleeding associated factor (ebaf) protein, which is associated with abnormal endometrial bleeding (Kothapalli et al. (1997).
The ebaf gene is located on human chromosome 1, at band q42.1, and its nucleotide and deduced amino acid sequences are known. Ebaf is highly expressed in human endometrium prior to and during menstrual bleeding or abnormal uterine bleeding (Kothapalli et al., 1997). The ebaf gene is also expressed in certain adenocarcinomas that exhibit mucinous differentiation, including colonic, duodenal, ovarian, and testicular carcinomas (Tabibzadeh et al., 1997). The amino acid sequence of the ebaf protein shows homology with, and structural features of, members of the TGF-&bgr; superfamily (Kothapalli et al., 1997), and ebaf is also recognized as a member of the TGF-&bgr; superfamily.
In view of the similarity in the nucleotide sequences of lefty-1 and ebaf, Kosaki et al. (1999) hypothesized, and subsequently showed, that mutations in the ebaf gene are associated with left-right axis malformations in humans. During the course of this investigation, a second human gene, lefty-B, was identified. In mice, both the lefty-1 gene and the lefty-2 gene reside on chromosome 1H2. In humans, both the lefty-A (ebaf) gene and the lefty-B gene map to human syntenic region 1q42, and are separated from each other by 50 kb. The nucleotide sequences of lefty-A (ebaf) and lefty-B are 97% identical, so these proteins are more closely related to each other than to either of the mouse homologues.
Human ebaf proteins are derived from a precursor with an approximate molecular weight of 42 kD. Polypeptides with approximate molecular weights of 34 kD and 28 kD are secreted by cells, along with the precursor. RGKR and RHGR are the cleavage sites, respectively, for the 34-kD and 28-kD protein forms. Lefty proteins are secreted in glycosylated form.
SUMMARY OF THE INVENTION
The present invention is based upon the discovery that ebaf inhibits activity of TGF-&bgr;. On the basis of this finding, the present invention provides a method for inhibiting activity of TGF-&bgr;, comprising contacting tissue expressing TGF-&bgr; with an amount of ebaf or an ebaf analogue effective to inhibit the activity of TGF-&bgr;.
The present invention further provides a method for treating a condition associated with overactivity of TGF-&bgr; in a subject in need of treatment, comprising contacting tissue expressing TGF-&bgr; in the subject with an amount of ebaf or an ebaf analogue effective to inhibit activity of TGF-&bgr;, thereby treating the condition.
The present invention also discloses a method for inhibiting activity of TGF-&bgr;, comprising contacting tissue expressing TGF-&bgr; with a modulator of ebaf expression, or a modulator of expression of an ebaf analogue, in an amount effective to induce or enhance expression of ebaf or the ebaf analogue, thereby inhibiting the activity of TGF-&bgr;.
The present invention is further directed to a method for treating fibrosis in a subject in need of treatment, comprising administering to the subject an amount of ebaf or an ebaf analogue effective to treat the fibrosis.
Finally, the present invention provides a method for treating a defect in cell proliferation in a subject in need of treatment, comprising administering to the subject an amount of ebaf or an ebaf analogue effective to treat the defect in cell proliferation.
Additional objects of the present invention will be apparent in view of the description which follows.
REFERENCES:
patent: 5821227 (1998-10-01), Dennis et al.
patent: 5916751 (1999-06-01), Tabibzadeh et al.
Crystal, transfer of genes to humans: early lessons and obstacles to success, 1995, SCIENCE, vol. 270, pp. 404-409.*
Giorgio Palu et al. In pursuit of new developments for gene therapy of human diseases Journal of Biotechnolgy 68 1999 1-13.*
Tabibzadeh, S., et al., Dysregulated Expression of ebaf, a Novel Molecular Defect in the Endometria of Patients with Infertility, The Journal of Clinical Endocrinology & Metabolism, 2000, vol. 85, No. 7, pp. 2526-2536.
Mason James M.
Tabibzadeh Siamak
Amster Rothstein & Ebenstein LLP
Katcheves Konstantina
North Shore - Long Island Jewish Research Institute
Yucel Remy
LandOfFree
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