Drug – bio-affecting and body treating compositions – Ophthalmic
Reexamination Certificate
1999-06-25
2001-07-10
Aulakh, Charanjit S. (Department: 1625)
Drug, bio-affecting and body treating compositions
Ophthalmic
C424S427000, C424S424000, C424S422000, C514S730000, C514S680000, C514S453000, C514S449000, C514S312000, C514S279000
Reexamination Certificate
active
06258856
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a method for preventing or controlling pathological changes which occur in association with cataract formation in the mammalian eye by protecting lens cells against the cataractogenic effects of transforming growth factor-&bgr; (TGF&bgr;). In particular, the present invention relates to a method for preventing or controlling TGF&bgr;-induced cataract formation in the mammalian eye by administering an estrogen or estrogenic substance to the mammal.
BACKGROUND ART
Cataract is an opacity of the lens that interferes with vision. It is one of the most common of eye diseases and, though it may occur at any time in life, it often accompanies aging. In the USA, for example, up to 45% of people aged between 74 and 89 years suffer from cataract. Predisposing factors include aging, diabetes, UV/sunlight, ocular surgery and malnutrition. Cataracts are most frequently classified according to the location of the lens opacity: nuclear, cortical, posterior subcapsular or anterior subcapsular (Tripathi and Tripathi, 1983). Currently, the most commonly used treatment for cataract is surgical removal of the lens cells and subsequent implantation of a synthetic replacement lens within the remaining lens capsule. However, implantation of a synthetic lens may only temporarily restore vision because residual cells associated with the lens capsule often grow to form new opacities. The latter condition is a form of cataract known as aftercataract and also known as posterior capsule opacification (Green and McDonnell, 1985; Kappelhof and Vrensen, 1992).
The inventors have previously shown that TGF&bgr; is cataractogenic. The inventors have also shown that the TGF&bgr;-induced changes to lens cells can be inhibited or prevented by reducing or inhibiting the action of TGF&bgr;, such as by administering an effective amount of one or more inhibitors of TGF&bgr;. This was disclosed in PCT/AU94/00694, the entire specification of which is incorporated into this patent specification by reference.
The inventors' previous work has shown that TGF&bgr; induces certain changes known to be associated with cataract, including anterior and posterior subcapsular cataract and aftercataract. These changes have been shown in rat lens explants cultured with TGF&bgr; and include accumulation of extracellular matrix, formation of spindle-shaped cells, capsule wrinkling and cell death with features of apoptosis (Liu et al., 1994; Hales et al., 1994). Further evidence of TGF&bgr; involvement in anterior subcapsular cataract formation comes from whole rat lens studies which show that TGF&bgr; induces anterior opacities that coincide with subcapsular plaques containing molecular markers for cataract, &agr;-smooth muscle actin and collagen type I (Hales et al., 1995). These proteins are not normally found in the lens but are present in certain forms of cataract in humans. The other changes discussed above are known to be associated with certain forms of cataract in humans. Further evidence of TGF&bgr; involvement in posterior subcapsular cataract and cortical cataract formation comes from studies described in Examples 1 and 3.
Sex-dependent and female sex hormone-related differences in susceptibility to cataract formation have been noted in epidemiological studies. While the prevalence and severity of cataract increases with aging in both men and women, a more marked increase occurs in women than in men later in life, over the time period when serum levels of sex hormones are low in women (Klein et al., 1992). Furthermore, early age at menarche or delayed menopause seems to protect against certain forms of cataract (Klein, 1993). Such studies do not provide evidence that the sex-(or sex hormone-) related protective effect observed is due to estrogen. In addition, researchers have reported the prevalence and severity of nuclear, cortical and posterior subcapsular cataracts in postmenopausal women on hormone replacement therapy, involving administration of pharmaceutical products containing ‘estrogen’ with or without ‘progesterone’, and in others not undergoing hormone replacement therapy (Klein, 1993). A statistically significant difference between these two groups of women was found for nuclear cataract only, and it is not clear whether the observed effect of hormone replacement therapy was due to estrogen. To date there is no evidence that estrogen per se has a protective effect against forms of cataract induced by TGF&bgr; or that a TGF&bgr;-linked process is involved in protecting individuals against cataract in such studies.
Some animal studies, however, teach that estrogen causes cataract or cataract-like changes in the lens. Progesterones and estrogens in vitro have been noted to lead to an increase in ion permeability which is accompanied by loss of clarity in cultured lenses (Lambert, 1968). It has also been reported that intramuscular injection of estrogen causes changes in the lens epithelium resulting in atrophy which may be a factor in the development of lenticular opacity (Bisaria, 1980).
Starka et al. (1976) have reported detecting estrogens in the ocular media in female and male rabbits but it is not clear what levels of active hormone are present.
According to published scientific literature, the effect of estrogen on the biological activity of TGF&bgr; is variable. Estrogens have been known to enhance the biological activity of TGF&bgr;. For example, 17-&bgr;-estradiol has been reported to stimulate release of active TGF&bgr; when added to cultures of rat granulosa cells (Dorrington et al., 1993). In addition, Herman et al. (1994) report an enhancing effect of estrogen on TGF&bgr; activity by showing that removing estrogen from the medium of cultured human breast cancer cells reduces their sensitivity to the growth-inhibitory effects of TGF&bgr;. Estrogens are also known to have a suppressive effect on TGF&bgr; activity or no effect. For example, estrogen-induced tumorigenesis in the anterior pituitary of rats is accompanied by a loss of sensitivity to TGF&bgr;1 (Pastorcic et al., 1995), and estradiol does not specifically block the growth-inhibitory effects of TGF&bgr; in hepatocyte cultures, although the cells are otherwise responsive to estradiol (Ni and Yager, 1994). Similarly, in studies on the expression of TGF&bgr; mRNA and protein rather than TGF&bgr; biological activity, no consistent trend is apparent i.e. estrogen may upregulate, downregulate or have no effect on TGF&bgr; expression depending on both the cell type and the TGF&bgr; isoform involved.
Many postmenopausal women are now receiving estrogen replacement therapy, in conjunction with progesterone where appropriate, but it is not universally advocated or available. In 1994, it was reported that only 5 to 10% of menopausal women in the USA were receiving this treatment (Griffing and Allen, 1994).
The TGF&bgr; family consists of a group of related proteins; TGF&bgr;1, TGF&bgr;2 and TGF&bgr;3 are the isoforms found in mammals. Mature TGF&bgr; in its biologically active form is a 25 kDa dimer that is cleaved from a latent precursor molecule (Kingsley et al., 1994).
DISCLOSURE OF THE INVENTION
In one aspect, the present invention provides a method of preventing or controlling TGF&bgr;-induced cataract or cataract-like disorders in the eye of a mammalian subject which comprises administering to the subject an effective amount of estrogen.
In another aspect, the present invention provides a method of preventing or controlling TGF&bgr;-induced cataract or cataract-like disorders in the eye of a mammalian subject which comprises administering directly to or near to the eye of the subject an effective amount of estrogen.
Preferably, the mammalian subject is a human being but the present invention is also suitable for treating TGF&bgr;-induced cataract or cataract-like disorders in other animals such as horses, cats, dogs or the like.
Even though the present invention is suitable for prevention or treatment of cataract in humans irrespective of their natural estrogen levels, the present invention is par
Chamberlain Coral Gwenda
Hales Angela Maria
McAvoy Johnston William
Aulakh Charanjit S.
Fulwider Patton Lee & Utecht LLP
The University of Sydney
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