Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Patent
1996-08-20
1999-07-27
Degen, Nancy
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
A61K 3170
Patent
active
059290404
DESCRIPTION:
BRIEF SUMMARY
The present invention relates generally to a method for the prophylaxis and/or treatment of skin disorders, and in particular proliferative and/or inflammatory skin disorders, and to genetic molecules useful for same. The present invention is particularly directed to genetic molecules capable of modulating growth factor interaction with its receptor on epidermal keratinocytes to inhibit, reduce or otherwise decrease stimulation of this layer of cells. The present invention contemplates, in a most preferred embodiment, a method for the prophylaxis and/or treatment of psoriasis.
Bibliographic details of the publications numerically referred to in this specification are collected at the end of the description. Sequence Identity Numbers (SEQ ID NOs.) for the nucleotide sequences referred to in the specification are defined following the bibliography.
Throughout this specification, unless the context requires otherwise, the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated element or integer or group of elements or integers but not the exclusion of any other element or integer or group of elements or integers.
Psoriasis and other similar conditions are common and often distressing proliferative and/or inflammatory skin disorders affecting or having the potential to affect a significant proportion of the population. The condition arises from over proliferation of basal keratinocytes in the epidermal layer of the skin associated with inflammation in the underlying dermis. Whilst a range of treatments have been developed, none is completely effective and free of adverse side effects. Although the underlying cause of psoriasis remains elusive, there is some consensus of opinion that the condition arises at least in part from over expression of local growth factors and their interaction with their receptors supporting keratinocyte proliferation via keratinocyte receptors which appear to be more abundant during psoriasis.
One important group of growth factors are the dermally-derived insulin-like growth factors (IGFs) which support keratinocyte proliferation. In particular, IGF-I and IGF-II are ubiquitous peptides each with potent mitogenic effects on a broad range of cells. Molecules of the IGF type are also known as "progression factors" promoting "competent" cells through DNA synthesis. The IGFs act through a common receptor known as the Type I or IGF-I receptor, which is tyrosine kinase linked. They are synthesised in mesenchymal tissues, including the dermis, and act on adjacent cells of mesodermal, endodermal or ectodermal origin. The regulation of their synthesis involves growth hormone (GH) in the liver, but is poorly defined in most tissues (1).
Particular proteins, referred to as IGF binding proteins (IGFBPs), appear to be involved in autocrine/paracrine regulation of tissue IGF availability (2). Six IGFBPs have so far been identified. The exact effects of the IGFBPs is not clear and observed effects in vitro have been inhibitory or stimulatory depending on the experimental method employed (3). There is some evidence, however, at certain IGFBPs are involved in targeting IGF-I to its cell surface receptor.
Skin, comprising epidermis and underlying dermis, has GH receptors on dermal fiboblasts (4). Fibroblasts synthesize IGF-I as well as IGFBPs-3, -4, -5 and -6 (5) which may be involved in targeting IGF-I to adjacent cells as well as to the overlaying epidermis. The major epidermal cell type, the keratinocyte, does not synthesize IGF-I, but possesses IGF-I receptors and is responsive to IGF-I (6).
It is apparent, therefore, that IGF-I and other growth promoting molecules, are responsible for or at least participate in a range of skin cell activities. In accordance with the present invention, the inventors have established that abberations in the normal functioning of these molecules or abberations in their interaction with their receptors is an important factor in proliferative and/or inflammatory skin disorders. It is proposed, therefore
REFERENCES:
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"Localization of Messenger Ribonucleic Acid for Insulin-Like Growth Factor-Binding Proteins in Human Skin by in Situ Hybridization" by J.A. Batch et al.; Journal of Clinical Endocrinology and Metabolism; vol. 79, No. 5, pp. 1444-1449. 1994.
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"Antisense-Mediated Reduction in Insulin-Like Growth Factor-1 Receptor Expression Suppresses the Malignant Phenotype of a Human Alveolar Rhabdomyosarcoma" by Shapiro et al.; The American Society for Clinical Investigation, Inc.; vol. 94, Sep. 1994, pp. 1235-1242.
"The Insulin-like Growth Factor 1 Receptor Is Expressed by Epithelial Cells with Proliferative Potential in Human Epidermis and Skin Appendages: Correlation of Increased Expression with Epidermal Hyperplasia" by Hodak et al.; Laboratory for Investigative Dermatology; pp. 564-570. 1996.
Werther George Arthur
Wraight Christopher John
Degen Nancy
Larson Thomas G.
Royal Children's Hospital Research Foundation
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