Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
2000-06-14
2002-06-25
Schwartzman, Robert A. (Department: 1636)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C536S023100
Reexamination Certificate
active
06410715
ABSTRACT:
This invention relates to methods for screening for agents useful for treating hormone disorders, the novel agents identified using such screening methods, and their use to treat hormone disorders.
BACKGROUND TO THE INVENTION
Millions of people around the world suffer from conditions caused by hormone disorders, including diabetes, pituitary dwarfism and other hypopituitarisms, pituitary gigantism and other hyperpituitarisms, galactorrhea, hypothyroidism (myxedema) and hypothyroidism, a adrenocortical insufficiencies (e.g., Addison's disease) or hyperfunctions (e.g., Cushing's syndrome), pheochromocytoma, multiple endocrine neoplasias, polyglandular deficiency syndromes, and disorders of reproductive function.
Diabetes mellitus is a hormone disorder which afflicts millions of people annually. It is a serious and important health problem, involving 2 per cent or more of the US population. It is characterized by an inability to maintain homeostasis of glucose in the bloodstream. Thus the primary symptom of acute diabetes is hyperglycemia. A secondary set of symptoms arises in chronic or long-standing diabetes. These include degeneration of the walls of blood vessels, causing serious vascular complications involving both macro- and microvessels. Many different organs are affected by these complications, and common late clinical manifestations are retinopathy (chronic diabetes is a leading cause of blindness), nephropathy, neuropathy and foot ulcers.
In normal individuals, an increase in glucose concentration in the blood (“blood glucose”) triggers the release of insulin from the pancreas into the bloodstream. This in turn leads to uptake of glucose into tissues and its conversion into glycogen and fatty acids. In most diabetic individuals there is a deficiency in the production, release, stability or uptake of insulin. This results in an inability to remove glucose from the bloodstream and to store its fuel content by metabolizing it into glycogen and fatty acids. Even in the presence of elevated blood glucose, the metabolism of a diabetic is geared towards the synthesis of glucose via gluconeogenesis and the oxidative breakdown of fatty acids.
Many other hormone disorders are characterized by an under- or over-abundance of the hormone in question, due to abnormalities in its synthesis, release or rate of elimination from the bloodstream, and/or by the inability of target cells to respond normally to the hormone, due to abnormalities in the number or function of receptors for the hormone or in the signal transduction pathways which mediate cells' responses to the hormone.
SUMMARY OF THE INVENTION
Applicant has determined that certain cellular components interact with translation factors in the cell and modulate cellular translation in response to a hormone. To this end, Applicant believes that agents which mimic this activity will be useful for treatment of hormone deficiencies. Applicant now provides a means to identify such useful agents. Thus, the present invention relates to methods for screening for agents useful to treat hormone disorders. The screening methods utilize a protocol in which potentially useful non-hormone agents are brought into contact with a system containing a cellular component and a translation factor which interact with one another in intact cells in a manner that is normally responsive to the hormone in question and results in a modulation of translation in the cell. The impact of the test agents on the interaction between the cellular component and the translation factor is then determined. Those agents which modify this interaction may be useful for the treatment of hormone disorders. Once identified, such agents can be formulated in therapeutic products (or even prophylactic products) in pharmaceutically acceptable formulations, and used for specific treatment of hormone disorders with few side effects. While such agents may be useful as hormone substitutes, they are also useful in test systems to allow an understanding of the action of the hormone.
Thus, in a first aspect, the invention features a method for screening for an agent useful to treat a hormone disorder by contacting a potential agent with a system containing a cellular component and a translation factor. The component and the factor have the property that they interact with one another in intact cells in a manner that is normally responsive to the hormone and results in a modulation of translation. The method also includes determining whether the agent causes a modification of any interaction between the component and the factor similar to any modification that would normally occur in intact cells in response to the hormone.
By “screening” is meant a process in which a large number of potentially useful agents are processed in the method of this invention. It is a process distinct from a single experiment in which a single agent is studied in detail to determine its method or mode of action.
By “high-throughput screening” is meant screening in which many potentially useful agents can be processed in a short period of time. By way of example, hundreds of the agents might be processed in a single day, or thousands in a single week.
By “hormone disorder” is meant any human or animal disease or condition caused by or characterized by abnormally high or low concentrations or availability of a hormone.
By “abnormally high” is meant any difference above normal sufficient to be manifested by physiological, biochemical, physical, mental, or psychological effects.
By “abnormally low” is meant any difference below normal sufficient to be manifested by physiological, biochemical, physical, mental, or psychological effects.
By “cellular component” is meant any component found within a cell. Such components include, but are not limited to, proteins, lipoproteins, glycoproteins, lipids, carbohydrates, nucleic acids, steroids, prostaglandins, and combinations and complexes thereof.
By “translation factor” is meant a molecule or group of molecules which participates directly at some stage in the process of translation but which is not permanently attached to or associated with the ribosome. Such factors include, but are not limited to, eIF-1, eIF-2 and its three known constituent polypeptides, eIF-2B (also known as GEF) and its five known constituent polypeptides, eIF-3 and its eight known constituent polypeptides, eIF-4A, eIF-4B, eIF-4C (also known as eIF-1A), eIF-4D (also known as eIF-5A), eIF-4E, eIF-4F and its three known constituent polypeptides, eIF-5, eIF-6 (also known as eIF-3A), eEF-1&agr;, eEF-1&bgr;&ggr; and its two known constituent polypeptides, eEF-2, and eRF.
By “interact with one another” is meant that the entities in question become physically associated with one another, transiently or for longer periods, or that one causes a biochemical or conformational change in the other.
By “normally responsive to the hormone” is meant that the molecule, molecules, complex or process in question undergoes some physical or biochemical alteration as a result of the presence, the absence, or a change in concentration of the hormone in question.
By “hormone” is meant any molecule or group of molecules released by a cell or cell type which has a physical or biochemical effect on the same or another cell or cell type. Such molecules include, but are not limited to, peptides and protein hormones such as insulin, glucagon, vasopressin, calcitonin, ACTH, growth hormone and the like, steroid hormones such as estrogen, testosterone and the like, and growth factors such as platelet-derived growth factor, epidermal growth factor, nerve growth factor, interleukins, other cytokines, and the like. Non-hormones are other components or other chemicals or biochemicals, as described below in “Libraries.”
By “modulation of translation” is meant a control, or change of control, of the efficiency or rate of translation of mRNAs which results in a change in the overall rate of protein synthesis, the relative quantities of different proteins synthesized, and/or the quantities of individual proteins synthes
Harford Joe B.
Miles Vincent J.
Pause Arnim
Sonenberg Nahum
Loeb Bronwen M.
Pennie & Edmonds LLP
Questcor Pharmaceuticals, Inc.
Schwartzman Robert A.
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