Suppression of vascular disorders by mucosal administration...

Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai

Reexamination Certificate

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C530S350000, C530S300000, C435S007100, C424S093210, C424S040000

Reexamination Certificate

active

06812205

ABSTRACT:

FIELD OF THE INVENTION
This invention pertains to an improvement in the treatment of vascular disorders and in the treatment of atherosclerosis in particular. More specifically, the invention is directed to the mucosal administration of heat shock protein peptides and biologically active fragments or analogs of such heat shock protein peptides for the prevention and therapeutic treatment of vascular disorders. The invention also includes aerosol, oral, and enteral formulations of heat shock protein peptides useful in the treatment of vascular disorders in mammals.
BACKGROUND OF THE INVENTION
Atherosclerosis, a multifactorial process resulting in thickening of the intimal layer of arterial vessels, is characterized by an accumulation of lipids within the vessel wall and accompanying mononuclear cell infiltration and smooth muscle cell proliferation. It is a leading cause of mortality and morbidity due to cardiovascular and cerebrovascular disease in the western world. The initial lesion of atherosclerosis is the fatty streak, the focal collection of lipoprotein particles within the intima.
The current treatments for the prevention and treatment of atherosclerosis include certain pharmacological approaches, in addition to alteration of lifestyle factors which can ameliorate atherosclerosis, such as diet control, weight loss, increased exercise, and smoking cessation. Examples of pharmacological agents in current use for the treatment and prevention of atherosclerosis are hydroxymnethylglutaryl-coenzyrne A (HMGCoA) reductase inhibitors (statins) to control high LDL, nicotinic acid to control high lipoprotein (a) and low high density lipoprotein (HDL), and fibric acid derivatives to control high levels of triglycerides. Adjunctive pharmacological treatment includes measures directed toward control of diabetes mellitus and hypertension.
In view of the foregoing, a need still exists to develop methods and compositions for treating and/or preventing vascular disorders such as atherosclerosis. Preferably, such methods and compositions would include non-invasive modes of administration and, more preferably, be based, in part, on the molecular interactions which mediate an inflammatory response.
SUMMARY OF THE INVENTION
The invention solves these and other problems by providing methods and compositions for treating vascular disorders, including atherosclerosis.
It has been unexpectedly discovered by the present inventors that mucosal administration of a heat shock protein peptide, for example mycobacterial heat shock protein 65 (HSP65), is an effective treatment for vascular disorders, such as atherosclerosis. In one aspect, the invention is directed to a method for treating vascular disorders in a mammal in need of such treatment, comprising orally (or more generally, mucosally) administering to the mammal an effective amount of an agent comprising a heat-shock protein (“HSP”), and/or therapeutically effective fragments or analogs of a heat shock protein. Preferably, the administration is continued for a period of time sufficient to achieve at least one of the following:
(i) reduction in the level of proinflammatory Th1 cytokines;
(ii) increase in the level of anti-inflammatory Th2 cytokines; or
(iii) amelioration, retardation or suppression of at least one clinical or histological symptom of a vascular disorder.
Although not wishing to be bound to any particular theory or mechanism, it is believed that mucosally administered HSPs according to the invention can initiate immunological responses in a subject which prevent, retard or arrest an inflammatory response associated with a vascular disorder. For ease of discussion, the invention is described in terms of administering a heat shock protein; however, it is to be understood that therapeutically effective fragments or analogs of HSPs can be used in addition to or in place of HSPs to practice the claimed invention.
The present invention also relates to formulations adapted for mucosal administration, and/or delivery systems adapted from mucosal administration, comprising a HSP and useful in the treatment of vascular disorders.
It has now been discovered that an improved and more effective method for preventing or treating vascular disorders in mammals comprises mucosal administration of one or more heat shock protein peptides. Heat shock proteins (HSPs) are well known in the art and are discussed in detail below. Therapeutically effective fragments and analogs of HSPs can be identified in screening assays which measure, e.g., any one or more of the above-listed parameters. Exemplary animal models for selecting therapeutically effective HSPs, fragments and analogs thereof, are provided in the Examples.
Thus, according to one aspect of the invention, a method for treating (including preventing) a vascular disorder in a mammal is provided The method involves administering to a mucosal surface of the mammal at least one agent selected from the group consisting of a heat shock protein, a therapeutically effective fragment of a heat shock protein, and a therapeutically effective analog of a heat shock protein, wherein the agent is present in an effective amount for treating the disorder. In certain embodiments, the vascular disorder is an inflammatory vascular disorder and the effective amount is an amount sufficient to suppress, in whole or in part, the inflanmmatory response.
According to one embodiment of this aspect of the invention, the mucosal surface an includes nasal epithelium. In a second embodiment the mucosal surface includes oral mucosa. In yet other embodiments the mucosal surface includes a luminal surface of a gastrointestinal organ selected from the group consisting of: stomach, small intestine, large intestine, and rectum. In certain embodiments of this aspect of the invention, the disorder includes a cell-mediated immune response. In certain other embodiments, the disorder includes an antibody-mediated immune response. In a preferred embodiment of this aspect of the invention, the disorder is atherosclerosis. In another preferred embodiment of this aspect of the invention, the heat shock protein is mycobacterial HSP65. In another preferred embodiment of this aspect of the invention, the beat shock protein is human HSP60. In yet another preferred embodiment of this aspect of the invention, the heat shock protein is chlamydial HSP60.
In a second aspect, the present invention provides a method for treating a vascular disorder (e.g., an inflammatory vascular disorder) in a mammal. The method includes administering to the mammal by inhalation an effective amount of a composition containing at least one agent selected from the group consisting of a heat shock protein, a therapeutically effective fragment of a heat shock protein, and a therapeutically effective analog of a heat shock protein, wherein the agent is present in an effective amount for treating the disorder. In certain embodiments, the vascular disorder is an inflammatory vascular disorder and the effective amount is an amount sufficient to suppress, in whole or in part, the inflammatory response.
In certain embodiments of this aspect of the invention, the disorder includes a cell-mediated immune response. In certain other embodiments, the disorder includes an antibody-mediated immune response. In a preferred embodiment of this aspect of the invention, the disorder is atherosclerosis. In another preferred embodiment of this aspect of the invention, the heat shock protein is mycobacterial HSP65. In another preferred embodiment of this aspect of the invention, the heat shock protein is human HSP60. In yet another preferred embodiment of this aspect of the invention, the heat shock protein is chlamydial HSP60. In yet another preferred embodiment of this aspect of the invention, the agent is in aerosol form.
In a third aspect, the present invention provides a method for suppressing a vascular disorder in a mammal, which includes administering to the mammal via the pulmonary tract an effective amount of a composition comprising at least one member selected from the group

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