Chemistry: molecular biology and microbiology – Differentiated tissue or organ other than blood – per se – or...
Reexamination Certificate
2001-07-11
2004-06-29
Saucier, Sandra E. (Department: 1651)
Chemistry: molecular biology and microbiology
Differentiated tissue or organ other than blood, per se, or...
C435S040520, C435S040500
Reexamination Certificate
active
06756194
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates generally to the fields of medicine and pharmacological research. More specifically, the invention provides standard control samples to be used to evaluate disease states or trauma that involve apoptosis or suppression of apoptosis. The control samples comprise natural or artificial tissues treated in vitro to display reproducible, predetermined indicators of apoptosis that are equivalent to indicators of apoptotic status of corresponding tissues and organs of a living subject.
BACKGROUND OF THE INVENTION
Several scientific or patent publications are referenced in this patent application to describe the state of the art to which the invention pertains. Each of these publications is incorporated by reference herein, in its entirety.
A coordination and balance between cell proliferation and cell death is critical for normal development and homeostasis of tissues and organs. Abnormalities in either of these processes may cause tissue atrophy or hypertrophy, either of which can lead to cancer, autoimmune disease or degenerative disorders.
It is becoming increasingly apparent that the processes of cellular proliferation and programmed cell death, i.e., apoptosis, are linked by many common signaling mechanisms. Thus, up-regulation of one process may be accompanied by down-regulation of the other, leading to the ultimate expression of a disease state or pathological condition. For instance, increased cell cycling due to overexpression of the c-myc oncogene and reduced apoptosis due to bcl-2 oncogene deregulation are two factors observed in the development of lymphomas and mammary tumorigenesis.
A variety of disease states and other pathological conditions are linked to dysregulated apoptosis in a particular tissue or organ. These include, for example, general conditions related to tissue rejection, immune/inflammatory responses, ischemia and injury, cardiovascular diseases such as dilated or ischemic cardiomyopathy, myocarditis and atherosclerosis, neurodegenerative disorders such as ALS, Alzheimer's disease, Parkinson's disease and retinal degeneration, hepatic and pancreatic disorders related to viral infection or alcohol consumption, which can lead to development of insulin-dependent diabetes mellitus or infection with certain viruses, such as adenoviruses, influenzaviruses and human immunodeficiency virus.
Additionally, a variety of cell proliferative diseases and disorders are linked to dysregulated apoptosis. These include, for example, psoriasis, lupus and other autoimmune conditions such as Crohn's disease, Hashimoto's thyroiditis and arthritis, infection with certain viruses, such as human papillomavirus, Epstein-Barr virus and herpes simplex virus; as well as a variety of cancers, including mammary carcinomas, lymphomas cervical and ovarian cancers, and neuroblastomas. As mentioned above, such proliferative deseases may be marked by a decrease in apoptosis in the affected tissue or organ, and may also be identified by up-regulation of enzymes and signaling molecules involved in cell growth or cell cycling.
Clearly, the apoptotic status of a particular tissue is relevant to the diagnosis and prognosis of type and severity of a wide variety of diseases or physiological conditions. Moreover, the efficacy of a selected therapeutic regime for treating such disease may be evaluated by assessing the apoptotic status of the tissue. For this reason, morphological and biochemical markers of apoptosis and mitosis are of great interest to investigators in their attempts to devise clinically relevant diagnostic and prognostic indicators of disease status in a patient.
In the development of clinically relevant models of disease states, current technology utilizes cultured cell lines, or tissues from subjects having a particular disease, or animal models to evaluate a particular pathological condition and/or to develop agents to treat the condition. Each of these methodologies has certain limitations.
For instance, cultured cell lines are often utilized for screening therapeutic agents and for studying the cellular physiology associated with diseases involving tissues comprising the cell type. The information gathered from the use of cultured cell lines is of limited value, however, because the physiological profile of cells in culture often does not accurately reflect the physiological profile of corresponding primary cells contained in a tissue or organ.
As another example, particularly utilized in the study of tumors, it is common practice to store excised tumor tissue of a particular type for use as comparison in diagnosis of other patients or evaluation of the efficacy of a patient's therapeutic regimen. One disadvantage of this practice is the lack of appropriate standardized controls. The excised tumor sample represents the end result of a disease progression. As such, it is of little value in diagnosis of early or intermediate stages of the disease. Furthermore, biopsied tissues can be extremely variable in their disease presentation and expression of biochemical markers of disease. Biopsied tissue also is often not readily available when needed, and moreover can present a health hazard in that it may contain infectious agents.
As another example, animal models are often used for studying a disease and developing new agents and methods of treatment. Whereas an animal model may offer biologically relevant information, their use has many disadvantages. From a practical standpoint, it is expensive and time-consuming to use animals in research. Moreover, results may not be reproducible from one animal study to another. Furthermore, there are numerous diseases and pathological conditions for which no relevant animal model exists. Finally, the use of animals in certain types of research (e.g., wound research) is increasingly being called into question for ethical reasons.
Thus, a need exists for a clinically relevant standardized control for use in evaluating the apoptotic status of a selected tissue or organ. It would be of great advantage to be able to reproducibly produce such standardized controls for any tissue or organ in which it is desirable to evaluate apoptosis. It would be of further advantage for such controls to be of high biological relevance, i.e., to display many, if not all, of the morphological and biochemical features of apoptosis as would be observed in a corresponding tissue in a living subject. Finally, such controls preferably should be capable of being standardized for incremental changes in apoptosis.
SUMMARY OF THE INVENTION
The present invention satisfies the need in the art for a clinically relevant standardized control for use in evaluating the apoptotic status of a selected tissue or organ. The invention provides compositions that can serve as standardized controls for any tissue or organ in which it is desirable to evaluate apoptosis. The controls are of high biological relevance, in that they display a variety of morphological and biochemical features of apoptosis, and can display incremental changes in apoptosis.
Thus, one aspect of the invention features a composition for use as a standardized measure of apoptosis in a test sample of tissue from a subject. The composition comprises at least one segment of an equivalent tissue that has been subjected to a treatment that reproducibly results in a predetermined, measurable amount of apoptosis in the segment. These tissue segments are sometimes referred to herein as “apoptosis tissue standards”. In a highly preferred embodiment, they are produced by culturing the tissue segment in a microgravity bioreactor for a period of time known to produce the predetermined amount of apoptosis in the tissue segment. Other means of producing the apoptosis tissue standards are also provided in accordance with the invention, as described in detail below.
In preferred embodiments of the invention, at least two tissue segments are featured, wherein one of the segments is a negative control segment which has not been subjected to the apoptosis-indu
Perkins Coie LLP
Saucier Sandra E.
University of Medicine and Dentistry of New Jersey
Wise Michael J.
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