Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Reexamination Certificate
1999-12-08
2002-04-16
Zitomer, Stephanie (Department: 1655)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
C435S091200, C435S471000, C435S091510, 53, 53, 53
Reexamination Certificate
active
06372432
ABSTRACT:
This application claims priority to the French application 99 11563 filed Sep. 16, 1999.
The present invention concerns new compositions and methods for the detection of pathological events. It more particularly concerns compositions and methods for the remote detection of pathological events. The invention also provides for the tools, kits and compositions for the implementation of such methods, as well as their uses in the field of human or animal health, or, for example, in experimental research.
The ageing of populations in industrialized countries has given rise to new needs in diagnostics. Diseases such as cancer or neurodegenerative disorders would be better managed to the benefit of both patients and society if diagnostic tools were available to predict the onset or progression of the disease.
Experience has shown that the earlier the diagnosis is made, the greater the chance of controlling the probable course of the disease. This has been very clearly established in the case of cancer. Early detection campaigns for breast cancer through the use of routine mammography have improved the life expectancy of these cancers. Likewise, it might be presumed that early intervention in patients who develop Alzheimer's disease would make it possible to significantly slow its progression.
The incidence of diseases such as cancer and neurodegenerative disorders increases sharply with the age of the population. It is likely that these diseases take years to develop to the point where they can be detected. It has been found, for example, that an accumulation of successive mutations in the human genome is required to initiate a cancer. Similarly, genetic studies in selected cohorts with a high incidence of Alzheimer's disease, together with genetic experiments in animals, further underscore the multifactorial nature of initiation of this disease.
These age-related diseases share some common features including:
cellular alterations occurring in response to a disequilibrium in the environment of the affected tissues due to damage by physical, chemical or biological agents;
the involvement of cells of the immune system.
Although alterations in the affected tissues are preferentially identified only by biopsy, it may be the case that alterations in immune cells, which reflect an ongoing disease process, can be detected far from the sites of development of these diseases, since most cells in the immune system circulate between tissues and the blood or lymph compartments.
Lymphocytic cells and macrophages are the principal mediators of the cellular immune response. Lymphocytes and macrophages are present in both tissues and blood. They are the first cells to come into contact with foreign tissues. Macrophages degrade the concerned tissues and substances. The peptides derived from the degraded proteins are then bound by the major histocompatibility system class II molecules which transport them to the macrophage surface, where the complexes are recognized by T lymphocytes. Other systems of peptide presentation and immune response activation exist and have been described notably in the case of development of cancer.
Today, diseases such as these are diagnosed after the pathology is already present. In the case of cancer, for example, the diagnosis is made on the basis of medical imaging studies and morphological diagnosis of biopsied tissues. For diseases such as Alzheimer's disease, the diagnosis is made on the basis of a body of medical findings.
Thus there is a real need for tools and methods enabling early, simple and reliable detection of the development of disease, particularly diseases related to defects in cell signalling regulatory mechanisms, especially those diseases characterized by excessive cell proliferation such as cancer, neurodegenerative disorders, stenosis, etc.
The advent of molecular biology methods combined with bio-information technologies has made it possible to construct libraries (or banks) of DNA fragments characteristic of a given pathology, enabling the detection of the presence or absence of pathological markers in a very small sample of any tissue.
The present invention now sets forth a new approach for the detection of pathologies in vitro. More specifically, the present invention describes new methods and compositions for the detection of pathological events, notably pathological genetic signatures. The invention further describes methods and compositions usable for the remote detection of pathological events, i.e. using biological materials distinct from the pathological tissues. The compositions and methods provided for by the invention now offer clinicians, biologists and industrialists new solutions for in vitro diagnosis, based on direct, rapid, sensitive and economical methods that can be automated.
More particularly, the present invention is based notably on the demonstration that it is possible to determine, from biological samples comprising circulating cells, the presence or the risk of development of a pathology. More particularly, the invention is based on the demonstration that it is possible to detect, in a biological sample comprising blood cells, the existence of a pathology, including at very early stages of initiation and development, for which all other existing diagnostics would be ineffective.
A first subject of the invention is based more specifically on a process for the detection in vitro of the presence of a pathology in a subject, comprising the taking of a sample of blood cells from the subject and the determination, in this sample, of the presence of blood cells displaying a physiological state characteristic of the disease.
In a specific embodiment, the process of the invention comprises the determination of the presence, in the sample, of blood cells presenting a protein or a protein domain characteristic of the disease. In this context, the term “presenting” refers to both the presence of this protein or protein domain inside the cell (in any cellular compartment) and its presence in the cell membrane or at the cell surface. In this embodiment, the presence of the protein (or protein domain) can be determined by means of antibodies (or fragments or derivatives of antibodies) or by any other method familiar to those skilled in the art.
In another specific embodiment, the process of the invention comprises the determination, in the sample, of the presence of blood cells presenting a genetic profile characteristic of the disease.
Even more preferably, the process of the invention comprises the determination, in the sample, of the presence of blood cells presenting alterations in gene expression characteristic of the presence of the disease.
Thus, the present invention is based firstly, on the use of blood cells in a remote test for the presence of a pathological event and, secondly, on the use of genomic methods of detection of alterations in the expression (particularly the transcription) of the genome in these cells.
In a specific variant, the present invention therefore comprises more preferably the determination, in a biological sample, of the presence of blood cells presenting transcriptional and/or post-transcriptional alterations in gene expression characteristic of the presence of a disease.
The invention is based on the demonstration that it is possible to detect a pathology in the progress of development from the genomic signatures identified in the blood cells, as pathological embryonic foci may exist in nerve tissue such as brain or spinal cord (sites of neurodegenerative diseases) or in any other tissue from which a cancer can develop, for example (breast, lung, prostate, liver, bone, etc.).
The invention demonstrates in an unexpected manner that there exist in blood cells (preferably nuclear cells such as lymphocytes, macrophages, monocytes, dendritic cells, etc.) transcriptional and post-transcriptional alterations in gene expression resulting from direct or indirect interaction(s) with the cells during initiation of the disease.
More particularly, the invention demonstrates in an unexpected manner th
Bracco Laurent
Schweighoffer Fabien
Tocque Bruno
Bieker-Brady, Ph.D. Kristina
Clark & Elbing LLP
Exonhit Therapeutics SA
Zitomer Stephanie
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