Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Reexamination Certificate
2000-11-30
2004-03-09
Benzion, Gary (Department: 1637)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
C435S091100, C435S091200, C536S024300, C536S024320, C536S024330, C536S023100
Reexamination Certificate
active
06703202
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to methods for evaluating and predicting clinical outcomes in patients by measuring levels of gene expression. Methods are provided for quantitating gene expression levels, and the measured levels are compared against reference levels. Deviations from the reference levels can be correlated with clinical outcomes. For example, the type and extent of a patient's response to a therapeutic intervention can be determined, or the prognosis for a patient's survival can be estimated. The gene expression levels can be measured in essentially any chosen body tissue or fluid. Surprisingly, it has been found that measurement of intracellular gene expression levels in blood are indicative of clinical outcomes.
BACKGROUND OF THE INVENTION
Methods for examining overall gene expression in, for example, disease states, previously have been described. See, for example, U.S. Pat. No. 5,874,219; Zakut et al.,
Cancer Research,
53:5-8 (1993); Mohaupt et al.,
Kidney International,
46:653-665 (1994); Liang and Pardee (1992)
Science
257, 967-971; Liang et al (1993),
Nucleic Acids Res.
21, 3269-3275; Bauer et al (1993)
Nucleic Acids Res.
21, 4272-4280; Stone and Wharton (1994),
Nucleic acid Res.
22, 2612-2618 and Wang and Feuerstein (1995)
Biotechniques
18, 448-452; WO 93/18176 and DE 43 17 414. These methods, however, generally provide a “snapshot” of gene expression that is qualitative, rather than quantitative. Accordingly, the methods provide an indication only of whether a gene is being expressed at a detectable level in a particular tissue. Moreover, even when applied to samples from patients suffering from a pathological syndrome, none of these methods provides any correlation with clinical outcome for the patient. It is apparent, therefore, that new and improved methods for measuring levels of gene expression and correlating those levels with clinical outcome are greatly to be desired.
SUMMARY OF THE INVENTION
There exists a need to determine and predict clinical outcomes in patients It is therefore an object of the invention to provide methods for evaluating (e.g., determining and/or predicting) clinical outcome for a patient suffering from a clinical condition or syndrome, comprising the steps of (a) providing a clinical specimen obtained or derived from the patient, (b) measuring the levels of expression of a preselected set of genes in the clinical specimen; and (c) comparing said levels of expression against a set of reference expression levels, where a deviation of the level of expression of one or more of the preselected set of genes is indicative of clinical outcome for the patient. The phrase “preselected gene(s)” refers to genes that have been determined to be suitable in practice of the invention. Preferably, in accordance with practice of the invention, such genes are selected where there is a correlation between the level of gene expression and the nature and extent of a disease state or other undesired condition.
In accordance with one aspect of the invention, the clinical specimen is a sample of blood, tissue, or cerebrospinal fluid. The clinical specimen may be a sample of blood, and derived therefrom, such as plasma or serum sample or fraction.
In accordance with another aspect of the invention, the expression levels of at least three preselected genes are measured. In one embodiment, the expression level of at least one proinflammatory cytokine is measured. In another embodiment, the expression level of at least three preselected proinflammatory cytokines is measured. In yet another embodiment, the preselected proinflammatory cytokine genes are selected from the group consisting of TNF-&agr;, IL-6, IL-1, IL-8, IP-10 and MIP-1&agr;.
In accordance with another aspect of the invention, the clinical condition or syndrome is an inflammatory disorder. In one embodiment, the inflammatory disorder is a chronic inflammatory disorder. In another embodiment, the chronic inflammatory disorder is selected from the group consisting of chronic hepatitis, hepatitis B and C, chronic obstructive pulmonary disease, inflammatory mucosal disease, autoimmune disease, dementia, cardiovascular disease, and cancer. The inflammatory mucosal disease may be selected from the group consisting of inflammatory bowel disease, Crohn's disease, and colitis. The dementia may be AIDS-related dementia or Alzheimer's disease. The cancer may be selected from the group consisting of lymphoma, prostate cancer, and colon cancer. In another embodiment, the clinical condition is transplant rejection in a patient with an allograft. The allograft may be a heart, liver, kidney, or other organ.
In accordance with still another aspect of the invention, the clinical outcome that is determined is response to a therapeutic intervention. The therapeutic intervention may be treatment with a drug. The drug may be a stabilized chlorite solution. In particular, the stabilized chlorite solution may be WF-10.
In accordance with yet another aspect of the invention, the clinical condition or syndrome is HIV infection. In one embodiment, the clinical condition or syndrome is AIDS.
In accordance with a still further aspect of the invention, the indicated clinical outcome is the probability of patient survival at a predetermined date. In one embodiment, the indicated clinical outcome is the probability of patient survival after six months.
In accordance with a further aspect of the invention, the levels of gene expression are measured by a quantitative polymerase chain reaction. The polymerase chain reaction may be a reverse transcriptase/polymerase chain reaction. The polymerase chain reaction may be carried out using fluorescent detection of the amplification products. In one embodiment, the polymerase chain reaction may be carried out using a LightCycler® instrument, or using other appropriate technology.
Other objects, features and advantages of the present invention will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating preferred embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.
REFERENCES:
patent: 5877222 (1999-03-01), McGrath
patent: 5965421 (1999-10-01), Ni et al.
patent: WO 9914237 (1999-03-01), None
Raffanti et al., “Randomized, Double-Blind, Placebo-Controlled Trial of the Immune Modulator WF10 in Patients with Advanced AIDS*”, Infection, vol 26, No. 4, pp. 202-206 (1998).*
Paturel et al., “Quantitative Analysis of Th1, Th2 And TGF-B1 Cytokine Expression In Tumor, TIL And PBL of Non-Small Cell Lung Cancer Patients”, Int. K. Cancer, vol. 77, pp. 7-12, (1998).*
Baan et al., “Intragraft IL-4 mRNA expression os associated with down-regulation of liver graft rejection”, Clin. Transplataion, vol. 10, pp. 542-549, (1996).*
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Stoetzer, et al., “Association of bcl-2, bax, bcl-xL and Interleukin-1-b-converting Enxyme Expression With Initial Response to Chemotherapy in Acute Myeloid Leukemia”, Leukemia, vol. 10, No. suppl. 3, 1996, pp. s18-s22.
Shi, et al., “Expression of Thyrotrophin Receptor Gene in Thyroid Carcinoma is Associated With a Good Prognosis”, Clinical Endocrinology, vo. 39, 1993, pp. 269-274.
Wong, et al., “Evidence for Rantes, Monocyte Chemotactic Protein-1, and Macrophage Inflammatory Protein-1b Expression in Kawasaki Disease”, The Journal of Rheumatology, vol. 24, No. 6, Jun. 1997.
Raffanti, S.P. et al., “Randomized Double-Blind, Placebo-Cnotrolled Trial of the Immune Modulator WF10 in Patients With Advanced AIDS”, Infection, vol.
Kuehne Friedrich-Wilhelm
McGrath Michael
Meuer Stefan
Benzion Gary
Heller Ehrman White and McAuliffe
Oxo Chemie AG
Wilder Cynthia
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