Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Reexamination Certificate
1999-06-16
2001-04-17
Brusia, Joe S. (Department: 1631)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
C435S091200, C435S007100, C435S069100, C436S501000, C536S023400, C536S024100
Reexamination Certificate
active
06218122
ABSTRACT:
1. FIELD OF THE INVENTION
The field of this invention relates to methods for determining or monitoring the progression of disease states or the efficacy of therapeutic regimens in a subject, preferably a human patient. In particular, the invention relates to methods for monitoring disease states or therapies at times and/or levels before changes in protein function or activity occur.
2. BACKGROUND
Within the past decade, several technologies have made it possible to monitor the expression level of a large number of transcripts within a cell at any one time (see, e.g., Schena et al., 1995, Quantitative monitoring of gene expression patterns with a complementary DNA micro-array, Science 270:467-470; Lockhart et al., 1996, Expression monitoring by hybridization to high-density oligonucleotide arrays, Nature Biotechnology 14:1675-1680; Blanchard et al., 1996, Sequence to array: Probing the genome's secrets, Nature Biotechnology 14, 1649; 1996, U.S. Pat. No. 5,569,588, issued Oct. 29, 1996 to Ashby et al. entitled “Methods for Drug Screening”). In organisms for which the complete genome is known, it is possible to analyze the transcripts of all genes within the cell. With other organisms, such as human, for which there is an increasing knowledge of the genome, it is possible to simultaneously monitor large numbers of the genes within the cell.
Early applications of transcript array technology have involved identification of genes which are up regulated or down regulated in various diseased states. Additional uses for transcript arrays have included the analyses of members of signaling pathways, and the identification of targets for various drugs. However, it has not previously been recognized that transcript arrays might be beneficial in monitoring the level of either disease states or effect of therapies therapies thereto. In particular, it has not been recognized that disease states and/or therapies might be monitored by using transcript arrays to detect compensatory changes that occur as a result of incipient, small changes in the activity of proteins due to perturbations from the disease state and/or therapy.
However, the identification of preliminary changes in biological pathways caused either by the actions of disease states or by therapeutic regimens, such as drug regimens, for disease states is a problem of great commercial and human importance. Most of the decisions that need to be made to run efficient clinical trials and to properly manage the health of patients rely on assays that monitor changes in cells in the body. For example, when physicians are following patients to determine if they have changes in organ function, such as in the kidney, liver, or heart, they rely on monitoring changes in enzymatic functions that can provide clues as to the cellular changes associated with various disease processes.
The ability to make correct therapeutic interventions therefore relies on the ability to have sensitive monitors of whether a patient has had changes in the physiology that have been impacted by disease or by therapy. Some of these needs are related to following particular protein activity levels. For example levels of alpha-fetoprotein (AFP) or alkaline phosphatase (ALP) are commonly used to monitor liver damage (see, e.g., Izumi, R. et al., 1992, Journal of Surgical Oncology 49:151-155). The action of immunosuppressants Cyclosporin A and mycophalote mofetil have also been monitored using activity assays for the target enzymes calcineurin and inosine monophosphate, respectively (see, Yatscoff, R. W. et al., 1996,
Transplantation Proceedings
28:3013-3015). Other examples involve monitoring protein function in patients who have defects in the clotting pathway.
Thus, the power of being able to monitor changes in subjects by monitoring protein functions are well known in the art, and such techniques are widespread both in the detection of drug effects in animal trials, and in the detection of drug and disease effects in humans. It would be a significant benefit, however, to be able to monitor early changes in a cell that correlate with levels of a disease state or therapy and which precede detectable changes in actual protein function or activity. Such techniques would allow, for example, earlier diagnosis or prognosis or determination of the level of a disease state. In particular, the existence of such techniques would allow for determination of the level of a disease state (e.g., the stage or level of progression of a disease) in a subject before symptoms of the disease state can be observed. Earlier, more effective therapeutic intervention would then be possible. The ability to monitor such early changes in a cell resulting from therapy would likewise be of significant benefit, since therapeutic regimens could then be monitored and readily modified for maximum effectiveness.
Discussion or citation of a reference herein shall not be construed as an admission that such reference is prior art to the present invention.
3. SUMMARY OF THE INVENTION
The present invention provides methods for monitoring diseases or disease states in a subject. The methods of the invention involve comparing a “diagnostic profile”, obtained by measuring RNA or protein abundances or activities in a cell of the subject, with “interpolated perturbation response profiles”, which are obtained by measuring RNA or protein abundances or activities in a cell of an analogous subject or subjects at various levels of disease, i.e., at various levels of progression of the diseases or disease states being monitored.
The present invention also provides methods for monitoring the efficacy or response of therapy upon a subject. The methods involve comparing a diagnostic profile, obtained by measuring gene or protein abundances in cells from a subject undergoing a particular therapy, with interpolated perturbation response profiles which are obtained by measuring RNA or protein abundances or activities in cells of analogous subjects in response to known levels of therapeutic efficacy or response.
The present invention also provides a computer system for analyzing levels of disease states and or therapeutic efficacy according to the above methods.
The methods of the invention are based at least in part on the discovery that perturbations on various constituents of a cell, such as perturbations on protein function or activity, which occur as a result of a disease state or therapy result in characteristic changes in the transcription and activity of other genes, and that such changes can be used to define a “signature” of the particular alterations which are correlated with the progression of the particular disease state or therapy. This is true even if there is no actual disruption in the function or activity level of proteins associated with the disease state. Thus, the methods of the present invention are different from and independent of monitoring protein function. Further, the methods of the invention can be used to monitor several diseases and/or therapies simultaneously.
In more detail, the present invention provides, first, methods for determining or monitoring the level of one or more disease states (i.e., the progression of one or more disease states) upon a subject by: (i) obtaining a diagnostic profile by measuring abundances of cellular constituents in a cell from a subject known or suspected of having a disease state; (ii) obtaining interpolated perturbation response profiles for each disease state being monitored by, first, obtaining response profiles by measuring abundances of cellular constituents that occur in cells of an analogous subject or subjects at a plurality of levels of each disease state, and second, interpolating the thus obtained response profiles; and (iii) determining the interpolated perturbation response profile for each disease state for which similarity is greatest between the diagnostic profile and a combination of the determined interpolated response profiles, according to some objective measure. The level of a particular disease state is thereby indicated by the dise
Friend Stephen H.
Stoughton Roland
Brusia Joe S.
Pennie & Edmonds LLP
Rosetta Inpharmatics, Inc.
Siu Stephen
LandOfFree
Methods of monitoring disease states and therapies using... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Methods of monitoring disease states and therapies using..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Methods of monitoring disease states and therapies using... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2498090