Methods to predict ederma as a side effect of drug treatment
OwnerMarlene Dressman, Sridhar Kudaravalli +3inventors
InventorsMarlene Dressman, Sridhar Kudaravalli, Rachel Malinowski, Lee McLean, Mihael Polymeropoulos
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Abstract
This invention provides methods to predict the likelihood of occurrence of the side effect of edema in patients treated with a drug including, but not limited to, a TKI, such as Imatinib or GLEEVEC™/GLIVEC®. The methods employed use gene expression profile comparisons and the determination of specific SNPs and in the IL-1β gene. Methods of treatment of edema and kits for the performance of the above assays are also provided.
Claims36
A method to predict which patient will be likely to develop edema when treated with a drug comprising the steps of:
- a) determining RNA expression levels in a biological sample for a plurality of the 13 predictor genes shown in Table 2;
- b) comparing patients gene expression profile to the mean No Edema expression profiles shown in Table 3;
- c) determining the similarity between the two gene expression profiles resulting from the comparison in (b);
- d) determining the likelihood that the patient will develop edema when treated with a drug by means of the degree of similarity determined in (c).
A method to predict, with high sensitivity, which patients will be more likely to develop edema when treated with a drug, such that no more than 15% of Edema cases will be misclassified as having No Edema, comprising the steps of:
- a) determining RNA expression levels in a biological sample for a plurality of the 13 predictor genes shown in Table 2;
- b) comparing patients gene expression profile to the mean No Edema expression profiles shown in Table 3;
- c) determining the PCC between the two gene expression profiles resulting from the comparison in (b);
- d) determining that the patient will be more likely to develop edema than not, when treated with a drug, if the PCC is negative and <0.78;
- and
- e) determining that the patient will be more likely not to develop edema than to develop it if the negative PCC is ≧0.78.
A method to predict which female patient will be likely to develop edema when treated with a drug, comprising the steps of:
- a) determining for the two copies of the IL-1β gene, present in the patient, the identity of the nucleotide pairs at the polymorphic site at position −511 base pairs upstream (at position 1423 of sequence X04500) from the transcriptional start site;
- and
- b) determining that the patient will be likely to develop edema if both nucleotide pairs at this site are GC and determining that the patient will not be likely to develop edema if at least one nucleotide pair at this site is AT.
A method to predict which female patient will be likely to develop edema when treated with a drug, comprising the steps of:
- a) determining for the two copies of the IL-1β gene, present in the patient, the identity of the nucleotide pairs at the polymorphic site at position −31 base pairs upstream (at position 1903 of sequence X04500) from the transcriptional start site;
- and
- b) determining that the patient will be likely to develop edema if both nucleotide pairs at this site are AT and determining that the patient will not be likely to develop edema if at least one nucleotide pair at this site is GC.
A method to predict which female patient will be likely to develop edema when treated with a drug, comprising the steps of:
- a) determination of the level of transcription of the IL-1β gene in a biological sample;
- and
- b) determining that the patient would be likely to develop edema when treated with a drug if the level is above a threshold level.
A method to predict which female patient will be more likely to develop edema when treated with a drug, comprising the steps of:
- a) determination of the level of the protein expressed by the IL-1β gene in a biological sample;
- and
- b) determining that the patient would be likely to develop edema when treated with a drug if the level is above a threshold level.
A method to predict which patient will be likely to develop edema when treated with a drug comprising the steps of:
- a) determining the pattern of protein expression in a biological sample for two or more of the protein products of the 13 predictor genes shown in Table 2;
- b) comparing the pattern of protein expression with the pattern expected for the Edema and the No Edema expression profile shown in Table 3;
- c) determining that if the pattern is more similar to the No Edema pattern that the patient will not be likely to develop edema when treated with a drug;
- and
- d) determining that if the pattern is more similar to the Edema pattern that the patient will be likely to develop edema when treated with a drug.
(canceled)
A method to design clinical trials for the testing of drugs comprising the steps of:
- a) determining by the use of either expression profiling or genotyping methods the likelihood that a particular patient will develop edema when exposed to the test drug;
- and
- b) assigning that patient to the appropriate classification in the clinical trial based on the results of the determination in (a).
27-42. (canceled)
A kit for predicting which patient will be likely to develop edema when treated with a drug comprising:
- (a) a means for determining the pattern of protein expression corresponding to the two or more of the 13 predictor genes shown in Table 2;
- (b) a container suitable for containing the means and the biological sample of the patient comprising the proteins, wherein the means can form complexes with the proteins;
- (c) a means to detect the complexes of (b);
- and
- (d) instructions for use and interpretation of the kit results.
(canceled)
A kit for predicting which patient will be likely to develop edema when treated with a drug comprising:
- (a) a means for determining the level of the protein expressed by the IL-1β gene;
- (b) a container suitable for containing the means and the biological sample of the patient comprising the protein, wherein the means can form complexes with the protein;
- (c) a means to detect the complexes of (b);
- and
- (d) instructions for use and interpretation of the kit results.
48-71. (canceled)
A kit for determining the identity of the nucleotide pair at the −511 position of the IL-1β gene (at position 1423 of sequence X04500) from the transcriptional start site for the two copies of the IL-1β gene present in the patient;
- comprising:
- a) a container comprising at least one reagent specific for detecting the nature of the nucleotide pair at the at the −511 position of the IL-1β gene (at position 1423 of sequence X04500) from the transcriptional start site for the two copies of the IL-1β gene present in the patient;
- and
- b) instructions for interpreting the results based on the nature of the said nucleotide pair.
A kit for determining the identity of the nucleotide pair at the polymorphic site at position −31 base pairs upstream (at position 1903 of sequence X04500) from the transcriptional start site;
- comprising:
- a) a container comprising at least one reagent specific for detecting the nature of the nucleotide pairs at the polymorphic site at position −31 base pairs upstream (at position 1903 of sequence X04500) from the transcriptional start site;
- and
- b) instructions for interpreting the results based on the nature of the said nucleotide pair.
74-75. (canceled)
Dependencies are inferred from the claim text.