Methods for artificial combinatorial control of biological systems
원문보기
IPC분류정보
국가/구분
United States(US) Patent
등록
국제특허분류(IPC7판)
G06F-019/00
C40B-050/02
G06F-019/12
출원번호
US-0118395
(2011-05-28)
등록번호
US-10095842
(2018-10-09)
발명자
/ 주소
Paternostro, Giovanni
Feala, Jacob D
출원인 / 주소
SALGOMED, INC.
대리인 / 주소
Wagenknecht IP Law Group PC
인용정보
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0인용 특허 :
2
초록▼
Methods and systems for determining a set of control molecules for use in a combinatorial approach for the treatment of medical conditions, including providing one or more sets of control molecules, where each control molecule within the set acts on a set of targets and the number of control molecul
Methods and systems for determining a set of control molecules for use in a combinatorial approach for the treatment of medical conditions, including providing one or more sets of control molecules, where each control molecule within the set acts on a set of targets and the number of control molecules within the one or more sets of control molecules is fewer than the number of targets within the sets of targets; and searching within the sets of control molecules to identify a subset of control molecules that together with a subset of targets form an artificial system to produce a biological effect through the modulation of the subset of targets.
대표청구항▼
1. A therapeutic method against a hematological cancer, the method comprising: a) providing a biological sample from blood or bone marrow of a patient suffering from a hematological cancer, the sample comprising cells;b) providing a plurality of control molecules as a set of control molecules, where
1. A therapeutic method against a hematological cancer, the method comprising: a) providing a biological sample from blood or bone marrow of a patient suffering from a hematological cancer, the sample comprising cells;b) providing a plurality of control molecules as a set of control molecules, wherein each control molecule of the set is independently selected from the group consisting of a microRNA, a small molecule, a peptide, a protein, a cytokine, and a metabolite;c) isolating cancer cells using density gradient centrifugation;d) obtaining RNA sequence data from the cancer cells and selecting a subset of control molecules from a measure of enrichment in differentially expressed genes in groups including targets of the control molecules and their neighbors within a network model of intracellular interactions, wherein the enrichment in differentially expressed genes is measured by measuring and comparing RNA expression data of the cancer cells and the control cells;e) assaying the subset of control molecules with the cells using an endpoint assay to obtain a set of assay results for a biological effect, wherein the endpoint assay is selected from the group consisting of an assay that determines growth, survival, or death of a living cell or an assay that determines differentiation from one cell type to another cell type under in vitro testing conditions providing a significant correlation between the effects of the same drugs in vitro and in vivo;f) executing a software platform that manages design of combinations with an algorithm, exchanges files between liquid handling and plate readout equipment, maps combinations to measured data, and compiles results;g) searching with a liquid handler, multi-well plates and a plate reader, an experimental space over iterations of measurements;h) retrieving and storing files from a database to identify reagents, track reagent combinations dispensed in wells of a series of multi-well plates, maintain assay data measured for each combination, and generate plate maps and files for interfacing liquid handlers and plate readers while searching the experimental space;i) searching the set of assay results to identify a subset of control molecules, wherein i) the subset of control molecules is composed of at least three of the plurality of control molecules,ii) each of the control molecules of the subset binds at least three targets,iii) each of the at least three targets binds at least three of the control molecules in the subset, andiv) at least three of the control molecules of the subset bind to one or more shared targets, wherein a shared target is a target that binds at least two of the control molecules;further wherein each target is a molecule independently selected from the group consisting of a cellular protein, an RNA, and a metabolite;j) providing the identified subset of control molecules as contributing to a combinatorial therapy for a patient having a same hematological cancer; andk) administering the subset of control molecules to the patient. 2. The method of claim 1, wherein a size of the set of control molecules, as a percentage of the targets, is between 0.5% and 20%. 3. The method of claim 1, where a number of interactions between the control molecules of the subset and the targets, as a percentage of all possible interactions between control molecules and targets, is between 0.1% and 10%. 4. The method of claim 1, wherein an average percentage of overlap between a first set of targets with another set of targets is between 0.1% and 10%. 5. The method of claim 1, wherein a number of control molecules of the subset per target follows a monotonically decreasing distribution, optionally comprising an exponential or power-law distribution. 6. The method of claim 5, wherein the number of control molecules of the subset per target is determined by prioritizing the targets using biological information. 7. The method of claim 1, wherein a number of targets per control molecule of the subset follows a monotonically decreasing distribution, optionally comprising an exponential or power-law distribution. 8. The method of claim 1, wherein the a majority of the targets are protein kinases or mRNA molecules. 9. The method of claim 1, wherein each target is a protein kinase. 10. The method of claim 1, wherein targets are a set of targets selected from the group consisting of a set of protein kinases, protein phosphatases, proteases, microRNAs, and metabolic enzymes. 11. The method of claim 1, wherein the biological sample is obtained by a same patient as the use of the combinatorial therapy, thereby optimizing the combinatorial therapy for an individual patient. 12. The method of claim 1 where a size of the subset of control molecules as a percentage of a size of targets is between 0.3% and 10%. 13. The method according to claim 1, wherein the subset of control molecules are kinase inhibitors. 14. The method of claim 1, where the set of control molecules are component of cell culture media used for testing and are optimized to provide the biological effect of a statistically significant correlation of the response to the same drugs in vitro and in vivo. 15. The method of claim 1, where the step of searching the set of assay results further comprises molecular profiling of the cancer cells and clustering of patient subpopulations.
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이 특허에 인용된 특허 (2)
Mehta, Arpita I.; Liotta, Lance A.; Petricoin, Emanuel F., Combinatorial therapy for protein signaling diseases.
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