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Method of identifying individuals at risk of thiopurine drug resistance and intolerance

A thiopurine and tolerance technology, applied in the identification of individuals at risk of thiopurine drug resistance and intolerance, can solve problems such as toxicity

Inactive Publication Date: 2010-09-01
UNIVERSITY OF OTAGO
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

6-TGN is beneficial, while 6-MMPR can be toxic
To date there is no satisfactory molecular explanation for this ultrametaboliser (UM) phenotype of TPMT

Method used

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  • Method of identifying individuals at risk of thiopurine drug resistance and intolerance
  • Method of identifying individuals at risk of thiopurine drug resistance and intolerance
  • Method of identifying individuals at risk of thiopurine drug resistance and intolerance

Examples

Experimental program
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Embodiment 1

[0130] A 50-year-old Caucasian male (patient A) with indeterminate colitis had RBC TPMT activity found to be as high as 25.6 units / ml RBC (referred to as figure 1 "Indicator Case" in ), using radiochemical analysis (Weinshilboum et al., 1999). TPMT phenotypes were first offered as a clinical service in Christchurch (New Zealand) in 2003 (Sies et al., 2005) and since then over 2000 individuals have been tested. The standard range of TPMT activity, as measured by phenotypic assays, is 9.3 to 17.6 units / ml RBC ( figure 1). The highest available activity previously recorded was 22.5 units / ml RBC (Sies et al., 2005). Since Patient A did not receive any inhibitory drug treatment to induce TPMT activity, it is conceivable that his UM status was due to a mutation within the TPMT promoter. To test this hypothesis, the TPMT promoter was sequenced in this patient, as were nine other individuals with the UM phenotype (18.4-22.5 units / ml RBC).

[0131] Genomic DNA was extracted from 5 ...

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Abstract

The invention relates to methods and kits for identifying individuals at risk of thiopurine drug intolerance based on detecting the presence of mutations in the TPMT gene promoter associated with thiopurine drug resistance or intolerance.

Description

field of invention [0001] The present invention relates to methods and kits for identifying individuals at risk of thiopurine drug intolerance. These methods and kits are based on detecting the appearance of mutations in the promoter of the TPMT gene associated with thiopurine resistance or intolerance. Background of the invention [0002] Thiopurine drugs (mainly azathioprine and 6-mercaptopurine) are used to treat a wide range of diseases. Among these are acute lymphoblastic leukemia, complications associated with solid organ transplantation, autoimmune diseases such as rheumatoid arthritis and inflammatory bowel disease (IBD), and dermatological conditions. [0003] Thiopurine drugs are inert and are metabolized in vivo to form the active metabolites 6-methylmercaptopurine nucleoside (6-MMPR) and 6-thioguanine (6-TGN). 6-TGN is beneficial, while 6-MMPR may be toxic. Unfortunately, up to 40% of individuals show resistance or intolerance to treatment with thiopurine drug...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12Q1/68C12N15/00
CPCC12N9/1007C12Q2600/156C12Y201/01067C12Q2600/158C12Q1/6883
Inventor 丽贝卡·L·罗伯茨理查德·B·吉尔里默里·L·巴克莱马丁·A·肯尼迪
Owner UNIVERSITY OF OTAGO
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