Researcher: Guy’s & St Thomas’ Hospital
Background: In recent years there has been a shift in IBD treatment paradigms away from symptomatic improvement alone towards mucosal healing and altered natural history. This dictates the use of early aggressive therapy, creating a demand to tailor treatments to the individual in order to maximise clinical response, limit toxicity and prevent treatment failure.
These drugs are recommended as the first line immunomodulators in IBD and have an important role in optimizing the response to biological agents. Hence, they remain a key component of nearly all IBD treatment regimens. However, thiopurines are not effective in up to half of patients and one-fifth have to discontinue therapy due to adverse reactions. Importantly, second line immunomodulators such as methotrexate are less proven and have greater overall toxicity. Hence there remains great value in any measures that improve the tolerance and efficacy of thiopurines.
Aims: In this research the aim is to establish the mechanism of thiopurine (azathioprine (AZA) / 6-mercaptopurine (6-MP)) drug hypermethylation, which has a strong association with thiopurine resistance, hepatotoxicity and other side effects. The research will identify novel genetic markers that predict thiopurine hypermethylation, which may be used in conjunction with thiopurine-S-methyltransferase (TPMT) testing prior to the start of treatment.
The aim of this research is therefore to identify biomarkers that predict hypermethylation prior to the start of treatment, which will translate into an improvement in treatment outcome for patients.
Anticipated Outcome: Hypothesis is thiopurine hypermethylation occurs due to changes in genes that affect the methylation potential of TPMT and is also influenced by changes in efflux of methylated metabolites from cells.
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