Welcome to Personalized Medicine In Translation (PERMIT)
Personalized medicine is both an emerging discipline and a destination. The goal of PERMIT--the ITMAT center for PERsonalized Medicine In Translation (PERMIT) -- is to shorten its path and accelerate its arrival. The paradigm is to integrate the skills of ITMAT investigators expert in (i) the Translational Therapeutics of small molecules (FitzGerald, Rader) and immunomodulators (June) (ii) Gene Function and Genomics (Hogenesch and Hakonarson) (iii) Pharmacokinetics and modeling (Barrett) (iv) Informatics (Landis) and Pharmacoepidemiology (Strom).
As such the activities of PERMIT are closely aligned with the ITMAT Biomedical Informatics in Translation (BIIT) center, the Kinetics Modeling and Simulation (KMAS) core and the Program in Novel Biotherapeutics (PINB).
The traditional approach to pharmacogenetics has been to harvest DNA from patients engaged in a trial designed for other purposes and to try to interpret how gene variation may have altered drug response. All too often, ethical and technical considerations limit the DNA available for analysis undermining the statistical power necessary to reach conclusions.
PERMIT investigators will act on hypotheses that emerge from epidemiological observations suggestive of an influence of gene variation on drug response and then subject this to rigorous proof of principle in settings such as cell based assays, high throughput in vivo systems, such as zebrafish and detailed mechanistic studies in humans in the Clinical and Translational Research Center (CTRC). These last will involve sophisticated approaches to evoking phenotypes which reveal drug–gene interactions. Internal consistency of evidence from these approaches will prompt the design of epidemiological approaches towards verification with the ultimate objective of rationally designed, controlled clinical trials.
A first example will be the study of nonsteroidal antinflammatory drugs (NSAIDs), the commonest drug class consumed worldwide. While NSAIDs relieve pain and inflammation they are associated with a small but absolute mechanism based hazard of gastrointestinal and cardiovascular injury. A program of research has been initiated to determine whether individuals differ in their susceptibility to benefit from a particular NSAID can be identified and if so, to elucidate the reasons why. Correspondingly, genomic, biomarker and physiological measurements are being deployed and integrated in systems approaches to determine whether emerging risk from this drug class can be detected.
Correspondingly, the search has begun for genetic signatures of individual drug response in vitro. Treating transformed B cells NSAIDs, high throughput genotyping and RNA expression dynamics experiments are being performed and will be analyzed in the context of clinical records in the search for diagnostic markers. This program has recently led to the submission of a NIGMS GLUE grant on the personalization of medicine.