Plenge Lab
Date posted: April 14, 2013 | Author: | No Comments »

Categories: Drug Discovery Human Genetics Immunogenomics

I prepared a lecture for immunology graduate students at Harvard Medical School on clinical features of rheumatoid arthritis (RA) for the G1 IMM302qc class. 

The slide deck can be found here

A brief summary:

•Clinical characteristics and pathophysiology
•Differential diagnosis
•Exam and laboratory studies
•Treatment strategy
•Research opportunities
•Case presentations
 
The future research opportunities include using human genetics as an anchor for drug discovery in RA.  I briefly go over three strategies:
 

(1) “look-up” method – simple and suggestive but undisciplined (examples in RA: IL6R/tocilizumab, CTLA4/abatacept)

(2) “Allelic series” method – powerful but likely infrequent (example in other disease: PCSK9)

(3) “pathway” method – powerful and comprehensive but target ID difficult (example in RA: CD40 signaling; Gang Li et al, in press PLoS Genetics)

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Date posted: April 3, 2013 | Author: | No Comments »

Categories: Drug Discovery Human Genetics Immunogenomics

This blog post pertains to the Systems Immunology graduate course at Harvard Medical School (Immunology 306qc; see here), which is led by Drs. Christophe Benoist, Nick Haining and Nir Hacohen.  My lecture is on the role of human genetics as a tool for understanding the human immune system in health and disease.  What follows is an informal description of my lecture.  The slide deck for the lecture can be downloaded here.  Throughout, I have added key references, with links to the manuscripts and other web-based resources embedded within the blog (and also listed at the end).  I highlight five key manuscripts (#1, #2, #3, #4, and #5), which should be reviewed prior to the lecture; the other references, while interesting, are optional.

Overview

It is increasingly clear that humans serve as the best model organism for understanding human health and disease.  One reason for this paradigm shift is the lack of fidelity of most animal models to human disease.  For systems immunology, the mouse is a powerful model organism to understand fundamental mechanisms of the immune system.  However, studies in humans are required to understand how these mechanisms can be translated into new biomarkers and drugs.…

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Date posted: February 8, 2013 | Author: | No Comments »

Categories: Drug Discovery Precision Medicine

Genetics can guide the first phase of drug development (identifying drug targets, see here ) as well as late phase clinical trials (e.g., patient segmentation for response/non-responder status, see here ). But is there a convergence between the two areas, or pharmaco-convergence (a term I just made up!)? And are there advantages to a program anchored at both ends in human genetics?

 

Consider the following two hypothetical examples.

(1) Human genetics identifies loss-of-function (LOF) mutations that protect from disease. The same LOF mutation is associated with an intermediate biomarker, but is not associated with other phenotypes that might be considered adverse drug events. A drug is developed that mimics the effect of the mutation; that is, a drug is developed that inhibits the protein product of the gene. In early mechanistic studies, the drug is shown to influence the intermediate biomarker in a way that is consistent to that predicted by the LOF-protective mutations. Further, because functional studies of the LOF-protective mutations provide insight into relevant biological pathways in humans (e.g., a gene expression signature that correlates with mutation carrier status), additional information is known about genomic signatures of those who carry the LOF-protective mutations (which mimics drug exposure) compared to those who do not carry the LOF-protective mutations (which mimics those who are not exposed to drug).…

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