Plenge Lab
Date posted: June 3, 2016 | Author: | No Comments »

Categories: Drug Discovery Human Genetics

 

One of the biggest challenges of drug discovery is to determine which targets, when perturbed, will have an acceptable efficacy-safety therapeutic window in patients. In fact, the success rate at choosing the right target and developing a safe and effective drug is quite low: less than 10% of drugs that enter Phase I are approved by regulatory authorities (see recent Nature Reviews Drug Discovery article here, Derek Lowe blog here). Most of the failures in Phase II and III are due to lack of efficacy or unexpected toxicity.

Human genetics offers one potential solution to identify new drug targets with an acceptable therapeutic window. A study published this week in Science Translational Medicine (STM) provides genetics support for an established therapeutic target in type 2 diabetes (T2D), glucagon-like peptide-1 receptor, GLP1R (link to STM article here).  What is surprising, however, is that human genetics suggests that GLP1R agonists may also protect from coronary heart disease (CHD).

[Disclaimer: I am a Merck/MSD employee. The opinions I am expressing are my own and do not necessarily represent the position of my employer.]

There are three points that I want to make in this blog. First, the STM study provides general support for the model that human genetics is useful to predict efficacy & safety in drug discovery.…

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Date posted: August 21, 2015 | Author: | No Comments »

Categories: Drug Discovery Embedded Genomics Human Genetics

I say article of the week, but I have been lazy this summer (or maybe just consumed by other things).  My last “article of the week” was in May and my last Plengegen blog post was over a month ago!

By now everyone knows the PCSK9 story. Human genetics identified the target; functional work in mouse and human cells led to a mechanistic understanding of PCSK9’s role in LDL receptor recycling; therapeutic modulation was shown to lower LDL cholesterol in clinical trials; and the FDA approved drugs based on LDL lowering, with outcome trials underway to demonstrate (presumably) cardiovascular benefit. What the story highlights is that a mechanistic understanding of causal pathways in human disease is key to the success of translating targets into therapies. Further, the PCSK9 story underscores the importance of a simple biomarker (LDL cholesterol) to measure a complex causal pathway in a clinical trial.

A recent study in the New England Journal of Medicine (NEJM) provides insight into a putative causal pathway in obesity, and thus a potentially a new mechanism for therapeutic modulation. The accompanying Editorial also provides a nice perspective.

[Disclaimer: I am a Merck/MSD employee. The opinions I am expressing are my own and do not necessarily represent the position of my employer.

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Date posted: December 19, 2014 | Author: | No Comments »

Categories: Drug Discovery Human Genetics

This week’s theme is genes to function for drug screens…with a macabre theme of zombies! As more genes are discovered through GWAS and large-scale sequencing in humans, there is a pressing need to understand function. There are at least two steps: (1) fine-mapping the most likely causal genes and causal variants; and (2) functional interrogation of causal genes and causal variants to move towards a better understanding of causal human biology for drug screens (“from genes to screens”).

Genome-editing represents one very powerful tool, and the latest article from the laboratory of Feng Zhang at the Broad Institute takes genome-editing to a new level (see Genetic Engineering & Biotechnology News commentary here).  They engineer the dead!

Genome-scale gene activation by an engineered CRISPR-Cas9 complex, Nature (December 2014).

Since its introduction in late 2012, the CRISPR-Cas9 gene-editing technology has revolutionized the ways scientists can apply to interrogate gene functions. Using a catalytically inactive Cas9 protein (dead Cas9, dCas9) tethered to an engineered single-guide RNA (sgRNA) molecule, the authors demonstrated the ability to conduct robust gain-of-function genetic screens through programmable, targeted gene activation.

Earlier this year, the laboratories of Stanley Qi, Jonathan Weissman and others \ reported the use of dCas9 conjugated with a transcriptional activator for gene activation (see Cell paper here).…

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Date posted: September 8, 2014 | Author: | No Comments »

Categories: Drug Discovery Human Genetics

So, you have a target and want to start a drug discovery program, do ya?  How would you do it?

When I was at Brigham and Women’s Hospital, Harvard Medical School and the Broad Institute, I presented an idea from an early GWAS of rheumatoid arthritis (RA, see here) to Ed Scolnick (former president of Merck Research Labs, now founding director of the Stanely Center at the Broad Institute, see here).  In this study, we found evidence that a non-coding variant at the CD40 gene locus increased risk of RA.  The first questions he asked: How does the genetic mutation alter CD40 function? Is it gain-of-function or loss-of-function?  What assay would you use for a high-throughput small molecule screen to recapitulate the genetic finding?

I was caught off-guard.  Sadly, I had never really thought about all of the details.  At the time, I knew enough as a clinician, biologist and a geneticist to appreciate that CD40 was an attractive drug target for RA.  However, I was quite naïve to the steps required to take a target into a drug screen.  That simple conversation led to several years worth of work, which ultimately led to a proof-of-concept phenotypic screen published in PLoS Genetics five years later (see here).…

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Date posted: August 29, 2014 | Author: | No Comments »

Categories: Drug Discovery Human Genetics Uncategorized

In my previous blog series I talked about why genetics is important in drug discovery: human genetics takes you to a target, informs on mechanism of action (MOA) for therapeutic perturbation, provides guidance for pre-clinical assays of target engagement, and facilitates indication selection for clinical trials.

Here, I provide an overview of a new blog series on how genetics influences decision-making during drug discovery.  The key principle: human genetics establishes a disciplined mindset and a firm foundation – anchoring points – for advancing targets through the complicated process of drug discovery.  [For those less familiar with drug discovery, the end of this blog provides a brief primer on the stages of drug discovery.]

I highlight three areas: establishing a balanced portfolio, identifying targets with novel MOA, and creating a framework for objective decision-making.  In subsequent posts, I will focus primarily on how human genetics informs on the latter (decision-making), with blogs pertaining to designing assays for screens and target engagement, utilizing pre-clinical animal models, predicting on-target adverse drug events, and selecting indications for clinical trials.

1. Establish a balanced portfolio

Whether in academic research, a small biotech company (see here) or a large pharmaceutical company (such as Merck, where I work), a balanced portfolio of projects is very important.…

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Date posted: August 16, 2014 | Author: | No Comments »

Categories: Drug Discovery Human Genetics

Question: What can we learn from Sputnik (see here), DARPA (see here) and disruptive innovation (see here) to invent new drugs?

Answer: The best way to prevent surprise is to create it. And if you don’t create the surprise, someone else will. (This is a cryptic answer, I know, but I hope the answer will become clearer by the end of the blog.)

My previous blogs highlighted (1) the pressing need to match an innovative R&D culture with an innovative R&D strategy rooted in basic science (see here), and (2) the importance of phenotype in target ID and validation (TIDVAL) efforts anchored in human genetics (see here).  Now, I want to flesh out more of the scientific strategy around human genetics – with a focus on single genes and single drug targets.

To start, I want to frame the problem using an unexpected source of innovation: the US government.

There is an interesting article in Harvard Business Review on DARPA and “Pasteur’s Quadrant” – use-inspired, basic-science research (see here and here).  This theme is critically important for drug discovery, as the biopharma industry has a profound responsibility to identify new targets with increased probability-of-success and unambiguous promotable advantage (see here).   …

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