Plenge Lab
Date posted: April 24, 2016 | Author: | No Comments »

Categories: Drug Discovery Human Genetics Immunogenomics

Inevitably when I post a blog on “human biology” I get a series of comments about the importance of non-human model organisms in drug discovery and development. My position is clear: pick targets based on causal human biology, and then use whatever means necessary to advance a drug discovery program to the clinic.

Very often, non-human model organisms are the “whatever means necessary” to understand mechanism of action. For example, while human genetic studies identified PCSK9 as an important regulator of LDL cholesterol, mouse studies were critical to understand that PCSK9 acts via binding to LDL receptor (LDLR) on the surface of cells (see here). As a consequence, therapeutic antibodies were designed to block circulating PCSK9 from the blood and increase LDLR-mediated removal of circulating LDL (and hopefully to protect from cardiovascular disease).

Moreover, non-human animal models are necessary to understand in vivo pharmacology and safety of therapeutic molecules before advancing into human clinical trials.

Beyond drug discovery, of course, studies from non-human animal models provide fundamental biological insights. Without studies of prokaryotic organisms, for example, we would not have powerful genome-editing tools such as CRISPR-Cas9. Without decades of work on mouse embryonic stem cells, we would not have human induced pluripotent stem cells (iPSCs).…

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Date posted: February 20, 2015 | Author: | No Comments »

Categories: Drug Discovery Human Genetics Immunogenomics

Oliver Sacks has terminal cancer. If you have not yet read his heart-warming Op-Ed piece in the New York Times and if you only have five-minutes to spare, then I suggest you read his essay rather than this blog about “experiments of nature” in drug discovery. In his essay, Dr. Sacks concludes with the poignant sentence: “Above all, I have been a sentient being, a thinking animal, on this beautiful planet, and that in itself has been an enormous privilege and adventure.

Why do I start this week’s blog about articles of the week with this reference? I do so because of two additional – and seemingly unrelated – items from this week: (1) a brief Twitter exchange with David Shaywitz, Derek Lowe, and others that “few people at public biopharmas write interesting stuff, vs consultant-and-PR-driven banality”; and (2) an article in the New York Times Magazine about how Twitter posts can get you into trouble with your employer (see here).

So why do I blog, tweet, etc. given the potential risk? I enjoy the public exchange of ideas because, as Dr. Sacks write, that is the essence of our “sentient being”. I enjoy a network of inter-related ideas for which I can create unique connections.…

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Date posted: December 11, 2014 | Author: | No Comments »

Categories: Drug Discovery Human Genetics Immunogenomics

Welcome to this second blog post on genetics/genomics for drug discovery! So far, we are 2 for 2. That is, this is the second week in a row where we have reviewed the literature for interesting journal articles and written a blog on why the study is relevant for drug discovery. I say “we”, because this week I asked for input from our Merck Genetic & Pharmacogenomics (GpGx) team. We received a number of interesting submissions from GpGx team members, as summarized at the end of the blog.

This week’s article uses antisense as therapeutic proof-of-concept in humans for a genetic target…again! This story is reminiscent of last week’s post on APOC3 (see here).

Factor XI Antisense Oligonucleotide for Prevention of Venous Thrombosis, New England Journal of Medicine (December 2014).

Summary of the manuscript: While patients with congenital Factor XI deficiency have a reduced risk of venous thromboembolism (VTE), it is unknown whether therapeutic modulation of Factor XI will prevent venous thromboembolism without increasing the risk of bleeding. In this open-label, parallel-group study, 300 patients who were undergoing elective primary unilateral total knee arthroplasty were randomly assigned to receive one of two doses of FXI-ASO (200 mg or 300 mg) or 40 mg of enoxaparin once daily.…

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Date posted: August 20, 2014 | Author: | No Comments »

Categories: Drug Discovery Human Genetics Uncategorized

In this post I will build on previous blogs (here, here, here) about genetics for target ID and validation (TIDVAL).  Here, I argue that new targets with unambiguous promotable advantage will emerge from studies that focus on genetic pathways rather than single genes.

This is not meant to contradict my previous post about the importance of genetic studies of single genes to identify new targets.  However, there are important assumptions about the single gene “allelic series” approach that remain unknown, which ultimately may limit its application. In particular, how many genes exist in the human genome have a series of disease-associated alleles?  There are enough examples today to keep biopharma busy.  Moreover, I am quite confident that with deep sequencing in extremely large sample sizes (>100,000 patients) such genes will be discovered (see PNAS article by Eric Lander here).  Given the explosion of efforts such as Genomics England, Sequencing Initiative Suomi (SISu) in Finland, Geisinger Health Systems, and Accelerating Medicines Partnership, I am sure that more detailed genotype-phenotype maps will be generated in the near future.

[Note: Sisu is a Finnish word meaning determination, bravery, and resilience; it is about taking action against the odds and displaying courage and resoluteness in the face of adversity. …

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