Over the holidays my family participated in an Escape Room, a live puzzle adventure game. We worked as a team to solve riddles, find clues and, over the course of 60-minutes, complete an old town bank heist. Many of the successful clues came from unexpected places – coordinates on maps, numbers inscribed in hidden places, and physical features of the room itself. Other clues seemed promising, but ultimately led to dead ends. In the end, everything came together and we escaped with only seconds to spare.
And so it goes with the invention of new medicines. The approval of a new medicine is an Escape Room of sorts, but over the course of decades not minutes. And like an Escape Room, clues can come from unexpected places, with some leading to new insights and others leading to dead ends.
I was in an Escape Room state-of-mind as I read a Science Translational Medicine article that developed a system to differentiate blood cells into microglia-like cells to study gene variants implicated in neurodegenerative disorders (here). In this blog, I provide a brief summary of the study, and then describe the potentially interesting phenomenon of genetically driven tissue-specific pathogenicity.…
There were so many good articles and news reports this week on genetics/genomics and drug discovery & development. A few examples include: article in Nature Communications on gene therapy via CRISPR/Cas9 for retinitis pigments (here); a partnership between Editas and Allergan (Matthew Herper story here); Nature Reviews Genetics article by Khera and Kathiresan on genetics of coronary heart disease (here); Genome Magazine article on the importance of pharmacogenetics across ethnic groups to prevent severe adverse events (here); and a victory for pre-prints in challenging the statistical robustness of a publication in Nature Genetics (here).
I decided to focus on a study that provides a mechanistic link between a genetic mutation and a therapeutic hypothesis in Parkinson’s disease. The reason I chose this article is that it highlights the challenges of going from a robust genetic association to a biology hypothesis, and ultimately how to gain confidence in a therapeutic hypothesis with pre-clinical models. As you will see at the end, a clinical trial is now underway to test the therapeutic hypothesis in humans.
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).…
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.…