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: April 16, 2016 | Author: | No Comments »

Categories: Drug Discovery Human Genetics Precision Medicine

Water does not resist. Water flows…But water always goes where it wants to go, and nothing in the end can stand against it.” – Margaret Atwood

The path of least resistance leads to crooked rivers and crooked men.” – Henry David Thoreau

What fraction of potential protein targets is accessible to conventional therapeutic modalities such as small molecules and protein biologics? The “druggable genome”, a term coined by Hopkins and Groom in 2002 (here), provides an estimate: approximately 10% of proteins in the human body are druggable by small molecule therapeutics. Greg Verdine and others estimate that an additional 10% of protein targets – those that are extracellular proteins – are druggable by biologics (here; excellent podcast by Janelle Anderson, humanPoC, here). Derek Lowe, however, has blogged that there is a lot of uncertainty in these estimates (here, here).

But just because a protein is druggable does not necessarily make it a potential drug target, for that honour belongs only to proteins that are also linked to disease”. That is, proteins that are compelling targets based on causal human biology may not be druggable.

These two issues create a natural tension for drug hunters at the start of a drug discovery program: pursue those targets that are druggable or those targets with the most compelling human evidence.

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