A recent study in the New England Journal of Medicine provides genetic support for a pharmacologically validated target, BAFF, in the treatment of systemic lupus erythematosus. But can human genetics also be used to estimate the target dose and a therapeutic window?
As readers of plengegen.com know, I am constantly on the lookout for published studies that provide insight into the utility of human genetics for drug discovery and development. This past week there was a great post from Francis Collins on the role of the NIH in the discovery (in part via human genetics) and development of tofacitinib (see here), anakinra and potentially novel targets (e.g., STING) for inflammatory diseases (here). Nature Reviews Drug Discovery published a News & Analysis on PCSK9 as a “fertile testing ground for new drug modalities including long-acting RNA interference drugs, vaccines against self-antigens, CRISPR therapeutics and small molecules that control ribosomal activity” (here). New York City released information about a new public health initiative, The NYC Macroscope, which will use electronic health records (EHRs) to track conditions managed by primary care practices that are important to public health..and one day may be linked to genetic data for discovery research (that is me just speculating).…
In response to an original research article published in Nature by Sekar Kathiresan and colleagues (see here), I penned a News & Views piece for Nature (here), a blog for the Timmerman Report (here, here), and a podcast for BBC Inside Science (here). An important theme for drug discovery & development is that human knockouts can rule-in and to rule-out drug targets.For human knock-out data, the key concept is to understand the effect of maximum genetic perturbation on human physiology.
Rule-in drug targets: As has been described by Matt Nelson and colleagues from GlaxoSmithKline (see 2015 Nature Genetics), and David Cook and colleagues from AstraZeneca (see 2014 Nature Reviews Drug Discovery), therapeutic molecules developed against targets with human geneticdata are more likely to lead to regulatory approval than those without.PCSK9 represents the poster child for human genetic knockouts in drug discovery & development (see my plengegen.com blog here).But there are many other examples, too.
Rule-out drug targets: But human genetics can also rule-out drug targets or mechanisms that are nominated through animal models, human epidemiology or other approaches.A prominent example is related to raising HDL cholesterol, the so-called “good cholesterol”.