Plenge Lab
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. But I also try to be very careful about the topics that I choose, as I have a corporate responsibility to my employer, Merck. In particular, I focus on those topics that appear in the public domain, and I try to add some value to the public discourse via my perspective in the pharmaceutical development.

So with that catharsis…

This week’s theme is about interesting “experiments of nature” in drug discovery that have appeared in the public domain over the past week. All public articles relate to the theme I have discussed previously about the fundamental challenge in drug discovery: we pick the wrong targets and test the wrong therapeutic hypotheses in humans. To overcome this challenge, I believe it is important to leverage “experiments of nature” in humans, the “ultimate model organism”.

I won’t comment on all of the wonderful epigenetics papers that came out in Nature journals (see NYT article here). I will point you to a cool YouTube video on the subject of Epigenome: The symphony in your cells (see here), and also to papers that implicate immune cells in Alzheimer’s disease (here) and genetic switches in autoimmunity (here). For the latter study, the authors used an approved therapy for rheumatoid arthritis, tofacitinib, to provide a therapeutic link between epigenetics and disease. [I cannot resist adding that tofacitinib was developed, in part, because of observations that human JAK3 mutations lead to immunodeficiency…but I digress.]

Chromothriptic Cure of WHIM Syndrome, McDermott et al (Cell, February 2015). A mother of 58 years old went to the NIH with her two daughters in their early twenties for an evaluation because she feared that her daughters had inherited a serious disease which she had when she was young. The two daughters were diagnosed with a rare genetic disease called WHIM syndrome (which stands for Warts, Hypogammaglobulinemia, Infections, and Myelokathexis), an immunodeficiency disease caused by gain-of-function mutation of the chemokine receptor CXCR4 (see “Shattered chromosome” story in Science here). The mother and her two daughters all carry the same causative CXCR4 mutation, but the mother who had symptoms as a child was now healthy. How had she been cured? The rigorous investigation into this question was performed by a team of scientists led by Dr. Philip Murphy at NIH. In the mother, as illustrated in an overview Figure from the paper, a large-scale chromosomal rearrangement (termed chromothripsis, or chromosome shattering) occurred in her hematopoietic cells carrying the CXCR4 mutation. This “cured” hematopoietic stem cell then took over the bone marrow and restored her normal immune function. Through competitive bone marrow transplantation experiments in mice, the authors further demonstrated that Cxcr4 haploinsufficiency was sufficient to provide a competitive advantage to hemotopoietic stem cells in repopulating bone marrow cell lineages, suggesting that partial CXCR4 inactivation may be considered as a strategy for enhancing bone marrow transplantation. As it relates to drug discovery, this fascinating outcome of “experiment of nature” points to, once again, the power of causal human biology in understanding human health and disease, which in turn opens up the possibility of new and more effective treatment strategies. [Thanks to Richard Chen.]

AAV-expressed eCD4-Ig provides durable protection from multiple SHIV challenges, Gardner et al (Nature, February 2015). The NYT has a nice review on the study, including a very nice graphic for how the therapeutic protein works (see here). The key point that I want to emphasize is that the molecule works by blocking both the CD4-binding site and the CCR5-binding site on the surface of human cells, and that CCR5 is a target because of – you guessed it – human genetics (here). The therapeutic hypothesis now needs to be tested in humans.

A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases, Coll et al (Nature Medicine, February 2015). Several nice reviews have been written about this study (for example, here). Mutations in the NLRP3 gene have been associated with a spectrum of dominantly inherited autoinflammatory diseases called cryopyrin-associated periodic syndrome (CAPS), which includes Muckle-Wells syndrome. The Nature Medicine study describes the development of a potent, selective, small-molecule inhibitor of NLRP3, termed MCC950. The molecule was active in animal models of inflammation, as well as in ex vivo samples from individuals with Muckle–Wells syndrome. The authors conclude: “MCC950 is thus a potential therapeutic for NLRP3-associated syndromes, including autoinflammatory and autoimmune diseases, and a tool for further study of the NLRP3 inflammasome in human health and disease.” The therapeutic hypothesis now needs to be tested in humans.

Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways, Cirulli et al (Science, February 2015). This article describes a “moderate-scale” exome sequencing in ALS, which was done as a public-private partnership between multiple academic institutions (e.g., Duke, HudsonAlpha, Columbia University), Biogen Idec and others (see press release here). The authors performed whole exome sequencing of 2,874 ALS patients and 6,405 controls. In addition to mutations in known ALS genes, a novel association was found with the non-canonical IκB kinase family TANK-Binding Kinase 1 (TBK1) gene was identified. As stated in the abstract: “TBK1 is known to bind to and phosphorylate a number of proteins involved in innate immunity and autophagy, including optineurin (OPTN) and p62 (SQSTM1/sequestosome), both of which have also been implicated in ALS. These observations reveal a key role of the autophagic pathway in ALS and suggest specific targets for therapeutic intervention.”  There is a long way to go to get to a drug based on these findings, but the study does highlight the interest in genetics for drug discovery by companies like Biogen Idec.

Finally, I want to briefly mention a biotech deal and an FDA approval that are consistent with the “experiments of nature” in drug discovery theme (see FierceBiotech story here, newsletter from WuXi here).

Merganser Biotech raised a $28 million A round with the help of Novartis Venture Fund. I don’t know the science well, but the concept seems pretty interesting. According to FierceBiotech: “The company is at work on peptides that mimic hepcidin, a hormone produced by the liver that controls iron levels in the blood. The body uses hepcidin as a regulatory protein, dialing down production when it needs iron to stop a hemorrhage and then turning it back up to avoid a toxic response. Merganser’s candidates, by replicating the effects of hepcidin, promise to treat rare hematological disorders that result in dangerous iron overload, including hemochromatosis, beta thalassemia and myelodysplastic syndrome.

NPS Pharmaceutical, Inc. won FDA approval for Natpara, the first bioengineered replacement therapy cleared for U.S. marketing to treat hypoparathyroidism. Here, the experiment of nature is relatively straightforward. From the WuXI newsletter: “Hypoparathyroidism is a rare endocrine disorder, which the body secretes abnormally low levels of parathyroid hormone (PTH), resulting in low calcium levels (hypocalcemia) in your blood and bones and increased levels of serum phosphorus (hyperphosphatemia)… There is no effective treatment for hypoparathyroidism currently and the disease is managed clinically by calcium and vitamin D supplementation…Natpara is a recombinant human PTH, the first kind of biologic to treat hypoparathyroidism.





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