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Yang X.,Merck And Co. | Zhang B.,Merck And Co. | Molony C.,Merck And Co. | Chudin E.,Merck And Co. | And 17 more authors.
Genome Research | Year: 2010

Liver cytochrome P450s (P450s) play critical roles in drug metabolism, toxicology, and metabolic processes. Despite rapid progress in the understanding of these enzymes, a systematic investigation of the full spectrum of functionality of individual P450s, the interrelationship or networks connecting them, and the genetic control of each gene/enzyme is lacking. To this end, we genotyped, expression-profiled, and measured P450 activities of 466 human liver samples and applied a systems biology approach via the integration of genetics, gene expression, and enzyme activity measurements. We found that most P450s were positively correlated among themselves and were highly correlated with known regulators as well as thousands of other genes enriched for pathways relevant to the metabolism of drugs, fatty acids, amino acids, and steroids. Genome-wide association analyses between genetic polymorphisms and P450 expression or enzyme activities revealed sets of SNPs associated with P450 traits, and suggested the existence of both cis-regulation of P450 expression (especially for CYP2D6) and more complex trans-regulation of P450 activity. Several novel SNPs associated with CYP2D6 expression and enzyme activity were validated in an independent human cohort. By constructing a weighted coexpression network and a Bayesian regulatory network, we defined the human liver transcriptional network structure, uncovered subnetworks representative of the P450 regulatory system, and identified novel candidate regulatory genes, namely, EHHADH, SLC10A1, and AKR1D1. The P450 subnetworks were then validated using gene signatures responsive to ligands of known P450 regulators in mouse and rat. This systematic survey provides a comprehensive view of the functionality, genetic control, and interactions of P450s. © 2010 by Cold Spring Harbor Laboratory Press. Source

Kim S.R.,Chonbuk National University | Lee K.S.,Chonbuk National University | Park H.S.,Chungnam National University | Park S.J.,Chonbuk National University | And 4 more authors.
European Journal of Immunology | Year: 2010

Hypoxia-inducible factor-1α (HIF-1α) plays a critical role in immune and inflammatory responses. One of the HIF-1α target genes is vascular endothelial growth factor (VEGF), which is a potent stimulator of inflammation, airway remodeling, and physiologic dysregulation in allergic airway diseases. Using OVA-treated mice and murine tracheal epithelial cells, the signaling networks involved in HIF-1α activation and the role of HIF-1α in the pathogenesis of allergic airway disease were investigated. Transfection of airway epithelial cells with HIF-1α siRNA suppressed VEGF expression. In addition, the increased levels of HIF-1α and VEGF in lung tissues after OVA inhalation were substantially decreased by an HIF-1α inhibitor, 2-methoxyestradiol. Our data also show that the increased numbers of inflammatory cells, increased airway hyperresponsiveness, levels of IL-4, IL-5, IL-13, and vascular permeability in the lungs after OVA inhalation were significantly reduced by 2-methoxyestradiol or a VEGF inhibitor, CBO-P11. Moreover, we found that inhibition of the PI3K p110d isoform (PI3K-δ) or HIF-1α reduced OVA-induced HIF-1α activation in airway epithelial cells. These findings indicate that HIF-1α inhibition may attenuate antigen-induced airway inflammation and hyperresponsiveness through the modulation of vascular leakage mediated by VEGF, and that PI3K-δ signaling may be involved in the allergen-induced HIF-1α activation. © 2010 Wiley-VCH Verlag GmbH & Co. KGaA. Source

Haylock-Jacobs S.,University of Adelaide | Comerford I.,University of Adelaide | Bunting M.,University of Adelaide | Kara E.,University of Adelaide | And 5 more authors.
Journal of Autoimmunity | Year: 2011

The Class IA phosphoinositide 3-kinase delta (PI3Kδ) has been implicated in multiple signaling pathways involved in leukocyte activation and hence is an attractive target in many human autoimmune diseases, including multiple sclerosis (MS). Here, using mice expressing a catalytically inactive form of the PI3Kδ subunit p110δ, we show that signaling through PI3Kδ is required for full and sustained pathology of experimental autoimmune encephalomyelitis (EAE), a Th17-driven model of MS. In p110δ-inactivated mice, T cell activation and function during EAE was markedly reduced and fewer T cells were observed in the central nervous system (CNS). The decrease in T cell activation is unlikely to be due to defects in dendritic cell (DC) function, as p110δ-inactivated DCs migrate and present antigen normally. However, significant increases in the proportion of T cells undergoing apoptosis at early stages of EAE were evident in the absence of PI3Kδ activity. Furthermore, a profound defect in Th17 cellular responses during EAE was apparent in the absence of PI3Kδ activity while Th1 responses were less affected. A highly selective PI3Kδ inhibitor, IC87114, also had greater inhibitory effects on Th17 cell generation in vitro than it did on Th1 cell generation. Thus, PI3Kδ plays an important role in Th17 responses in EAE, suggesting that small molecule inhibitors of PI3Kδ may be useful therapeutics for treatment of MS and other autoimmune diseases. © 2011 Elsevier Ltd. Source

News Article | October 29, 2015
Site: techcrunch.com

Frazier Healthcare Partners, a 24-year-old venture firm that invests only in healthcare and has offices in both Seattle and Menlo Park, Ca., has just closed its eighth fund with $262 million from mostly earlier backers. While a coup, the pool is much smaller than Frazier’s predecessor fund, a $375 million vehicle raised in 2013. Yesterday, to find out why, we talked with general partner Jamie Topper, an M.D. and Ph.D who joined Frazier 13 years ago. TC: You’ve raised a far smaller fund this time around. What happened? JT: In the past, we’ve had multiple strategies within the same fund, including life sciences and health care services. Our newest fund is dedicated exclusively to life sciences. TC: For people who don’t follow healthcare, what distinguishes life sciences investing from health care services? JT: Life sciences investing is drug development, diagnostics, funding pre-clinical drugs and even drugs on the verge of getting commercialized. Health care services are things like pharmaceutical services or companies that package pharmaceuticals or deliver dialysis to patients and may have hundreds of centers. The latter more or less requires growth-stage capital. TC: What happens now to the partners who focused on those bigger, later-stage deals? JT: No one has left Frazier. It’s not splitting up. We’re likely instead to have multiple offerings. TC: What are some of your hits over the last five years? JT: We’ve had 10 M&A [exits] over the last five years and 7 IPOs, including Calistoga Pharmaceuticals’ sale to Gillead Sciences for $600 million; Incline Therapeutics’ sale for $275 million [to The Medicines Company]; and PreCision Dermatology’s sale to Valeant Pharmaceuticals for $575 million. We also had Collegium Pharmaceuticals and ProNai go public over the spring and summer. TC: Good timing. Life sciences IPOs have slowed down dramatically in the last two months, correct? JT: They have, after a four-year bull market in biotech. It’s not a terrible thing. It’s not the crash that happened in 2000. The biggest issue for life sciences investors is that we have to improve healthcare and develop new drugs at lower cost. We don’t need another drug where there are three other examples and we’re just going to jack up the price. Also, reimbursement and access to novel therapies receive more scrutiny in the past. So we look for teams that are innovative; companies that addressing a true, unmet need – not just because we think we can sell it but to ensure that regulators and reimbursers will agree with the companies; and we look for opportunities where we can see certain inflection points met within three to five years. TC: What size checks are you writing? JT: Two thirds of our investments have been seed or Series A deals, so we’re comfortable coming in early, but it has to be the right opportunity. We also create one to two companies per year. We created Calistoga and Incline. In terms of check sizes, we typically syndicate deals, investing around $5 million to $10 million up front, and between $15 million and $25 million across the life of a company. TC: Are you seeing many IT investors coming into deals suddenly? We hear a lot of talk about how big data is making drug development a more accessible, affordable endeavor for everyone. JT: There’s no question that technology is making drug development more effective. I could sequence your genome for $1,000 today and it used to cost $3 million just a few years ago. Computing power is an amazing thing. But you read about these guys from wherever who think, “This drug stuff can’t be hard. I’m going to take my strong computers and figure it out.” I’ve been hearing that a long time. Biology is incredibly complex and leveraging your insights is an enormously difficult enterprise. It takes a lot of experience and teams that are committed to doing it over time. So I don’t care how smart you are or how big your computer is, you won’t solve all the problems. It’s an iterative process.

Gilead Antes Up for Cancer, Genentech Eye Drug Passes Big Trial, Bigger Isn’t Better, & More Bay Area Life Sciences News This was a light news week in SF biotech, but it still flew by, as we get ready to make some small media biz news at our own little startup here on Monday. Stay tuned. —South San Francisco-based Genentech said its hit drug for eye diseases, ranibizumab (Lucentis) passed the second big pivotal trial in patients with diabetic macular edema. This is important not just to patients with a common condition that impairs vision, but it could help Genentech offset some of the sales it may lose if more patients with macular degeneration switch to a cheap, low-dose form of bevacizumab (Avastin) as an alternative. —Gilead Sciences (NASDAQ: GILD) said this week it has agreed to sponsor cancer research at Yale University in a deal that could be worth as much as $100 million over a 10-year period to the university. It’s the latest big bet on cancer by Foster City, CA-based Gilead, which agreed in February to pay as much as $600 million to buy Calistoga Pharmaceuticals, a cancer drug developer on the verge of pivotal studies. —In this week’s installment of the BioBeat column, I argued that Big Pharma has been its own worst enemy through its penchant for mega-mergers that make it next to impossible to foster innovation. —With all the talk about the crisis in venture capital, I’ve been thinking a bit lately about whether angels might somehow find a new niche in biotech financing. Angels, as Morgenthaler Ventures’ Bob Pavey points out in this guest editorial, have always played a role in backing new businesses, and they are particularly visible now in tech startups that can really run lean and mean in the cloud computing era. Biotech drug development has traditionally taken too long and cost too much for angels to play a serious role, but I wonder if readers see ways for angels to get in here now.

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