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News Article | November 10, 2016
Site: www.eurekalert.org

Fuquay Varina, N.C. (November 10, 2016) - The National Center for Advancing Translational Sciences (NCATS) recently awarded $596,533.00 to Collaborations Pharmaceuticals, Inc. (CPI) to initiate a partnership with Texas Biomedical Research Institute aimed at repurposing an antimalarial for use against the Ebola virus. Since 2014, the outbreak of the Ebola virus in West Africa has resulted in 28,657 suspected cases and 11,325 deaths (according to WHO statistics) and highlighted the need for broad-spectrum antiviral drugs for this and other emerging viruses. Data from a published large scale high throughput screen performed by SRI International and Texas Biomedical Research Institute was used to create machine learning models that identified 3 compounds active against the virus in vitro (in a lab, outside of a living organism). This earlier work had suggested that antimalarial compounds, as well as other classes of approved drugs could be of interest for repurposing. "We used Bayesian machine learning models based on the earlier published dataset to screen a library of more than 2000 drugs and drug-like molecules, which then lead to the discovery that of the 3 compounds identified, a relatively new antimalarial called pyronaridine, approved in Europe had promising activity in vitro and could be worthy of testing in vivo (in a living organism) against the Ebola virus" said Sean Ekins, CEO CPI. "My lab has screened thousands of compounds against Ebola virus," said Dr. Robert Davey, Interim Chair of Texas Biomed's Department of Virology and Immunology. "This particular compound, pyronaridine, is promising because it is already an approved drug in Europe, has been used in thousands of patients and may have favorable molecular properties that could speed up its transition to clinical testing. We do not currently know the target of the three compounds and there is still considerable research needed." Dr. Davey is interested in understanding how viruses like Ebola virus penetrate the cell membrane and establish infection. In addition, Dr. Davey's laboratory has developed safe, efficient, high-throughput screening techniques for Ebola virus and performs contract work on testing drugs and compounds against Ebola virus infection in the biosafety level-4 maximum containment laboratory. This work has resulted in exciting findings towards potential drug candidates to combat Ebola virus. "This collaboration involves Texas Biomedical Research Institute, Stanford Research International and Rutgers University, and we are very grateful to NCATS for funding so we can illustrate how computational approaches can be used to repurpose drugs already approved for other uses and instead use for neglected diseases" said Dr. Ekins. Texas Biomed is one of the world's leading independent biomedical research institutions dedicated to advancing health worldwide through innovative biomedical research. Texas Biomed partners with hundreds of researchers and institutions around the world to develop vaccines and therapeutics against viral pathogens causing AIDS, hepatitis, herpes, hemorrhagic fevers and parasitic diseases responsible for malaria and schistosomiasis. The Institute also has programs in the genetics of cardiovascular disease, diabetes, obesity, psychiatric disorders and other diseases. Texas Biomed is home to the Southwest National Primate Research Center, one of seven NIH-supported primate research centers in the United States. For more information on Texas Biomed, go to http://www. . Collaborations Pharmaceuticals, Inc. performs research and development on innovative therapeutics for multiple rare and infectious diseases. We partner with leading academics and companies to identify and translate early preclinical to clinical stage assets. We have considerable experience in preclinical and computational approaches to drug discovery and toxicity prediction. For more information, please visit http://www.


Muir E.R.,University of Texas Health Science Center at San Antonio | De La Garza B.,University of Texas Health Science Center at San Antonio | Duong T.Q.,University of Texas Health Science Center at San Antonio | Duong T.Q.,South Texas Veterans Health Care System | Duong T.Q.,Southwest National Primate Research Center
Magnetic Resonance in Medicine | Year: 2013

This study tested the sensitivity of an arterial spin labeling MRI method to image changes in retinal and choroidal blood flow (BF) and anatomical thickness of the retina in the rd10 mouse model of retinitis pigmentosa. High-resolution (42 × 42 μm) MRI was performed on rd10 mice and age-matched controls at 25, 35, and 60 days of age (n = 6 each group) on a 7-T scanner. Anatomical MRI was acquired, and quantitative BF was imaged using arterial spin labeling MRI with a separate cardiac labeling coil. Histology was obtained to confirm thickness changes in the retina. In control mice, the retinal and choroidal vascular layers were quantitatively resolved. In rd10 mice, retinal BF decreased progressively over time, while choroidal BF was unchanged. The rd10 retina became progressively thinner at later time points compared with age-matched controls by anatomical MRI and histology (P < 0.01). BF and anatomical MRI were capable of detecting decreased BF and thickness in the rd10 mouse retina. Because BF is tightly coupled to metabolic function, BF MRI has the potential to noninvasively assess retinal diseases in which metabolism and function are perturbed and to evaluate novel treatments, complementing existing retinal imaging techniques. Magn Reson Med, 2013. © 2012 Wiley Periodicals, Inc. Copyright © 2012 Wiley Periodicals, Inc.


Kochunov P.,University of Texas Health Science Center at San Antonio | Kochunov P.,Southwest National Primate Research Center | Duff Davis M.,University of Texas Health Science Center at San Antonio | Duff Davis M.,Southwest National Primate Research Center
Methods | Year: 2010

Structural imaging research offers excellent translational benefits when non-human primate (NHP) models are employed. In this paper, we will discuss the development of anatomical MR imaging protocols for two important applications of structural imaging in NHPs: studies of genetic variability in brain morphology and longitudinal imaging of fetal brain maturation trends. In contrast with imaging studies of adult humans, structural imaging in the NHPs is challenging due to a comparatively small brain size (2- to 200-fold smaller volume, depending on the species). This difference in size is further accentuated in NHP studies of brain development in which fetal brain volumes are 10-50% of their adult size. The sizes of cortical gyri and sulci scale allometrically with brain size. Thus, achieving spatial sampling that is comparable to that of high-quality human studies (∼1.0 mm3) requires a brain-size-adjusted reduction in the sampling volumes of from 500-to-150 μm3. Imaging at this spatial resolution while maintaining sufficient contrast and signal to noise ratio necessitates the development of specialized MRI protocols. Here we discuss our strategy to optimize the protocol parameters for two commonly available structural imaging sequences: MPRAGE and TrueFisp. In addition, computational tools developed for the analysis of human structural images were applied to the NHP studies. These included removal of non-brain tissues, correction for RF inhomogeneity, spatial normalization, building of optimized target brain and analysis of cerebral gyrification and individual cortical variability. Finally, recent findings in the genetics of cerebral gyrification and tracking of maturation trends in the fetal, newborn and adult brain are described. © 2009 Elsevier Inc. All rights reserved.


Duong T.Q.,University of Texas Health Science Center at San Antonio | Duong T.Q.,Southwest National Primate Research Center
Methods | Year: 2010

This paper reviews recent non-human primate (NHP) neuroimaging literature using MRI in macaque, baboon and chimpanzee. It describes general challenges and limitations for NHP MRI studies, and reviews recent applications of anatomical, diffusion tensor, cerebral blood flow MRI. Applications to NHP stroke is discussed in some detail. © 2009 Elsevier Inc. All rights reserved.


Wonganan P.,University of Texas at Austin | Clemens C.C.,University of Texas at Austin | Brasky K.,Southwest National Primate Research Center | Pastore L.,University of Naples Federico II | Croyle M.A.,University of Texas at Austin
Molecular Pharmaceutics | Year: 2011

Clinically relevant doses of helper-dependent adenoviruses (HDAds) provoke the host response against capsid proteins in primates and rodents. To determine if PEGylation truly affects this, baboons and mice were given either HDAd or PEG-HDAd expressing beta-galactosidase at 5 × 1011 or 3 × 1012 virus particles per kilogram (vp/kg) by iv infusion. Serum cytokines and blood chemistries were assessed for 96 h. PEG-HDAd reduced IL-6 6-fold in mice and 3-fold in the primate. This vector reduced IL-12 by 50% in both animal models. PEGylation reduced serum transaminases by approximately 50% at each dose in the primate and the mouse. PEGylation did not alter hepatic transduction efficiency in the mouse but did reduce transduction efficiency in the liver and the spleen of primates. Unmodified and PEGylated virus suppressed hepatic CYP3A activity in both animal models. PEGylation doubled the half-life (t1/2) of the virus in the mouse and cut plasma clearance (CL) in half without affecting the half-life in primates. These results suggest that there are notable species-specific differences in the biodistribution of and response to PEG-modified vectors which may be linked to differences in binding properties to coagulation factors, receptor density and tissue architecture in the liver. © 2011 American Chemical Society.


Lanford R.E.,The Texas Institute | Lanford R.E.,Southwest National Primate Research Center | Guerra B.,The Texas Institute | Chavez D.,The Texas Institute | And 10 more authors.
Gastroenterology | Year: 2013

Background & Aims: Direct-acting antiviral agents suppress hepatitis B virus (HBV) load, but they require life-long use. Stimulation of the innate immune system could increase its ability to control the virus and have long-lasting effects after a finite regimen. We investigated the effects of immune activation with GS-9620 - a potent and selective orally active small molecule agonist of Toll-like receptor 7 - in chimpanzees with chronic HBV infection. Methods: GS-9620 was administered to chimpanzees every other day (3 times each week) for 4 weeks at 1 mg/kg and, after a 1-week rest, for 4 weeks at 2 mg/kg. We measured viral load in plasma and liver samples, the pharmacokinetics of GS-9620, and the following pharmacodynamics parameters: interferon-stimulated gene expression, cytokine and chemokine levels, lymphocyte and natural killer cell activation, and viral antigen expression. Clinical pathology parameters were monitored to determine the safety and tolerability of GS-9620. Results: Short-term oral administration of GS-9620 provided long-term suppression of serum and liver HBV DNA. The mean maximum reduction of viral DNA was 2.2 logs, which occurred within 1 week of the end of GS-9620 administration; reductions of >1 log persisted for months. Serum levels of HBV surface antigen and HBV e antigen, and numbers of HBV antigen-positive hepatocytes, were reduced as hepatocyte apoptosis increased. GS-9620 administration induced production of interferon-α and other cytokines and chemokines, and activated interferon-stimulated genes, natural killer cells, and lymphocyte subsets. Conclusions: The small molecule GS-9620 activates Toll-like receptor 7 signaling in immune cells of chimpanzees to induce clearance of HBV-infected cells. This reagent might be developed for treatment of patients with chronic HBV infection. © 2013 AGA Institute.


Comuzzie A.G.,Southwest National Primate Research Center
Progress in molecular biology and translational science | Year: 2010

Variation in body weight and composition, as well as adipose tissue function, is regulated by environmental and genetic factors, combined with a variety of interactions, including environment-by-environment, gene-by-gene, and gene-by-environment interactions. Although the recent increase in obesity can in large part be attributed to the increased availability of low-cost but energy-dense foods and an increasingly sedentary lifestyle throughout most of the developed world, the impact of these factors is more pronounced in individuals who are genetically susceptible to these environmental insults. Hence, it is likely to be the response of an individual's genetic background to a given environment that determines susceptibility to obesity. Candidate gene studies, genome-wide linkage studies, and more recently genome-wide association studies (GWASs) have been used to decipher the effect of genetics on obesity. Heritability estimates suggest that 40-70% of the variation in obesity-related phenotypes is attributable to underlying genetic variation. To date, the findings from human cohort studies (both family and case/control studies) summarized in this chapter suggest that there are likely numerous genes impacting the expression of obesity-related phenotypes, with many of these genes seeming to have modest effects. The establishment of many population-based studies that have collected genome-wide data on genetic variation has recently led to the formation of multiple consortia facilitating powerful meta-analyses in order to identify additional genetic variation influencing obesity-related traits through GWAS, as well as to replicate and further characterize previously identified genetic variants and their gene regions. These consortia may have the power to elucidate how genetic and environmental factors act and interact to produce variation in obesity-related phenotypes. Copyright © 2010 Elsevier Inc. All rights reserved.


Varki N.M.,University of California at San Diego | Strobert E.,Emory University | Dick Jr. E.J.,Southwest National Primate Research Center | Benirschke K.,University of California at San Diego | Varki A.,University of California at San Diego
Annual Review of Pathology: Mechanisms of Disease | Year: 2011

Although humans are genetically very similar to the evolutionarily related nonhuman hominids (chimpanzees, bonobos, gorillas, and orangutans), comparative studies suggest a surprising number of uniquely human differences in the incidence and/or severity of biomedical conditions. Some differences are due to anatomical changes that occurred during human evolution. However, many cannot be explained either by these changes or by known environmental factors. Because chimpanzees were long considered models for human disease, it is important to be aware of these differences, which appear to have been deemphasized relative to similarities. We focus on the pathophysiology and pathobiology of biomedical conditions that appear unique to humans, including several speculative possibilities that require further study. We pay particular attention to the possible contributions of uniquely human changes in the biology of cell-surface sialic acids and the proteins that recognize them. We also discuss the metabolic incorporation of a diet-derived nonhuman sialic acid, which generates a novel xeno-autoantigen reaction, and chronic inflammation known as xenosialitis. Copyright © 2011 by Annual Reviews. All rights reserved.


Iredale S.K.,Southwest National Primate Research Center | Nevill C.H.,Southwest National Primate Research Center | Lutz C.K.,Southwest National Primate Research Center
Applied Animal Behaviour Science | Year: 2010

A common method for collecting behavioral data is through direct observations. However, there is very little information available on how a human observer affects the behavior of the animals being observed. This study assesses the effects of a human observer on the behavior of captive nonhuman primates. The subjects were 19 singly housed baboons (nine males, 10 females) and 20 singly housed rhesus macaques (10 males, 10 females) that were not habituated to the presence of an observer. Four 30-min observations were conducted on each animal. Two observations were conducted with an observer present ("present" condition), while the remaining two observations had no observer present ("absent" condition). All observations were recorded with a video camera and were balanced for time of day, with one of each type of observation taking place in the morning and afternoon. In the presence of an observer, appetitive behavior was significantly reduced in both species [F(1,35) = 8.22, P < 0.01]. When an observer was present, females of both species also rested more and performed fewer manipulative behaviors than males [rest: F(1,35) = 7.10, P < 0.05; manipulative: F(1,35) = 6.66, P < 0.05]. Likewise, macaques rested significantly more [F(1,35) = 11.62, P < 0.005] and exhibited fewer manipulative behaviors in the presence of an observer [F(1,35) = 11.06, P < 0.005], while baboons showed no change. Female macaques showed the greatest decrease in activity while an observer was present [F(1,35) = 4.22, P < 0.05]. Based on these results, the presence of a human observer does appear to affect the behavior of unhabituated, singly housed baboons and macaques, but the effect differs by both sex and species. © 2009 Elsevier B.V. All rights reserved.


Zhou M.,The Texas Institute | Ruprecht R.M.,The Texas Institute | Ruprecht R.M.,Southwest National Primate Research Center
Retrovirology | Year: 2014

An estimated 90% of all HIV transmissions occur mucosally. Immunoglobulin A (IgA) molecules are important components of mucosal fluids. In a vaccine efficacy study, in which virosomes displaying HIV gp41 antigens protected most rhesus monkeys (RMs) against simian-human immunodeficiency virus (SHIV), protection correlated with vaginal IgA capable of blocking HIV transcytosis in vitro. Furthermore, vaginal IgG exhibiting virus neutralization and/or antibody-dependent cellular cytotoxicity (ADCC) correlated with prevention of systemic infection. In contrast, plasma IgG had neither neutralizing nor ADCC activity. More recently, a passive mucosal immunization study provided the first direct proof that dimeric IgAs (dIgAs) can prevent SHIV acquisition in RMs challenged mucosally. This study compared dimeric IgA1 (dIgA1), dIgA2, or IgG1 versions of a human neutralizing monoclonal antibody (nmAb) targeting a conserved HIV Env epitope. While the nmAb neutralization profiles were identical in vitro, dIgA1 was significantly more protective in vivo than dIgA2. Protection was linked to a new mechanism: virion capture. Protection also correlated with inhibition of transcytosis of cell-free virus in vitro. While both of these primate model studies demonstrated protective effects of mucosal IgAs, the RV144 clinical trial identified plasma IgA responses to HIV Env as risk factors for increased HIV acquisition. In a secondary analysis of RV144, plasma IgA decreased the in vitro ADCC activity of vaccine-induced, Env-specific IgG with the same epitope specificity. Here we review the current literature regarding the potential of IgA - systemic as well as mucosal - in modulating virus acquisition and address the question whether anti-HIV IgA responses could help or harm the host. © 2014 Zhou and Ruprecht; licensee BioMed Central.

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