New body-on-a-chip technology to advance pharmacological research

Researchers from MIT have developed “physiome on chip” technology that could be used to evaluate new drugs and detect side effects before the drugs are tested in human clinical trials. This could be used an alternative to animal testing for pharmacological testing before human clinical trials.

Body on a chip. Credit: Felice Frankel

They used a microfluidic platform that connects engineered tissues from ten different organs,. By doing so, the researchers were able to accurately replicate human organ interactions considerable periods at a time, allowing them to measure the effects of medication on different organs. This system is also well designed to test immunotherapy as the antibodies are unique to humans and could not be reliably tested in animals. This research is published in the journal Scientific Reports.

“Some of these effects are really hard to predict from animal models because the situations that lead to them are idiosyncratic,” says Linda Griffith, one of the senior authors of the study. “With our chip, you can distribute a drug and then look for the effects on other tissues and measure the exposure and how it is metabolized.”

Griffith believes that the immediate applications of this technology involve modeling  on fewer organ systems. Griffith’s lab is now developing a model system to investigate the role of the gut microbiome in Parkinson’s disease by creating body on chip that contains  brain, liver, and gastrointestinal tissue.

“An advantage of our platform is that we can scale it up or down and accommodate a lot of different configurations,” Griffith says. “I think the field is going to go through a transition where we start to get more information out of a three-organ or four-organ system, and it will start to become cost-competitive because the information you’re getting is so much more valuable.”

Citation: Edington, Collin D., Wen Li Kelly Chen, Emily Geishecker, Timothy Kassis, Luis R. Soenksen, Brij M. Bhushan, Duncan Freake, Jared Kirschner, Christian Maass, Nikolaos Tsamandouras, Jorge Valdez, Christi D. Cook, Tom Parent, Stephen Snyder, Jiajie Yu, Emily Suter, Michael Shockley, Jason Velazquez, Jeremy J. Velazquez, Linda Stockdale, Julia P. Papps, Iris Lee, Nicholas Vann, Mario Gamboa, Matthew E. Labarge, Zhe Zhong, Xin Wang, Laurie A. Boyer, Douglas A. Lauffenburger, Rebecca L. Carrier, Catherine Communal, Steven R. Tannenbaum, Cynthia L. Stokes, David J. Hughes, Gaurav Rohatgi, David L. Trumper, Murat Cirit, and Linda G. Griffith. “Interconnected Microphysiological Systems for Quantitative Biology and Pharmacology Studies.” Scientific Reports 8, no. 1 (2018). doi:10.1038/s41598-018-22749-0.

Research funding: U.S. Army Research Office and DARPA.

Adapted from press release by MIT.

Hemanthamine found in Daffodils has anti-cancer properties

Researchers from Université Libre de Bruxelles discover that alkaloid found in Daffodils has anti-cancer properties. This alkaloid called haemanthamine works by triggering activation of anti-tumor surveillance pathway. This study was led by Dennis Lafontaine and is published in journal Structure.

Structure of Ribosome. Credit ULB

Researchers found that this compound binds to the ribosome and blocks the production of proteins. Haemanthamine also inhibits the production of these ribosomes in the nucleolus. This nucleolar stress triggers the activation of an anti-tumoral surveillance pathway leading to the stabilization of the protein p53 and the elimination of cancer cells.

In the near future, the team of Denis Lafontaine, in collaboration with Veronique Mathieu (Faculty of Pharmacy- ULB), will test the effect on ribosome biogenesis and function of four Amaryllidaceae alkaloids, representative of the chemical diversity of these molecules. Their goal will be to identify the most promising chemical backbone to be further developed as a lead compound in cancer therapeutics.

Reference: Pellegrino, Simone, Mélanie Meyer, Christiane Zorbas, Soumaya A. Bouchta, Kritika Saraf, Stephen C. Pelly, Gulnara Yusupova, Antonio Evidente, Véronique Mathieu, Alexander Kornienko, Denis L.j. Lafontaine, and Marat Yusupov. “The Amaryllidaceae Alkaloid Haemanthamine Binds the Eukaryotic Ribosome to Repress Cancer Cell Growth.” Structure, 2018. doi:10.1016/j.str.2018.01.009.

Adapted from press release by Université Libre de Bruxelles.

Research shows efficacy of malarial drug Chloroquine in treating Zika infection

Zika virus remains a major global health risk. In most adults, Zika causes mild flu-like symptoms. But in pregnant women, the virus can cause serious birth defects in babies including microcephaly a neurological condition in which newborns have unusually small heads and fail to develop properly. There is no treatment or way to reverse the condition.

A new research study led by researchers at Sanford Burnham Prebys Medical Discovery Institute (SBP) and UC San Diego School of Medicine has found that chloroquine, a medication used to prevent and treat malaria may also be effective for Zika virus. The drug has a long history of safe use during pregnancy, and is relatively inexpensive. The research was published today in Scientific Reports.

Terskikh is co-senior author of a new study that examined the effect of chloroquine in human brain organoids and pregnant mice infected with the virus, and found the drug markedly reduced the amount of Zika virus in maternal blood and neural progenitor cells in the fetal brain. Pregnant mice received chloroquine through drinking water in dosages equivalent to acceptable levels used in humans.

Citation: Shiryaev, Sergey A., Pinar Mesci, Antonella Pinto, Isabella Fernandes, Nicholas Sheets, Sujan Shresta, Chen Farhy, Chun-Teng Huang, Alex Y. Strongin, Alysson R. Muotri, and Alexey V. Terskikh. “Repurposing of the anti-malaria drug chloroquine for Zika Virus treatment and prophylaxis.” Scientific Reports 7, no. 1 (2017).
Funding: California Institute for Regenerative Medicine, National Institutes of Health, NARSAD Independent Investigator Grant, International Rett Syndrome Foundation.
Adapted from press release by Sanford-Burnham Prebys Medical Discovery Institute.

Finding new uses for old medication using computer program DrugPredict

Researchers at Case Western Reserve University School of Medicine have developed a computer program called DrugPredict to discover new indications for old drugs. This program matches existing data about FDA-approved drugs to diseases, and predicts potential drug efficacy.

In a recent study published in Oncogene, the researchers successfully translated DrugPredict results into the laboratory, and showed common pain medications non-steroidal anti-inflammatory drugs, also known as NSAIDs could have applications for epithelial ovarian cancer.

DrugPredict was developed by co-first author QuanQiu Wang of ThinTek, LLC, and co-senior author Rong Xu, PhD, associate professor of biomedical informatics in the department of population and quantitative health sciences at Case Western Reserve University School of Medicine. The program works by connecting computer-generated drug profiles including mechanisms of action, clinical efficacy, and side effects with information about how a molecule may interact with human proteins in specific diseases, such as ovarian cancer.

DrugPredict searches databases of FDA-approved drugs, chemicals, and other naturally occurring compounds. It finds compounds with characteristics related to a disease-fighting mechanism. These include observable characteristics (phenotypes) and genetic factors that may influence drug efficacy. Researchers can collaborate with Xu to input a disease into DrugPredict and receive an output list of drugs or potential drugs with molecular features that correlate with strategies to fight the disease.

In the Oncogene study, DrugPredict produced a prioritized list of 6,996 chemicals with potential to treat epithelial ovarian cancer. At the top of the list were 15 drugs already FDA-approved to treat the cancer, helping to validate the DrugPredict approach. Of other FDA-approved medications on the list, NSAIDs ranked significantly higher than other drug classes. The researchers combined the DrugPredict results with anecdotal evidence about NSAIDs and cancer before confirming DrugPredict results in their laboratory experiments.

Citation: Nagaraj, A. B., Q. Q. Wang, P. Joseph, C. Zheng, Y. Chen, O. Kovalenko, S. Singh, A. Armstrong, K. Resnick, K. Zanotti, S. Waggoner, R. Xu, and A. Difeo. “Using a novel computational drug-repositioning approach (DrugPredict) to rapidly identify potent drug candidates for cancer treatment.” Oncogene, 2017.

DOI: 10.1038/onc.2017.328

Funding: Gynecological Cancer Translation Research Program, Case Comprehensive Cancer Center, The Mary Kay Foundation, NIH/Eunice Kennedy Shriver National Institute Of Child Health & Human Development.

Adapted from press release by Case Western Reserve University.

New plant based compounds show promise for hepatitis B

Researchers have found that certain plant-derived products may help prevent and treat hepatitis B virus (HBV) infection. Proanthocyanidin (PAC) and its analogs, oolonghomobisflavanes, act by inhibiting viral entry into host cells.

Hepatis B life cycle
The life cycle of Hepatitis B Virus. Credit Dr. Graham Colm Wikipedia

The investigators noted that PAC was effective even against treatment-resistant HBV strains, and it augmented the ability of the antiviral drug tenofovir to interrupt HBV spread in human cells.

“PAC represents a specific inhibitor against HBV that is a less toxic plant-derived agent used as a dietary supplement,” said Dr. Koichi Watashi, co-author of the Hepatology study.

Senko Tsukuda, Koichi Watashi, Taichi Hojima, Masanori Isogawa, Masashi Iwamoto, Katsumi Omagari, Ryosuke Suzuki, Hideki Aizaki, Soichi Kojima, Masaya Sugiyama, Akiko Saito, Yasuhito Tanaka, Masashi Mizokami, Camille Sureau and Takaji Wakita. “A new class of hepatitis B and D virus entry inhibitors, proanthocyanidin and its analogs, that directly act on the viral large surface proteins.” Hepatology 2017.
DOI: 10.1002/hep.28952
Adapted from press release by Wiley Publications.