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Anti-malaria drug shows promise against Zika virus
A new collaborative study led by researchers at Sanford Burnham Prebys Medical Discovery Institute (SBP) and UC San Diego School of Medicine has found that a medication used to prevent and treat malaria may also be effective for Zika virus. The drug, called chloroquine, has a long history of safe use during pregnancy while being relatively inexpensive. The research is published in Scientific Reports.
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 that can reverse the condition.
"There is still an urgent need to bolster our preparedness and capacity to respond to the next Zika outbreak," says Alexey Terskikh PhD, associate professor at SBP. "Our latest research suggests the anti-malaria drug chloroquine may be an effective drug to treat and prevent Zika infections."
A new study examined the effect of chloroquine in human brain organoids and pregnant mice infected with Zika virus, finding 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.
"Our research is the first to study Zika infection in a mouse model that transmits the virus in a way similar to humans," explains Alysson R. Muotri PhD, professor and director of the Stem Cell Program at UC San Diego and co-senior author of the study. "Until now, researchers used a mouse strain that is deficient in interferon — a signaling protein that heightens anti-viral defenses. Those mice actually die from Zika infection, making it difficult to study the natural transmission of the virus from father and mother to fetus and to assess the effect of this transmission on the newborns."
"We believe our mouse model more accurately represents the way Zika virus infects men, women and babies while in the womb. Although chloroquine didn't completely clear Zika from infected mice it did reduce the viral load, suggesting it could limit the neurological damage found in newborns infected by the virus."
"In the 1950's, the Brazilian health agencies added chloroquine into cooking salt and distributed it to the population in endemic areas as an effective way of spreading the inexpensive anti-malarial drug as a prophylactic on a wide scale. This strategy was known as Pinotti's Method, named after its originator Dr. Mario Pinotti. It might be worth considering this medicated salt program one more time in Brazil," suggests Muotri.
"Chloroquine has a long history of successfully treating malaria, and there are no reports of it causing birth defects," says Terskikh. "Additional studies are certainly needed to determine the precise details of how it works. But given its low cost, availability and safety history further study in a clinical trial to test its effectiveness against Zika virus in humans is merited."
Human pluripotent stem cells (hPSC) are used to study the early stages of human development in vitro and, increasingly due to somatic cell reprogramming, cellular and molecular mechanisms of disease. Cell culture medium is a critical factor for hPSC to maintain pluripotency and self-renewal. Numerous defined culture media have been empirically developed but never systematically optimized for culturing hPSC. We applied design of experiments (DOE), a powerful statistical tool, to improve the medium formulation for hPSC. Using pluripotency and cell growth as read-outs, we determined the optimal concentration of both basic fibroblast growth factor (bFGF) and neuregulin-1 beta 1 (NRG1?1). The resulting formulation, named iDEAL, improved the maintenance and passage of hPSC in both normal and stressful conditions, and affected trimethylated histone 3 lysine 27 (H3K27me3) epigenetic status after genetic reprogramming. It also enhances efficient hPSC plating as single cells. Altogether, iDEAL potentially allows scalable and controllable hPSC culture routine in translational research. Our DOE strategy could also be applied to hPSC differentiation protocols, which often require numerous and complex cell culture media.
Authors: Paulo A. Marinho, Thanathom Chailangkarn & Alysson R. Muotri
Co-authors: Sergey A. Shiryaev, Antonella Pinto, Chen Farhy, Chun-Teng Huang, Alex Y. Strongin, SBP; Pinar Mesci, Isabella Fernandes, UC San Diego; Nicholas Sheets, Sujan Shresta, La Jolla Institute for Allergy & Immunology.
Funding sources for this study include: California Institute for Regenerative Medicine (DISC2-09649), National Institutes of Health (U19MH107367), NARSAD Independent Investigator Grant and the International Rett Syndrome Foundation.
Sanford Burnham Prebys Medical Discovery Institute (SBP) is an independent nonprofit medical research organization that conducts world-class, collaborative, biological research and translates its discoveries for the benefit of patients. SBP focuses its research on cancer, immunity, neurodegeneration, metabolic disorders and rare children's diseases. The Institute invests in talent, technology and partnerships to accelerate the translation of laboratory discoveries that will have the greatest impact on patients. Recognized for its world-class NCI-designated Cancer Center and the Conrad Prebys Center for Chemical Genomics, SBP employs about 1,100 scientists and staff in San Diego (La Jolla), Calif., and Orlando (Lake Nona), Fla. For more information, visit us at SBPdiscovery.org or on Facebook at facebook.com/SBPdiscovery and on Twitter @SBPdiscovery.
About UC San Diego School of Medicine
UC San Diego School of Medicine, established in 1968, is the region's only medical school. As a top-tier academic medical center, our role is to improve health through innovative research, education and patient care. The School of Medicine is closely tied to the Skaggs School of Pharmacy and Pharmaceutical Sciences and UC San Diego Health, which includes the Hillcrest Medical Center, Jacobs Medical Center, Moores Cancer Center, Sulpizio Cardiovascular Center, Shiley Eye Institute and many other centers, clinics and affiliates throughout Southern California. We have long been at the forefront of translational research, transforming patient care through discovery and innovation leading to new drugs and technologies. Learn more at healthsciences.ucsd.edu.
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In the 1950's, Brazilian health agencies added chloroquine into cooking salt and distributed it to the population in endemic areas as an effective anti-malarial drug. This strategy might be worth considering again as a prophylactic to ZIKA. Image credit: Wikipedia.