Category Archives: Genetic Medicine

Zika virus infection can stunt neonatal brain development, a condition known as microcephaly, in which babies are born with abnormally small heads. To determine how best to prevent and treat the viral infection, scientists first need to understand how the pathogen gets inside brain cells.

Employing different approaches to answer different questions, two research teams at University of California San Diego School of Medicine independently identified the same molecule v5 integrin as Zika virus key to entering brain stem cells.

In a pair of papers published January 16, 2020 by Cell Press, the researchers also found ways to take advantage of the integrin to both block Zika virus from infecting cells and turn it into something good: a way to shrink brain cancer stem cells.

Integrins are molecules embedded in cell surfaces. They play important roles in cell adherence and communication, and are known to be involved in cancer progression and metastasis. Several other integrins are known entry points for other viruses, including adenovirus, foot-and-mouth disease virus and rotavirus, but v5 was not previously known for its role in viral infections.

One team, led by Tariq Rana, PhD, professor and chief of the Division of Genetics in the Department of Pediatrics at UC San Diego School of Medicine and Moores Cancer Center, used CRISPR gene editing to systematically delete every gene in a 3D culture of human glioblastoma (brain cancer) stem cells growing in a laboratory dish. Then they exposed each variation to Zika virus to determine which genes, and the proteins they encode, are required for the virus to enter the cells. The virus was for the first time labeled with green fluorescent protein (GFP) to allow the researchers to visualize viral entry into the cells.

3D human brain organoids. Left: normal, uninfected. Center: infected with Zika virus. Right: infected with Zika virus and treated with cilengitide, which protects the cells from destruction by the virus.

Their study, published in Cell Reports, uncovered 92 specific human brain cancer stem cell genes that Zika virus requires to infect and replicate in the cells. But one gene stood out, the one that encodes v5 integrin.

Integrins are well known as molecules that many different viruses use as doorknobs to gain entry into human cells, Rana said. I was expecting to find Zika using multiple integrins, or other cell surface molecules also used by other viruses. But instead we found Zika uses v5, which is unique. When we further examined v5 expression in brain, it made perfect sense because v5 is the only integrin member enriched in neural stem cells, which Zika preferentially infects. Therefore, we believe that v5 is the key contributor to Zikas ability to infect brain cells.

The second study, published in Cell Stem Cell, was led by Jeremy Rich, MD, professor in the Department of Medicine at UC San Diego School of Medicine and director of neuro-oncology and of the Brain Tumor Institute at UC San Diego Health. Knowing that many viruses use integrins for entry into human cells, Richs team inhibited each integrin with a different antibody to see which would have the greatest effect.

When we blocked other integrins, there was no difference. You might as well be putting water on a cell, said Rich, who is also a faculty member in the Sanford Consortium for Regenerative Medicine and Sanford Stem Cell Clinical Center at UC San Diego Health. But with v5, blocking it with an antibody almost completely blocked the ability of the virus to infect brain cancer stem cells and normal brain stem cells.

Richs team followed up by inhibiting v5 in a glioblastoma mouse model with either an antibody or by deactivating the gene that encodes it. Both approaches blocked Zika virus infection and allowed the treated mice to live longer than untreated mice. They also found that blocking the v5 integrin in glioblastoma tumor samples removed from patients during surgery blocked Zika virus infection.

Ranas team also blocked v5 in mice, treating them daily with cilengitide or SB273005, two experimental cancer drugs that target the integrin. Six days after Zika virus infection, the brains of their drug-treated mice contained half as much virus as mock-treated mice.

The neat thing is that these findings not only help advance the Zika virus research field, but also opens the possibility that we could similarly block the entry of multiple viruses that use other integrins with antibodies or small molecule inhibitors, Rana said.

Rana and team are now engineering a mouse model that lacks v5 integrin in the brain a tool that would allow them to definitively prove the molecule is necessary for Zika viral entry and replication.

Rich is a neuro-oncologist who specializes in diagnosing and treating patients with glioblastoma, a particularly aggressive and deadly type of brain tumor. When he first saw how the Zika virus shrinks brain tissue, it reminded him of what he hopes to achieve when hes treating a patient with glioblastoma. In 2017, he and collaborators published a study in which they determined that Zika virus selectively targets and kills glioblastoma stem cells, which tend to be resistant to standard treatments and are a big reason why glioblastomas recur after surgery and result in shorter patient survival rates.

Richs latest study helps account for the virus preference for glioblastoma stem cells over healthy brain cells. The v5 integrin is made up of two separate subunits v and 5. The team found that glioblastoma stem cells produce a lot of both the v subunit (associated with stem cells) and 5 subunit (associated with cancer cells). Together, these units form the v5 integrin, which, the team discovered, plays an important role in glioblastoma stem cell survival. Those high levels of v5 integrin also help explain why, in the study, glioblastoma stem cells were killed by Zika virus at much higher rates than normal stem cells or other brain cell types.

It turns out that the very thing that helps cancer cells become aggressive cancer stem cells is the same thing Zika virus uses to infect our cells, Rich said.

To see how this might play out in a more realistic model of human disease, Richs team partnered with an expert in human brain disease modeling Alysson Muotri, PhD, professor at UC San Diego School of Medicine, director of the UC San Diego Stem Cell Program and a member of the Sanford Consortium for Regenerative Medicine, and team. Pinar Mesci, PhD, a postdoctoral researcher in Muotris lab, generated a new brain tumor model, where human glioblastoma tumors were transplanted into human brain organoids, laboratory mini-brains that can be used for drug discovery. The researchers discovered that Zika virus selectively eliminates glioblastoma stem cells from the brain organoids. Inhibiting v5 integrin reversed that anti-cancer activity, further underscoring the molecules crucial role in Zika virus ability to destroy cells.

Now Richs team is partnering with other research groups to perform targeted drug studies. In addition to searching for drugs to block Zika virus, as Ranas group is doing, Rich is interested in genetic modifications to the virus that could help better target its destruction to brain cancer cells, while leaving healthy cells alone.

While we would likely need to modify the normal Zika virus to make it safer to treat brain tumors, we may also be able to take advantage of the mechanisms the virus uses to destroy cells to improve the way we treat glioblastoma, Rich said. We should pay attention to viruses. They have evolved over many years to be very good at targeting and entering specific cells in the body.

Zika virus was perhaps best known in 2015-16, when a large outbreak affected primarily Latin America, but also several other regions of the world. While that particular epidemic has passed, Zika virus has not gone away. Smaller, local outbreaks continue and this past summer, the first few cases of native Zika virus infection were recorded in Europe. Scientists warn Zika could continue to spread as climate change affects the habitat range of the mosquito that carries it. The virus can also be transmitted from pregnant mother to fetus, and via sexual contact. More than half of all people on Earth are at risk for Zika virus infection, and there is no safe and effective treatment or vaccine.

Co-authors of Ranas study, published January 16, 2020 in Cell Reports, include: Shaobo Wang, Qiong Zhang, Shashi Kant Tiwari, Gianluigi Lichinchi, Edwin H. Yau, Hui Hui, Wanyu Li, UC San Diego; and Frank Furnari, UC San Diego and Ludwig Institute for Cancer Research.

This research was funded, in part, by the National Institutes of Health (grants AI125103, CA177322, DA039562, DA046171 and DA049524).

Co-authors of Richs study, published January 16, 2020 in Cell Stem Cell, also include: Zhe Zhu, Jean A. Bernatchez, Xiuxing Wang, Hiromi I. Wettersten, Sungjun Beck, Alex E. Clark, Qiulian Wu, Sara M. Weis, Priscilla D. Negraes, Cleber A. Trujillo, Jair L. Siqueira-Neto, David A. Cheresh, UC San Diego; Ryan C. Gimple, Leo J.Y. Kim, UC San Diego and Case Western Reserve University; Simon T. Schafer, Fred H. Gage, Salk Institute for Biological Studies; Briana C. Prager, UC San Diego, Case Western Reserve University and Cleveland Clinic; Rekha Dhanwani, Sonia Sharma, La Jolla Institute for Allergy and Immunology; Alexandra Garancher, Robert J. Wechsler-Reya, Sanford Burnham Prebys Medical Discovery Institute; Stephen C. Mack, Baylor College of Medicine, Texas Childrens Hospital; Luiz O. Penalva, Childrens Cancer Research Institute; Jing Feng, Zhou Lan, Rong Zhang, Alex W. Wessel, Michael S. Diamond, Hongzhen Hu, Washington University School of Medicine; Sanjay Dhawan, and Clark C. Chen, University of Minnesota.

The research was funded, in part, by the National Institutes of Health (grants CA217065, CA217066, CA203101, CA159859, CA199376, NS097649-01, CA240953-01, NS096368, R01DK103901,R01AA027065, MH107367, N5105969, CA045726, CA050286, CA197718, CA154130, CA169117, CA171652, NS087913, NS089272), California Institute for Regenerative Medicine (CIRM, grants FA1-00607, DISC209649) and International Rett Syndrome Foundation.

Disclosures: Tariq Rana is a co-founder of, member of the scientific advisory board for, and has equity interest in ViRx Pharmaceuticals. Alysson Muotri is a co-founder and has equity interest in TISMOO, a company dedicated to genetic analysis focusing on therapeutic applications customized for autism spectrum disorder and other neurological disorders. David Cheresh is a co-founder of TargeGen and AlphaBeta Therapeutics, a new but currently unfunded company developing an antibody to integrin v5 involved in cancer treatment. The terms of these arrangements have been reviewed and approved by UC San Diego in accordance with its conflict of interest policies. In addition, Michael Diamond, of Washington University School of Medicine, is a consultant for Inbios and Atreca and serves on the Scientific Advisory Board of Moderna.

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Zika Virus' Key into Brain Cells ID'd, Leveraged to Block Infection and Kill Cancer Cells - UC San Diego Health

A diagnostics subsidiary of Swiss drugmaker Roche has filed for approval of its liquid biopsy test and anticipates a Food and Drug Administration ruling in the first half of this year.

In an interview at the J.P. Morgan Healthcare Conference in San Francisco, Foundation Medicine CEO Cindy Perettie said the company filed for FDA approval of the FoundationOne Liquid test at the end of December. The approval would include companion diagnostics claims, as well as claims for microsatellite instability and blood tumor mutation burden. The company anticipates that the test would be covered under the National Coverage Determination for next-generation sequencing, rather than there being a need to obtain a new NCD. The company applied for approval in parallel with its biopharma partners, though Perettie declined to name them.

In October, the company presented data from the Phase II/III BFAST study which is enrolling 580 patients with non-small cell lung cancer on people receiving Roches drug Alecensa (alectinib), a drug that targets ALK fusions, a genetic driver of NSCLC. Among 2,219 screened and 2,188 whose tests yielded blood-based next-generation sequencing results, 5.8% were found to have ALK fusions. The overall response rate for patients in the study who received Alecensa was 87.4%, which investigators wrote resulted in a high response rate and clinical benefit among patients receiving the drug and validated liquid biopsys clinical utility in ALK fusion-positive NSCLC.

Having that concordance gives us a lot of confidence, Perettie said, referring to the ability of liquid biopsy to detect mutations at a rate comparable to what has been found before.

Although BFAST was not specifically designed to show head-to-head concordance with tissue biopsy, research has indicated that ALK fusions are present in 4-6% of NSCLC cases.

The study is also enrolling patients who receive Rozlytrek (entrectinib), an inhibitor of NTRK fusions, which are also genetic drivers of cancers, among other drugs.

Concordance is a crucial consideration with liquid biopsy because, while significantly less cumbersome than tissue biopsy, it of course would defeat the purpose of using liquid biopsy if patients who have undergone it nevertheless must still undergo tissue biopsy as well.

Photo: ImagesBazaar, Getty Images

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Foundation Medicine touts concordance ahead of FDA ruling on liquid biopsy test - MedCity News

Research on psychedelics, which have been profoundly stigmatized, highly restricted, and tragically undeveloped for more than half a century, is stirring back to life and rekindling scientific, medical, and cultural interest in these compounds.

In 2008, a psychedelic compound related to the primary psychoactive alkaloid in peyote was discovered to exert extraordinarily potent anti-inflammatory effects at very low drug concentrationsin vitroandin vivo. Additional studies have confirmed the capacity of psychedelics to modulate processes that perpetuate chronic low-grade inflammation and thus exert significant therapeutic effects in a diverse array of preclinical disease models, includingasthma,atherosclerosis,inflammatory bowel disease, andretinal disease.

The U.S. Defense Advanced Research Projects Agency recently acknowledged thepotential of subperceptual psychedelics. To address the high rate of mental illness among active duty military personnel, DARPA aims to discover new compounds that can exert the rapid and robust antidepressant effects of psychedelics without the associated trip.

In the private sector,Compass Pathwaysis conducting Phase 2 trials of psilocybin for treatment-resistant depression.

The time has come to make psychedelics, once seen as out there substances, mainstream and boring again.

Read full, original post: Transforming psychedelics into mainstream medicines

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Psychedelics have 'extraordinarily potent' anti-inflammatory power. Is there a place for them in mainstream medicine? - Genetic Literacy Project

AsianScientist (Jan. 14, 2019) An international team of scientists has sequenced the genomes of almost 2,000 Asians to find clues about Asian ancestry, health and disease. Their findings are published in Nature.

Despite forming over 40 percent of the worlds population, Asian people have previously accounted for only six percent of the worlds recorded genome sequences.

To raise the representation of Asian genomes in biomedical studies, Nanyang Technological University, Singaporetogether with Macrogen, South Korea; Genentech, US; and MedGenome, India/USlaunched the GenomeAsia 100K consortium in 2016. The consortium aims to understand the genome diversity of Asian ethnicities by sequencing 100,000 genomes of people living in Asia.

GenomeAsia 100K is a significant and far-reaching project that will affect the well-being and health of Asians worldwide, said NTU Professor Stephan C. Schuster, the consortiums scientific chairman and a co-leader of the study.

In the present study, the researchers analyzed the genomes of 1,739 people, which represents the widest coverage of genetic diversity in Asia to date. Genomic DNA was extracted from blood and saliva samples, then sequenced in the laboratories of the four consortium members. The digital sequencing data were subsequently sent to Singapore for processing and storage.

The team reported that the frequencies of known genetic variants related to adverse drug response to Warfarin, a common anticoagulant drug prescribed to treat cardiovascular diseases, were higher in individuals with North Asian ancestry, such as Japanese, Korean, Mongolian or Chinese.

Using this data, scientists can now screen populations to identify groups that are more likely to have a negative predisposition to a specific drug. Knowing a persons population group and their predisposition to drugs is extremely important if personalized medicine is to work, Schuster emphasized.

In addition, the researchers discovered that Asia has at least ten ancestral lineages, whereas northern Europe has a single ancestral lineage. Moving forward, the GenomeAsia 100K consortium will continue to collect and analyze up to 100,000 genomes from all of Asias geographic regions to fill in the gaps of the worlds genetic map and to account for Asias unexpected genetic diversity.The article can be found at: GenomeAsia100K Consortium (2019) The GenomeAsia 100K Project Enables Genetic Discoveries Across Asia.

Source: Nanyang Technological University; Photo: Shutterstock.Disclaimer: This article does not necessarily reflect the views of AsianScientist or its staff.

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Filling In The Gaps Of Asia's Genetic Map - Asian Scientist Magazine

Brett Finlay

A new paper by UBC Faculty of Medicines Dr. Brett Finlay and a team of fellows from the Canadian Institute for Advanced Research (CIFAR) proposes that non-communicable diseases may be transmitted between people through the microbiome.

Non-communicable diseases, including heart disease, cancer, and lung disease account for 70 percent of deaths worldwide. These diseases are considered non-communicable because they are thought to be caused by a combination of genetic, lifestyle, and environmental factors and cant be transmitted between people.

The paper, published today in Science, throws this long-held belief into question by providing evidence that many diseases may be transmissible between people through microbes (including bacteria, fungi, and viruses) that live in and on our bodies.

If our hypothesis is proven correct, it will rewrite the entire book on public health, says Finlay, the papers lead author and a professor in the department of biochemistry and molecular biology and CIFAR fellow.

The authors base their hypothesis on connections between three distinct lines of evidence. First, they demonstrate that people with a wide range of conditions, from obesity and inflammatory bowel disease to type 2 diabetes and cardiovascular disease, have altered microbiomes. Next, they show that altered microbiomes, when taken from diseased people and put into animal models, cause disease. Finally, they provide evidence that the microbiome is naturally transmissible, for example: spouses who share a house have more similar microbiomes than twins who live separately.

When you put those facts together, it points to the idea that many traditionally non-communicable diseases may be communicable after all, says Finlay.

Brett Finlay

This paper provides a provocative new way to think about non-communicable diseases, with important implications for public health, says Alan Bernstein, the president and CEO of CIFAR. Ideas like this are a great example of what happens when top researchers from around the world work together in an environment of trust, transparency, and knowledge sharing.

While there is a lot of excitement about this hypothesis, the researchers are clear that much remains unknown about the mechanisms involved.

We hope the paper will inspire further research into the mechanisms and extent of communicability, says Finlay. We encourage researchers studying any disease to think about what effect microbes may be having.

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Obesity, heart disease, and diabetes may be communicable - UBC Faculty of Medicine

Injuries happen. But sometimes, more injuries seem to happen to certain players. Of course, the sporting world has a term for that player injury prone. In the NFL, that can be a tough label to shed.

The term is used frequently, but rarely with regard to the cause of injury or the circumstances behind it. Take for instance, Carson Wentz. Former players and the media questioned Wentzs durability after he left his first playoff game with a concussion. In most cases, as with Wentz, injuries arent the fault of players, trainers or strength and conditioning coaches, but rather the nature of playing a sport where large, fast individuals regularly crash into each other.

We all use that term, said Dr. James Andrews, but we dont have any scientific basis for it in most cases. We prefer to say, injury-unfortunate rather than pinning that (injury-prone label) on somebody. Psychologically, you cant throw that word around.

Injuries can...

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More injuries seem to happen to certain NFL players: examining the fairness of the injury-prone label - The Athletic