Zika Virus Targets and Kills Brain Cancer Stem Cells – UC San Diego Health

In developing fetuses, infection by the Zika virus can result in devastating neurological damage, most notably microcephaly and other brain malformations. In a new study, published today in The Journal of Experimental Medicine, researchers at the University of California San Diego School of Medicine and Washington University School of Medicine in St. Louis report the virus specifically targets and kills brain cancer stem cells.

The findings suggest the lethal power of the virus notorious for causing infected babies to be born with under-sized, misshapen heads could be directed at malignant cells in adult brains. Doing so might potentially improve survival rates for patients diagnosed with glioblastomas, the most common and aggressive form of brain cancer, with a median survival rate of just over 14 months after diagnosis.

The Zika virus specifically targets neuroprogenitor cells in fetal and adult brains. Our research shows it also selectively targets and kills cancer stem cells, which tend to be resistant to standard treatments and a big reason why glioblastomas recur after surgery and result in shorter patient survival rates, said Jeremy Rich, MD, professor of medicine at UC San Diego School of Medicine. Rich is co-senior author of the study with Michael S. Diamond, MD, PhD, professor, and Milan G. Chheda, MD, assistant professor, both at Washington University School of Medicine in St. Louis.

Transmission electron microscope image of negative-stained, Fortaleza-strain Zika virus (red), isolated from a microcephaly case in Brazil. Image courtesy of NIAID.

This year, more than 12,000 Americans will be diagnosed with glioblastomas, according to the American Brain Tumor Association. Among them: U.S. Senator John McCain, who announced his diagnosis in July. They are highly malignant. The two-year survival rate is 30 percent.

Standard treatment is aggressive: surgery, followed by chemotherapy and radiation. Yet most tumors recur within six months, fueled by a small population of glioblastoma stem cells that resist and survive treatment, continuing to divide and produce new tumor cells to replace those killed by cancer drugs.

For Zhe Zhu, MD, PhD, a postdoctoral scholar in Richs lab and first author of the study, the hyper-reproductive capabilities of glioblastoma stem cells reminded him of neuroprogenitor cells, which fuel the explosive growth of developing brains. Zika virus specifically targets and kills neuroprogenitor cells.

So Zhu, with Rich, Diamond, Chheda and other collaborators, investigated whether the Zika virus might also target and kill cultured glioblastoma stem cells derived from patients being treated for the disease. They infected cultured tumors with one of two strains of the virus. Both strains spread through the tumors, infecting and killing stem cells while largely avoiding other tumor cells.

The findings, the authors said, suggest that chemotherapy-radiation treatment and a Zika infection appear to produce complementary results. Standard treatment kills most tumor cells but typically leaves stem cells intact. The Zika virus attacks stem cells but bypasses ordinary tumor cells.

We see Zika one day being used in combination with current therapies to eradicate the whole tumor, said Chheda, an assistant professor of medicine and of neurology at Washington University School of Medicine.

To find out whether the virus could boost treatment efficacy in a live animal, researchers injected either the Zika virus or a saltwater placebo directly into glioblastoma tumors in 18 and 15 mice, respectively. Two weeks after injection, tumors were significantly smaller in the Zika-treated mice, who survived significantly longer than those given the placebo.

The scientists note that the idea of injecting a virus notorious for causing brain damage into patients brains seems alarming, but they say Zika may prove a safe therapy with further testing because its primary target neuroprogenitor cells are rare in adult brains. The opposite is true of fetal brains, which is part of the reason why a Zika infection before birth produces widespread and severe brain damage while a normal Zika infection in adults typically causes mild symptoms or none at all.

The researchers also conducted studies of the virus using brain tissue from epilepsy patients that showed the virus does not infect non-cancerous brain cells.

As an additional safety feature, the research team introduced two mutations that weakened the viruss ability to combat natural cellular defenses against infection, reasoning that while the mutated virus would still be able to grow in tumor cells, which have a poor anti-viral defense system, it would be quickly eliminated in healthy cells with a robust anti-viral response.

When they tested the mutated viral strain and the original parental strain in glioblastoma stem cells, they found that the original strain was more potent, but that the mutant strain also succeeded in killing the cancerous cells.

Were going to introduce additional mutations to sensitize the virus even more to the innate immune response and prevent the infection from spreading, said Diamond, a professor of molecular microbiology, pathology and immunology. Once we add a couple more, I think its going to be impossible for the virus to overcome them and cause disease.

Co-authors of the study include: Matthew Gorman, Estefania Fernandez, Lisa McKenzie, Jiani Chai, Justin M. Richner, and Rong Zhang, Washington University, St. Louis; Christopher Hubert, and Briana Prager, Cleveland Clinic; Chao Shan, and Pei-Yong Shi, University of Texas Medical Branch; and Xiuxing Wang, UC San Diego.

Funding for this research came, in part, from the National Institutes of Health (R01 AI073755, R01 AI104972, CA197718, CA154130, CA169117, CA171652, NS087913, NS089272), the Pardee Foundation, the Concern Foundation, the Cancer Research Foundation and the McDonnell Center for Cellular and Molecular Neurobiology of Washington University.

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Zika Virus Targets and Kills Brain Cancer Stem Cells - UC San Diego Health

Longeveron Initiates Phase 2b Stem Cell Therapy Trial to Treat Aging Frailty – Markets Insider

MIAMI, Sept. 6, 2017 /PRNewswire/ --Longeveron LLC, a regenerative medicine company developing cellular therapies, announced today that it treated its first patient in the Company's Phase 2b clinical trial evaluating the safety and efficacy of Longeveron human Allogeneic Mesenchymal Stem Cells (LMSCs) in patients with Aging Frailty Syndrome. This trial is being conducted pursuant to an Investigational New Drug Application (IND) in conformance with U.S. Food & Drug Administration (FDA) regulations. Aging Frailty is a common geriatric medical condition that is serious and life-threatening, and for which there are currently no U.S. Food and Drug Administration-approved therapeutics available.

The clinical trial is designed to enroll 120 subjects from approximately 10 medical centers around the U.S. The primary objective of the study is to evaluate the effect that LMSCs have on functional mobility and exercise tolerance in elderly Aging Frailty subjects. Three different LMSC dose groups will be compared to placebo over 12 months in a randomized, double-blinded, parallel arm design.Specifically, the trial will evaluate changes to the following:

"Frailty Syndrome is a very common and difficult situation to manage from a clinician's and caregiver's standpoint," stated Marco Pahor, M.D., Director of the Institute on Aging at the University of Florida. "The goal of intervention is to stop or slow the progression towards dependence and adverse health outcomes common to the syndrome, and to restore the patient to a state of healthy aging and functional independence. Longeveron's regenerative medicine trial is an important step towards the development of an effective therapeutic."

Allogeneic mesenchymal stem cells (MSCs) were previously tested in a Phase I/2 proof-of-concept study conducted by investigators at the University of Miami'sMiller School of Medicine. In that study, MSCs were shown to be safe and well-tolerated in frail, elderly subjects in a Phase 1 open label single ascending dose trial (publication link here) with a similar safety profile observed in the randomized, placebo-controlled Phase 2 study (publication link here) Subjects treated with a dose of 100 million MSCs showed significant improvements in six minute walking distance, and significant decreases in systemic inflammation, both relative to baseline.

"As individuals age, stem cell production and proliferation decreases, systemic inflammation increases, and a person's ability to repair and regenerate worn out or damaged tissue diminishes," remarked Suzanne Liv Page, Longeveron Chief Operating Officer. "In frail individuals this is particularly problematic. Our hypothesis is that exogenously infused allogeneic mesenchymal stem cells that are derived from the bone marrow of a healthy young donor, and culture expanded in our lab, will have potent regenerative and restorative effects."

Participants in this study must be between the ages of 70 and 85, be diagnosed as mildly to moderately frail due primarily to aging, and be able to walk between 200 and 400 meters over six minutes. Detailed information about the trial, subject eligibility and participating centers can be found by clicking here or by visiting the website http://www.clinicaltrials.gov and entering trial ID: NCT03169231.

About LMSCs

LMSCs is an allogeneic product, which means it is produced from stem cells derived from human donor bone marrow, and not from the patient's own stem cells, (referred to as autologous). LMSCs are manufactured at Longeveron's Cell Processing Facility in Miami, Fl. using a proprietary ex vivo culture expansion process.

About Longeveron

Longeveron is a regenerative medicine therapy company founded in 2014. Longeveron's goal is to provide the first of its kind biological solution for aging-related diseases, and is dedicated to developing safe cell-based therapeutics to revolutionize the aging process and improve quality of life. The company's research focus areas include Alzheimer's disease, Aging Frailty and the Metabolic Syndrome. Longeveron produces LMSCs in its own state-of-the-art cGMP cell processing facility. http://www.longeveron.com

Contact: Suzanne Liv Page rel="nofollow">spage@longeveron.com 305.909.0850

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SOURCE Longeveron LLC

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Longeveron Initiates Phase 2b Stem Cell Therapy Trial to Treat Aging Frailty - Markets Insider

Stem Cell Therapy Expands Beyond Chronic Pain – WBAY

APPLETON, Wisc. (WBAY) As stem cell therapy grows in popularity in Northeast Wisconsin, treatment is expanding beyond chronic pain in the knees, hips, back and shoulders.

A Green Bay man battling lung disease says stem cell therapy saved his life.

Ken Schiller has lived on oxygen for the past 12 years while suffering from COPD, emphysema and Agent Orange.

"Tried to get a lung transplant and they told me well, can't do it, you're too old," says Schiller.

Five years ago, doctors gave Schiller four years to live.

But now he's breathing a sigh of relief.

"I couldn't walk 15-feet nine months ago without stopping to rest for 3-5 minutes, now I can walk through the grocery store, can walk out of this building to the car, I don't have a big problem," says Schiller.

Schiller turned to stem cell therapy at Optimal Stem Cell & Wellness Institute in Appleton.

"Now we've really seen incredible results with lung disease, COPD, pulmonary fibrosis, emphysema, these patients have nowhere else to go," says Dr. Michael Johnson who runs the clinic.

Dr. Johnson says patients like Schiller begin with a platelet rich plasma treatment, followed by stem cell treatment using stem cells from their own body fat.

"We draw off the fat, adipose, spin it down, draw off the stem cells and IV it back into them, after one round of stem cell therapy they're already doing better, it usually takes two or three for severe cases," says Dr. Johnson.

Schiller just underwent his third treatment and says he has a new lease on life.

"Two weeks ago we went to Laughlin, Nevada for four days, took a plane and came back, I thought those days were over, but they're not," says Schiller.

While stem cell therapy is still not FDA approved, or covered by insurance, Dr. Johnson says his office is fielding around 100 calls a week.

"This is the future," says Dr. Johnson.

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Stem Cell Therapy Expands Beyond Chronic Pain - WBAY

Zika virus kills brain cancer stem cells; could potentially be used to treat deadly disease – Medical Xpress

September 5, 2017 Brain cancer stem cells (left) are killed by Zika virus infection (image at right shows cells after Zika treatment). A new study shows that the virus, known for killing cells in the brains of developing fetuses, could be redirected to destroy the kind of brain cancer cells that are most likely to be resistant to treatment. Credit: Zhe Zhu

While Zika virus causes devastating damage to the brains of developing fetuses, it one day may be an effective treatment for glioblastoma, a deadly form of brain cancer. New research from Washington University School of Medicine in St. Louis and the University of California San Diego School of Medicine shows that the virus kills brain cancer stem cells, the kind of cells most resistant to standard treatments.

The findings suggest that the lethal power of the virus - known for infecting and killing cells in the brains of fetuses, causing babies to be born with tiny, misshapen heads - could be directed at malignant cells in the brain. Doing so potentially could improve people's chances against a brain cancer - glioblastoma - that is most often fatal within a year of diagnosis.

"We showed that Zika virus can kill the kind of glioblastoma cells that tend to be resistant to current treatments and lead to death," said Michael S. Diamond, MD, PhD, the Herbert S. Gasser Professor of Medicine at Washington University School of Medicine and the study's co-senior author.

The findings are published Sept. 5 in The Journal of Experimental Medicine.

Each year in the United States, about 12,000 people are diagnosed with glioblastoma, the most common form of brain cancer. Among them is U.S. Sen. John McCain, who announced his diagnosis in July.

The standard treatment is aggressive - surgery, followed by chemotherapy and radiation - yet most tumors recur within six months. A small population of cells, known as glioblastoma stem cells, often survives the onslaught and continues to divide, producing new tumor cells to replace the ones killed by the cancer drugs.

In their neurological origins and near-limitless ability to create new cells, glioblastoma stem cells reminded postdoctoral researcher Zhe Zhu, PhD, of neuroprogenitor cells, which generate cells for the growing brain. Zika virus specifically targets and kills neuroprogenitor cells.

In collaboration with co-senior authors Diamond and Milan G. Chheda, MD, of Washington University School of Medicine, and Jeremy N. Rich, MD, of UC San Diego, Zhu tested whether the virus could kill stem cells in glioblastomas removed from patients at diagnosis. They infected tumors with one of two strains of Zika virus. Both strains spread through the tumors, infecting and killing the cancer stem cells while largely avoiding other tumor cells.

The findings suggest that Zika infection and chemotherapy-radiation treatment have complementary effects. The standard treatment kills the bulk of the tumor cells but often leaves the stem cells intact to regenerate the tumor. Zika virus attacks the stem cells but bypasses the greater part of the tumor.

"We see Zika one day being used in combination with current therapies to eradicate the whole tumor," said Chheda, an assistant professor of medicine and of neurology.

To find out whether the virus could help treat cancer in a living animal, the researchers injected either Zika virus or saltwater (a placebo) directly into the brain tumors of 18 and 15 mice, respectively. Tumors were significantly smaller in the Zika-treated mice two weeks after injection, and those mice survived significantly longer than the ones given saltwater.

If Zika were used in people, it would have to be injected into the brain, most likely during surgery to remove the primary tumor. If introduced through another part of the body, the person's immune system would sweep it away before it could reach the brain.

The idea of injecting a virus notorious for causing brain damage into people's brains seems alarming, but Zika may be safer for use in adults because its primary targets - neuroprogenitor cells - are rare in the adult brain. The fetal brain, on the other hand, is loaded with such cells, which is part of the reason why Zika infection before birth produces widespread and severe brain damage, while natural infection in adulthood causes mild symptoms.

The researchers conducted additional studies of the virus using brain tissue from epilepsy patients and showed that the virus does not infect noncancerous brain cells.

As an additional safety feature, the researchers introduced two mutations that weakened the virus's ability to combat the cell's defenses against infection, reasoning that the mutated virus still would be able to grow in tumor cells - which have a poor antiviral defense system - but would be eliminated quickly in healthy cells with a robust antiviral response.

When they tested the mutant viral strain and the original parental strain in glioblastoma stem cells, they found that the original strain was more potent, but that the mutant strain also succeeded in killing the cancerous cells.

"We're going to introduce additional mutations to sensitize the virus even more to the innate immune response and prevent the infection from spreading," said Diamond, who also is a professor of molecular microbiology, and of pathology and immunology. "Once we add a few more changes, I think it's going to be impossible for the virus to overcome them and cause disease."

Explore further: Scientists to test Zika virus on brain tumors

More information: Zhu et al., 2017. J. Exp. Med. jem.rupress.org/cgi/doi/10.1084/jem.20171093

In a revolutionary first, Cancer Research UK-funded scientists will test whether the Zika virus can destroy brain tumour cells, potentially leading to new treatments for one of the hardest to treat cancers.

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Zika virus kills brain cancer stem cells; could potentially be used to treat deadly disease - Medical Xpress