Category Archives: Cell Medicine

PUBLISHED: 13:11 05 May 2017 | UPDATED: 13:23 05 May 2017

Jason Noble

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The department for science and technology at the university recently began the collaboration with the aim of ensuring that the MSc Regenerative Medicine and BSc (Hons) Bioscience courses are informed by high-standards in the industry.

The tie-up will also mean a boost for research into regenerative medicine and stem cell use at the university.

Dr Federica Masieri, senior lecturer and course leader for MSc Regenerative Medicine said: We are delighted to be collaborating with what is considered one of the most reputable bodies in the field of stem cell industry.

It is recognised that employers in the regenerative medicine industry require graduates and postgraduates equipped with the most up to date skills, to ensure a seamless assimilation in the constantly evolving stem cellrelated work environment.

This collaboration will help us ensure our students are trained in line with requirements of such employers, by reviewing and developing courses as informed by the standards applied at UKSCB.

To launch the joint scheme, final year students paid a visit to the stem cell bank in London to help the students understand the logistics and complexities of the work there, as well as lectures from leading figures at the leading institution.

The university is aiming to make the trip an annual visit for final year students.

Dr Masieri said: A career in life science is a busy, fast-evolving and challenging one. It makes it an exciting area of endeavour, however there is a constant need to keep up with the rapid pace of change.

By establishing this relationship we are better placed to do this, at par with well-established universities with many years of history in the industry.

Prof Glyn Stacey, director of UKSCB added: The UKSCB is committed to advancing scientific research; we welcome the opportunity to educate, train and inspire the next generation of scientists.

Moreover finalisation of agreements are underway which could see MSc student placements with the UKSCB.

Read more:
University of Suffolk begins link with UK Stem Cell Bank for science courses - East Anglian Daily Times

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Research in mice and patients suggests biomarker could predict vision loss

At the center of the image is an optic nerve with glaucoma damage, signified by loss of color and a round rim of pink tissue within the nerve. Researchers at Washington University School of Medicine in St. Louis have identified a biomarker that appears linked to damage to cells in the retina of the eye. The marker may make it possible to better monitor the progression of glaucoma, as well as the effectiveness of treatment for the blinding disease.

Glaucoma, a leading cause of blindness worldwide, most often is diagnosed during a routine eye exam. Over time, elevated pressure inside the eye damages the optic nerve, leading to vision loss. Unfortunately, theres no way to accurately predict which patients might lose vision most rapidly.

Now, studying mice, rats and fluid removed from the eyes of patients with glaucoma, researchers at Washington University School of Medicine in St. Louis have identified a marker of damage to cells in the eye that potentially could be used to monitor progression of the disease and the effectiveness of treatment.

The findings are published online May 4 in the journal JCI Insight.

There hasnt been a reliable way to predict which patients with glaucoma have a high risk of rapid vision loss, said principal investigator Rajendra S. Apte, MD, PhD, the Paul A. Cibis Distinguished Professor of Ophthalmology and Visual Sciences. But weve identified a biomarker that seems to correlate with disease severity in patients, and what that marker is measuring is stress to the cells rather than cell death. Other glaucoma tests are measuring cell death, which is not reversible, but if we can identify when cells are under stress, then theres the potential to save those cells to preserve vision.

Glaucoma is the second-leading cause of blindness in the world, affecting more than 60 million people. The disease often begins silently, with peripheral vision loss that occurs so gradually that it can go unnoticed. Over time, central vision becomes affected, which can mean substantial damage already has occurred before any aggressive therapy begins.

Manypatients start receiving treatment when their doctors discover they have elevated pressure in the eye. Those treatments, such as eye drops, are aimed at lowering pressure in the eye, but such therapies may not always protect ganglion cells in the retina, which are the cells destroyed in glaucoma, leading to vision loss.

Apte, also a professor of developmental biology, of medicine and of neuroscience, said that all current treatments for glaucoma are aimed at lowering pressure in the eye to reduce ganglion cell loss and not necessarily at directly preserving ganglion cells.

Glaucoma specialists attempt to track the vision loss caused by ganglion cell death with visual field testing. Thats when a patient pushes a button when they see a blinking light. As vision is lost, patients see fewer lights blinking in the periphery of the visual field, but such testing is not always completely reliable, according to the papers first author, Norimitsu Ban, MD, an ophthalmologist and a postdoctoral research associate in Aptes laboratory.

Some older people dont do as well on the visual field test for reasons that may not be related to whats going on in their eyes, Ban explained. He said that finding a marker of cell damage in the eye would be a much more reliable way to track the progression of glaucoma.

We were lucky to be able to identify a gene and are very excited that the same gene seems to be a marker of stress to ganglion cells in the retinas of mice, rats and humans, Ban said.

Studying mouse models of glaucoma, Ban, Apte and their colleagues identified a molecule in the eye called growth differentiation factor 15 (GDF15), noting that the levels of the molecule increased as the animals aged and developed optic nerve damage.

When they repeated the experiments in rats, they replicated their results. Further, in patients undergoing eye surgery to treat glaucoma, cataracts and other issues, the researchers found that those with glaucoma also had elevated GDF15 in the fluid of their eyes.

That was exciting because comparing the fluid from patients without glaucoma to those with glaucoma, the GDF15 biomarker was significantly elevated in the glaucoma patients, Apte said. We also found that higher levels of the molecule were associated with worse functional outcomes, so this biomarker seems to correlate with disease severity.

Apte and Ban dont believe that the molecule causes cells in the retina to die; rather, that it is a marker of stress in retinal cells.

It seems to be a harbinger of future cell death rather than a molecule thats actually damaging the cells, Apte said.

A potential limitation of this study is that the fluid samples were taken from the eyes of patients only once, so it was not possible to monitor levels of GDF15 over time. In future studies, it will be important to measure the biomarker at several time points to determine whether levels of the biomarker increase as the disease progresses, Apte said.

He also would like to learn whether GDF15 levels eventually decline in those who have significant vision loss from glaucoma. In theory, Apte said, when most of the ganglion cells in the retina already have died, fewer cells would be under stress, and that could mean lower levels.

So we are interested in doing a prospective study and sampling fluid from the eye over several months or years to correlate glaucoma progression with levels of this marker, he said. Wed also like to learn whether levels of GDF15 change after treatment, a particularly important question as we try to develop therapies that preserve vision more effectively in these patients.

Ban N, Siegfried CJ, Lin JB, Shiu YB, Sein J, Pita-Thomas W, Sene A, Santeford A, Gordon M, Lamb R, Dong Z, Kelly SC, Cavalli V, Yoshino J, Apte RS. GDF15 is elevated in mice following retinal ganglion cell death and in glaucoma patients. JCI Insight. May 4, 2017.

This work was supported by the National Eye Institute, the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Neurological Disorders and Stroke and the National Institute of General Medical Sciences, of the National Institutes of Health (NIH), grant numbers R01 EY019287, UL1 KL2TR000450, P30 DK56341, P30 DK02057, DK104995, R01 EY021515, R01 DE0220000, R01 NS0824446, P30 EY02687, T32 GM007200, UL1 TR000448 and TL1 TR000449. Additional funding provided by the Schulak Family Gift Fund for Retinal Research, the Jeffrey Fort Innovation Fund, the Kuzma Family Gift Fund, the Central Society for Clinical and Translational Research, a Research to Prevent Blindness Physician Scientist Award, the Washington University Institute of Clinical and Translational Sciences, the American Federation for Aging Research, the Vitreoretinal Surgery Foundation and an unrestricted grant from Research to Prevent Blindness Inc.

Washington Universitys Office of Technology Management has filed intellectual property applications based on these studies in which the authors Rajendra S. Apte and Jun Yoshino are listed as inventors.

Washington University School of Medicines 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Childrens hospitals. The School of Medicine is one of the leading medical research, teaching and patient-care institutions in the nation, currently ranked seventh in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Childrens hospitals, the School of Medicine is linked to BJC HealthCare.

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Potential predictor of glaucoma damage identified - Washington University School of Medicine in St. Louis

Scientists at theUniversity of California San Diego School of Medicine usedsingle-cell RNA sequencing to map out pathways that regulate cell growth that could be exploited to trick them to regenerate.

Pancreatic cells help maintain normal blood glucose levels by producing insulin, the master regulator of energy (glucose). Impairment and the loss of cells interrupts insulin production, leading to types 1 and 2 diabetes.The team's study ("Pseudotemporal Ordering of Single Cells Reveals Metabolic Control of Postnatal Cell Proliferation") is published in Cell Metabolism.

"If we can find a drug that makes cells grow, it could improve blood sugar levels in people with diabetes," said Maike Sander, M.D., professor in the Department of Pediatrics and Cellular and Molecular Medicine at UC San Diego School of Medicine. "These people often have residual cells, but not enough to maintain normal blood glucose levels."

The body generates cells in utero and they continue to regenerate after birth. But as people age, cell regeneration diminishes. The predominant way to grow new cells is through cell division; but cells capable of dividing are rare, compromising less than 1% of all cells. Scientists have been investigating molecular pathways that govern cell growth in hopes of finding new therapies that would help people regain blood glucose control after the onset of diabetes.

In their work, Dr. Sander's team identified the pathways that are active when cells divide, providing insight into possible drug targets. The investigators were able to profile molecular features and metabolic activity of individual cells to determine how dividing cells differ from nondividing cells.

"No one has been able to do this analysis because the 1% or less of cells that are dividing are masked by the 99% percent of cells that are not dividing," said Dr. Sander. "This in-depth characterization of individual cells in different proliferative states was enabled by newer technology. It provides a better picture of what sends cells into cell division and clues we can use to try to develop drugs to stimulate certain pathways."

Whether stimulating cells to grow will result in therapeutic interventions for diabetes is still to be seen, but this new information opens the door to find out, she added.

More here:
Beta Cell Growth Finding May Lead to Improved Therapies for Diabetics - Genetic Engineering & Biotechnology News (press release)

Californias stem cell agency is on the hunt for a new president and CEO after the surprise announcement this week that C. Randal Mills will be departing the California Institute for Regenerative Medicine. He will leave at the end of June.

Mills, who has headed the agency for three years, will become the next president and CEO of the National Marrow Donor Program. CIRM is replacing him on an interim basis with Maria Millan, M.D., the agencys vice president of therapeutics.

The state agency will soon begin a search for a permanent replacement, said Jonathan Thomas, CIRMs chairman. Millan is a candidate to fill that position, with Mills strong endorsement.

Mills is noted for reorganizing CIRM to provide greater systemic support for translating basic research into clinical science, and to provide quicker and more helpful responses to researchers seeking funding.

His initiative, called CIRM 2.0, was a response to criticism that the agency, funded with $3 billion in California bond money in 2004, has been too slow in getting treatments to patients.

Agency-supported treatments are now being tested in medical centers throughout the state, including San Diego County. Most prominently, CIRM has established an alpha stem cell clinic at UC San Diego. It is the cell therapy arm of UCSDs Sanford Stem Cell Clinical Center.

Mills said he decided to leave because the National Marrow Donor Program, which he was familiar with, resonated with his own goals of making personal connections with patients.

Before joining CIRM in 2014, Mills was president and CEO of Osiris Therapeutics, developer of a pediatric stem cell drug called Prochymal, used to treat a complication of bone marrow transplants called graft vs. host disease.

If you look at my office, the walls are covered with pictures of the children that we treated who went through bone marrow transplantation, Mills said. Getting to know them, and getting to know their families that had a tremendous effect.

The unexpected announcement drew surprise and concern from stem cell researchers and observers. As admirers of CIRM 2.0, they expressed uncertainty about what direction the agency would take. And with the $3 billion beginning to run out, looking for a new source of funding will be a top concern of Mills successor.

Confidence

But Mills said Wednesday the agency will do well.

If me leaving CIRM is a problem, then I didnt do a good job at CIRM, Mills said. Whether its because Im going to be the head of the National Marrow Donor Program or I get hit by a car, the success of this organization, or any organization thats healthy and functional, should never pivot on one person, Mills said. Ive assembled a team at CIRM that I have absolute, absolute confidence in.

Mills said he would be surprised if Millan didnt turn out to be the agency boards overwhelming choice to be his permanent successor. She assisted in developing the agencys strategic plan and helped it run smoothly, he said.

In 2015, Mills named Millan as senior director of medical affairs and stem cell centers, one of three appointments to CIRMs leadership team. Before joining CIRM, she was vice president and acting chief medical officer at StemCells, Inc. Before that, Millan was director of the Pediatric Liver and Kidney Transplant Program at Stanford University School of Medicine.

Millan said the agencys strategic plan is working, and taking the agency where it needs to go. That plan was developed to guide researchers, doctors and companies over the predictable hurdles they encounter in translating basic research into therapies testable in the clinic and that companies would want to commercialize.

Weve already done the challenging piece of identifying the how how to get to the mission, which is to accelerate these stem cell treatments to those with unmet medical needs, Millan said. Team members are all aligned in accomplishing these goals One cant help but be more energized and motivated to execute on the strategic plan.

About 30 stem cell clinical trials are under way that the agency has funded at one stage or another in research and development.

Jonathan Thomas, the CIRM chairman, said Mills has done what he promised when joining CIRM, and the agency is operating markedly better, in productivity, speed and efficiency.

He has made it, through CIRM 2.0 and beyond, a humming machine that is operating on all cylinders, Thomas said. In doing that, hes worked extensively and highly collaboratively with Maria (Millan) and the rest of the team. That has made CIRM an even better operation than it ever was. So we are in extremely good shape right now to go forward.

Goals accomplished

Jeanne Loring, a CIRM-funded stem cell scientist at The Scripps Research Institute, said Mills made the agency friendlier and more predictable for the scientists it funds.

The first and most dramatic thing he did was to end the process of independent grants, Loring said. Under that process, each grant proposal was considered on its own, with no consideration for success under a previous grant for an earlier stage of the research.

It was always very troubling to people, I think, that they could do very well with CIRM money on an early-stage grant, and that would earn them nothing in a further application to continue the work, Loring said.

As part of CIRM 2.0, Mills emphasized that once projects were accepted for funding, CIRM would become a partner with the scientists to help them accelerate research and development, and ultimately commercialization.

Loring leads a team researching the use of stem cells for Parkinsons therapy. The cells are collected from the patients to be treated, making them a genetic match. They are then genetically reprogrammed to resemble embryonic stem cells, and then matured into the brain cells destroyed in Parkinsons.

Lorings team was awarded $2.4 million in 2016 from CIRM to advance its research. A next-stage grant to translate the research to a clinically ready approach would need about $7 million, Loring said. The work is part of Summit for Stem Cell, a nonprofit alliance of scientists, doctors, patients and Parkinsons disease community supporters.

Veteran stem cell watcher David Jensen praised Mills on his blog, California Stem Cell Report.

"Dr. Mills made substantial contributions to the agency during his tenure, improving both efficiency of the grant making process and transparency of CIRM's operations, Jensen quoted stem cell observer John M. Simpson of Consumer Watchdog as saying.

Simpson added that as CIRM draws down the rest of its $3 billion with no new funding in sight, its not surprising that Mills would accept another job.

Paul Knoepfler, a CIRM-funded stem cell scientist and blogger, wrote Tuesday that Mills had a big positive impact on CIRM and helped it go to the next level.

About the only thing I wasnt a fan of in terms of his leadership was my perception of his negativity toward the FDA and toward FDA oversight of stem cells, and how that manifested at CIRM during his time there, Knoepfler wrote. But good people can strongly disagree on policy.

bradley.fikes@sduniontribune.com

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Amid uncertain future, state's stem cell agency loses transformational leader - The San Diego Union-Tribune

The ability of stem cells to divide into different mature cell types has ignited the field of regenerative medicine. Stem cells promise to repair and regenerate damaged or diseased tissues without the need for orthodox medical or surgical interventions.

However, there is disparity between the expectations held by the general public and some medical professionals versus the reality of the emerging clinical evidence. This disconnect was highlighted recently by the case of three elderly patients who were blinded by the use of an unproven stem cell therapy at a clinic in Florida, USA (BioNews 893).

While stem cell therapies in the field of haematology are showing promise, there are still many challenges in using them in any other disease models. In some countries, medical professionals are using unproven stem cell therapies as medical procedures to treat patients in lieu of conventional treatment pathways. What is more, these practitioners are operating under the premise of a trial.

Proponents of using stem cell therapies outside the context of a true clinical trial believe that these therapies are inherently safe, particularly if the stem cells derive from the individual patient themselves. And the medical professionals offering unproven stem cell therapies are convinced that the potential benefits of undergoing the therapy far outweigh the potential risks.

These benefits are used as an argument to forge ahead with unproven therapies outside ofclinical trials, as regulatory bodies are often to slow to regulate for the fast-paced field of regenerative medicine;gaining regulatory approval is usually a lengthy and costly process. And the regulation that is in place is often narrow in scope and does not account for the variety of products and manipulative techniques used in the field.

An anecdotal account of a stem cell therapys potential to cure a disease, however, does not make for an adequate standard of evidence. In the Florida case, three elderly patients with a progressive eye disease sought out an unproven stem cell therapy. The clinic involved was offering the therapy under the guise of a trial, however the patients had to pay for the procedure (in itself a 'red flag') that promised to 'cure' their disease. The therapy not only failed, but all three patients are now blind as described in The New England Journal of Medicine on 16 March.

Referring back to the disparity in expectations, how the word 'trial' is understood helps to clarify the basis of thedisconnect between the public and clinicians, and emerging evidence. The word 'trial' in the sense of a clinical trial calls for a robust experimental framework and sets of regulations and standards that safeguard the enrolled patients' rights and overall health. Furthermore, trials are performed in a phased manner to ensure any potential risks are minimised. The results generated from a certain phase informs the researchers as to the most effective way to proceed or indeed not proceed.

Using the word 'trial' in the sense of administering a therapy outside of the setting described above, however, only truly refers to the inherent risk of the therapy not working. Moreover, when being administered by a trusted medical professional, the harms of the therapy are often overshadowed by the promise of a'cure' relayed bythese professionals.

The differences in the interpretation of the word trial among medical professionals is reflected by the lack of strict regulation among professional bodies, such as medical councils and regulatory bodies including the Food & Drug Administration (FDA). While the FDA, for example, has published more specific guidelines in October 2015, these are unenforceable on a global scale.

Interestingly, on a regulatory level, there are opportunities afforded to medical professionals to use unproven stem cell therapies outside the context of a clinical trial as noted in the International Society for Stem Cell Research (ISSCR) 2016 guidelines:

...the ISSCR acknowledges that in some very limited cases, clinicians may be justified in attempting medically innovative stem cell-based interventions in a small number of seriously ill patients.

However the ISSCR goes on to clarify that it 'condemns' the use of unproven stem cell therapies in any other setting where clinical need is not deemed serious.

In relation to classifying unproven stem cell therapies as a medical procedure, the 2014 United States of America v Regenerative Sciences, LLC et al case dealt with the use of mesenchymal stem cells taken from a sample of a patient's own bone marrow to treat their own orthopaedic disorders. In this case, the court was not convinced that manipulating stem cells outside the body and reintroducing them to the patient was a matter of standard 'medical procedure', as argued by the companyRegenerative Sciences LLC. Instead, the court upheld the FDAs right to regulate the manufacturing (or manipulating) of these stem cells: however cases where there is significantly less manipulation of stem cells are yet to be tested.

Issues remain regarding how best to regulate the use of stem cell therapies, particularly in the early phases of their development. There have been calls for strict regulation through bodies such as the FDA, but others argue that strict regulation will only curtail the benefits stem cell therapies can impart. On the other hand, regulations that are too lenient, it is argued, will only harm the patient seeking the therapy, as a solid evidence base will not yet have been compiled for the therapy.

Read more:
Unproven stem cell therapies promise versus evidence - BioNews

May 2, 2017 by Jennifer Gundersen A microscope image of brain cancer cells, a glioma tumor type known as anaplastic astrocytoma. Credit: Wikimedia/ CC BY-SA 3.0

Brain tumors recruit immune cells derived from bone marrow to transform what began as benign masses into deadly malignancies, according to two studies from Weill Cornell Medicine scientists. The findings suggest that inhibiting this cell-recruitment process can suppress tumor growth and may offer a way to predict which patients are at greatest risk for developing brain cancer.

Brain tumors, or gliomas, are classified as either low-grade, which are relatively benign, or high-grade, which are malignant and fatal. Some patients can live with low-grade gliomas for years without issue, particularly if the tumors are in a part of the brain that doesn't interfere with major cognitive functions. However, when the low-grade glioma develops into a malignancy, little can be done to halt or reverse tumor growth. Glioblastoma (GBM) develops in about 3 out of 100,000 people per year, and the typical prognosis is 17 months. There has previously been no way to predict which low-grade tumors will become malignant and when.

In two studies, published April 10 in the Journal of Clinical Investigation and Dec. 30 in Clinical Cancer Research, Weill Cornell Medicine scientists discovered that the tumor microenvironment recruits immune cells from bone marrow that normally play an important role in repairing and regenerating tissues. The team found that these cells play a critical role transforming tumors into high-grade glioblastomas. The team then identified a distinctive therapeutic target to halt this recruitment and prevent tumor growth.

"The reason our studies are unique is that we're looking at the glioma a couple of steps before the malignant state," said senior author Dr. Jeffrey Greenfield, associate professor of neurological surgery and of neurological surgery in pediatrics at Weill Cornell Medicine, and a neurological surgeon at NewYork-Presbyterian/Weill Cornell Medical Center. "As a neurosurgeon, I didn't want to keep seeing incurable tumors in the operating room. Therefore, as a neuroscientist I decided to ask: 'How can we predict which tumors will become more aggressive, and how can we intervene before it's too late and the tumor becomes incurable?'"

The body's immune system normally functions to fight off infection, but with glioblastoma, the tumors turn the immune system against itself. In the Journal of Clinical Investigation study, the investigators discovered molecular communication between the low-grade tumors and the immune cells, called bone marrow-derived immune cells (BMDCs), which play a crucial role in the development of blood vessels. This communication reprograms BMDCs to support cancer development, the investigators found, instructing them to leave the bone marrow and travel through the bloodstream to the tumor's microenvironment.

The team then developed a blood test to detect BMDCs, theorizing that an overabundance of immune cells in the bloodstream may indicate increased cell-recruitment activity. They used their assay in mice with glioblastoma and found higher levels of BMDCs in the bloodstreams of rodents whose tumors were progressing to high grade or had already become malignant. The investigators say their findings demonstrate a new method to predict which tumors are most likely to progress and provide a more accurate prognosis (the current diagnostic standard is an MRI and tumor biopsy).

"Essentially you can take patients who look the same clinically or whose MRI scans look identical," Greenfield said. "With this data we believe that we can predict who will progress to more aggressive disease within a shorter time frame."

To validate this finding, the investigators in the Clinical Cancer Research study tested blood samples taken from mice with brain tumors as well as those from human patients with low-and high-grade tumors, and non-tumor controls. They found an increase in BMDC production in the bone marrow and the bloodstreams of mice and humans as the tumors progressed from low to high grade. Rodent tumor samples also revealed a thirtyfold increase of BMDCs in the microenvironment of the tumors between these stages.

"Our findings suggest that many of these bone marrow-derived cells may contribute to the creation of new blood vessels that support tumor growth," said lead author Dr. Prajwal Rajappa, a fellow in neurological surgery at Weill Cornell Medicine. "Subsequent to our initial findings, our aim was to impair the recruitment of BMDCs to the tumor."

To accomplish this, the investigators identified a cellular pathway called JAK/STAT3 that plays an important role in BMDC production and potentially in their recruitment into the tumor microenvironment. Using a JAK 1/2 inhibitor, the researchers found in mice that they could prevent the recruitment of BMDCs to the tumor site thereby stymying malignant transformation. Mice that received the treatment lived significantly longer than those that did not.

This opens the possibility of human clinical trials using a U.S. Food and Drug Administration-approved drug that targets the JAK/STAT3 pathway.

"If we intervene at an early stage with these tumors, we have a chance of turning this basic science progress into a clinical success reminiscent of how the script was flipped with HIV: a fatal disease turned into a chronic disease. We are hoping to keep pushing this until we can tell the story where one lives with a brain tumor that indefinitely remains benign," Greenfield said. "With suppressive therapy, a patient could theoretically turn a prognosis of 17 months into one of 17 years."

Explore further: Genetic mutations help brain tumors evade targeting by immunotherapy treatments

More information: Yujie Huang et al. A proangiogenic signaling axis in myeloid cells promotes malignant progression of glioma, Journal of Clinical Investigation (2017). DOI: 10.1172/JCI86443

Prajwal Rajappa et al. Malignant Astrocytic Tumor Progression Potentiated by JAK-mediated Recruitment of Myeloid Cells, Clinical Cancer Research (2016). DOI: 10.1158/1078-0432.CCR-16-1508

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Immune cells play crucial role in brain cancer development - Medical Xpress

CAMBRIDGE, Mass.--(BUSINESS WIRE)--Magenta Therapeutics, a biotechnology company developing therapies to improve and expand the use of curative stem cell transplantation for more patients, today announced rapid progress in advancing the companys strategic vision, including the completion of a $50 million Series B financing; in-licensing a clinical-stage program from Novartis to support the use of stem cell transplantation in a variety of disease settings; and a strategic partnership with Be The Match BioTherapiesSM, an organization offering solutions for delivering autologous and allogeneic cellular therapies.

The financing announced today is intended to fuel development of innovative product candidates across multiple aspects of transplantation medicine, including more precise preparation of patients, stem cell harvesting and stem cell expansion. The Series B round, which was oversubscribed, was led by GV (formerly Google Ventures), with participation from all existing investors, including Atlas Venture, Third Rock Ventures, Partners Innovation Fund and Access Industries. The financing also included Casdin Capital and other crossover investors, as well as Be The Match BioTherapies, a subsidiary of National Marrow Donor Program(NMDP)/Be The Match, the worlds leading organization focused on saving lives through bone marrow and umbilical cord blood transplantation.

Magenta has quickly established itself as a nexus of innovation in stem cell science, catalyzing interest in this area of medicine with the recognition that improvements will have profound impact on patients, said Jason Gardner, D. Phil., chief executive officer, president and cofounder of Magenta Therapeutics. We aspire to accelerate products that could unleash the potential of transplantation to more patients, including those with autoimmune diseases, genetic blood disorders and cancer. The resounding interest in Magenta from such a high-quality set of investors is a testament to our solid progress since launch, including building a world-class team and a robust pipeline, and generating promising early data.

MGTA-456: Investigational Product Addressing Significant Unmet Need in Stem Cell Transplant

The clinical-stage program in-licensed by Magenta from Novartis, MGTA-456 (formerly HSC835), aims to expand the number of cord blood stem cells used in transplants to achieve superior clinical outcomes compared to standard transplant procedures, and to enable more patients to benefit from a transplant. Under this agreement, Magenta gains rights to use MGTA-456 in selected applications and will develop MGTA-456 in multiple diseases, including immune and blood diseases.

Early results published in Science1 demonstrated the ability of MGTA-456 to significantly increase the number of umbilical cord blood stem cells. Clinical results reported in Cell Stem Cell2 demonstrated that this approach yielded an increased expansion of stem cells.

John E. Wagner, M.D., executive medical director of the Bone Marrow Transplantation Program at the University of Minnesota and the studys lead author, stated: MGTA-456 markedly shortens time to recovery, addressing one of the most significant challenges in stem cell transplantation today. MGTA-456 achieved a remarkable increase in the number of blood-forming stem cells, greater than that observed by all other methods that have been tested to date. This product has the potential to further improve cord blood transplant outcomes.

Be The Match BioTherapies Strategic Partnership Agreement

Magenta and Be The Match BioTherapies also announced today that in addition to the equity investment, the two organizations have initiated a collaboration to support their shared goals of improving transplant medicine. Magenta and Be The Match BioTherapies will explore opportunities to work together across all of Magentas research efforts, from discovery through clinical development. Under this agreement, Magenta may leverage Be The Match BioTherapies capabilities, including its cell therapy delivery platform, industry relationships, clinical trial design and management, and patient outcomes data derived from the NMDP/Be The Match, which operates the largest and most diverse marrow registry in the world. NMDP/Be The Match has a network of more than 486 organizations that support marrow transplant worldwide, including 178 transplant centers in the United States and more than 45 international donor centers and cooperative registries.

We are proud to have made our first equity investment as an organization in Magenta Therapeutics, and we share a vision to improve and advance the use of curative stem cell transplantation for patients with a wide range of diseases, said Amy Ronneberg, president of Be The Match Biotherapies.

About Magenta Therapeutics

Magenta Therapeutics is a biotechnology company harnessing the power of stem cell science to revolutionize stem cell transplantation for patients with immune- and blood-based diseases. By creating a platform focused on critical areas of transplant medicine, Magenta Therapeutics is pioneering an integrated, but modular approach to stem cell therapies to create patient benefits. Founded by internationally recognized leaders in stem cell transplant medicine, Magenta Therapeutics was launched in 2016 by Third Rock Ventures and Atlas Venture and is headquartered in Cambridge, Mass. For more information, please visitwww.magentatx.com.

About Third Rock Ventures

Third Rock Ventures is a leading healthcare venture firm focused on investing and launching companies that make a difference in peoples lives. The Third Rock team has a unique vision for ideating and building transformative healthcare companies. Working closely with our strategic partners and entrepreneurs, Third Rock has an extensive track record for managing the value creation path to deliver exceptional performance. For more information, please visit the firms website atwww.thirdrockventures.com.

About Atlas Venture

Atlas Venture is a leading biotech venture capital firm. With the goal of doing well by doing good, we have been building breakthrough biotech startups since 1993. We work side by side with exceptional scientists and entrepreneurs to translate high impact science into medicines for patients. Our seed-led venture creation strategy rigorously selects and focuses investment on the most compelling opportunities to build scalable businesses and realize value. For more information, please visitwww.atlasventure.com.

About GV

GV provides venture capital funding to bold new companies. In the fields of life science, healthcare, artificial intelligence, robotics, transportation, cyber security, and agriculture, GV's companies aim to improve lives and change industries. GV's team of world-class engineers, designers, physicians, scientists, marketers, and investors work together to provide these startups exceptional support on the road to success.

Launched as Google Ventures in 2009, GV is the venture capital arm of Alphabet, Inc. GV helps startups interface with Google, providing unique access to the worlds best technology and talent. GV has $2.4 billion under management and is headquartered in Mountain View, California, with offices in San Francisco, Boston, New York, and London. Launched as Google Ventures in 2009, GV is the venture capital arm of Alphabet, Inc. For more information, please visit http://www.gv.com.

About Be The Match BioTherapies

Be The Match BioTherapies partners with organizations pursuing new life-saving treatments in cellular therapy. Built on the foundation established over the last 30 years by theNMDP/Be The Match, the organization has unparalleled experience in personalized patient management with a single point of contact, cell sourcing and collection, cell therapy delivery platform, immunogenetics and bioinformatics, research and regulatory compliance. By leveraging proven capabilities and established relationships, Be The Match BioTherapies can bring customizable solutions to organizations in every stage of cellular therapy developmentfrom discovery through commercialization. Discover how Be The Match BioTherapies can assist your company atBeTheMatchBioTherapies.com.

For more information on todays announcement, see Jason Gardners post in the Life Sci VC blog: https://lifescivc.com/2017/05/building-a-bioteth-a-triple-play/.

1Science.2010 Sep 10;329(5997):1345-8. 2Cell Stem Cell.2016 Jan 7;18(1):144-55.

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Magenta Therapeutics Advances Stem Cell Transplantation Strategy with $50 Million Series B Financing, Licensing of ... - Business Wire (press release)

Endothelial progenitor cell (or EPC) is a term that has been applied to multiple different cell types that play roles in the regeneration of the endothelial lining of blood vessels. Outgrowth endothelial cells are an EPC subtype committed to endothelial cell formation.[1] Despite the history and controversy, the EPC in all its forms remains a promising target of regenerative medicine research.

Developmentally, the endothelium arises in close contact with the hematopoietic system. This, and the existence of hemogenic endothelium, led to a belief and search for adult hemangioblast- or angioblast-like cells; cells which could give rise to functional vasculature in adults.[2] The existence of endothelial progenitor cells has been posited since the mid-twentieth century, however their existence was not confirmed until the 1990s when Asahara et al. published the discovery of the first putative EPC.[3]

Recently, controversy has developed over the definition of true endothelial progenitors.[4] Although bone marrow-derived cells do appear to localize to injured vessels and promote an angiogenic switch, other studies have suggested these cells do not contribute directly to the functional endothelium, instead acting via paracrine methods to provide support for the resident endothelial cells.[5][6] While some other authors have contested these, and maintained that they are true EPCs,[7] many investigators have begun to term these cells colony forming unit-Hill cells (CFU-Hill) or circulating angiogenic cells (CAC) instead (depending on the method of isolation), highlighting their role as hematopoietic myeloid cells involved in promoting new vessel growth.[8][9]

Molecular genetic analysis of early outgrowth putative EPC populations suggests they do indeed have monocyte-like expression patterns, and support the existence of a separate population of progenitors, the late outgrowth, or endothelial colony forming cell (ECFC).[10] Furthermore, early outgrowth cells maintain other monocyte functions such as high Dil-Ac-LDL and India ink uptake and low eNOS expression. These original, early outgrowth, CFU-Hill or CACs are also shown to express CD14, a lipopolysaccharide receptor expressed by monocytes but not endothelial cells.[11]

Endothelial colony forming cells represent a distinct population that has been found to have the potential to differentiate and promote vessel repair. ECFCs are now known to be tissue-resident progenitor cells in adults that maintain some vasculogenic ability.[12]

By method of isolation and cell function, three main populations of putative adult EPCs have been described. The behavior of the cells can be found in the following table.[9][13]

EPCs also have variable phenotypic markers used for identification. Unfortunately, there are no unique markers for endothelial progenitors that are not shared with other endothelial or hematopoietic cells, which has contributed to the historical controversy surrounding the field. A detailed overview of current markers can be found in the following table.[2][13]

As originally isolated by Asahara et al., the CFU-Hill population is an early outgrowth, formed by plating peripheral blood mononuclear cells on fibronectin-coated dishes, allowing adhesion and depleting non-adherent cells, and isolating discrete colonies.[8][9]

A similar method is to culture the peripheral blood mononuclear fraction in supplemented endothelial growth medium, removing the non-adherent cells, and isolating the remaining. While these cells display some endothelial characteristics, they do not form colonies.[8][9]

Endothelial colony forming cells are a late outgrowth cell type; that is, they are only isolated after significantly longer culture than CFU-Hill cells. ECFCs are isolated by plating peripheral blood mononuclear fraction on collagen-coated plates, removing non-adherent cells, and culturing for weeks until the emergence of colonies with a distinctive cobblestone morphology. These cells are phenotypically similar to endothelial cells and have been shown to create vessel-like structures in vitro and in vivo.[8][9]

Certain developmental cells may be similar to or the same as other endothelial progenitors, though not typically referred to as EPCs. Hemangioblasts (or their in vitro counterpart, blast - colony forming cells) are cells believed to give rise to both the endothelial and hematopoietic systems during early development. Angioblasts are believed to be a form of early progenitor or stem cell which gives rise to the endothelium alone. More recently, mesoangioblasts have been theorized as a cell giving rise to multiple mesodermal tissues.[14][15][16]

Endothelial progenitor cells are likely important in tumour growth and are thought to be critical for metastasis and the angiogenesis.[17][18] A large amount of research has been done on CFU-Hill bone marrow-derived putative EPCs. Ablation of the endothelial progenitor cells in the bone marrow lead to a significant decrease in tumour growth and vasculature development. This indicates that endothelial progenitor cells present novel therapeutic targets.[19]Inhibitor of DNA Binding 1 (ID1) has been used as a marker for these cells;[20] this allows for tracking EPCs from the bone marrow to the blood to the tumour-stroma and even incorporated in tumour vasculature.

Recently it has been found that miRNAs regulate EPC biology and tumour angiogenesis. This work by Plummer et al. found that in particular targeting of the miRNAs miR-10b and miR-196b led to significant defects in angiogenesis-mediated tumor growth by decreasing the mobilization of proangiogenic EPCs to the tumour. These findings indicate that directed targeting these miRNAs in EPCs may result in a novel strategy for inhibiting tumor angiogenesis.[21]

Studies have shown ECFCs and human umbilical vein endothelial cells (HUVECs) to have a capacity for tumor migration and neoangiogenesis even greater than that of other CD34+ hematopoietic cells when implanted in immunodeficient mice, suggesting the endothelial progenitors play a key role, but further supporting the importance of both cell types as targets for pharmacological therapy.[22]

Higher levels of circulating "endothelial progenitor cells" were detected in the bloodstream of patients, predicted better outcomes, and patients experienced fewer repeat heart attacks,[23] though statistical correlations between these outcomes and circulating endothelial progenitor cell numbers were scant in the original research. Endothelial progenitor cells are mobilized after a myocardial infarction, and that they function to restore the lining of blood vessels that are damaged during the heart attack.

A number of small phase clinical trials have begun to point to EPCs as a potential treatment for various cardiovascular diseases (CVDs). For instance, the year long "Transplantation of Progenitor Cells and Regeneration Enhancement in Acute Myocardial Infarction" (TOPCARE-AMI) studied the therapeutic effect of infusing ex-vivo expanded bone marrow EPCs and culture enriched EPCs derived from peripheral blood into 20 patients suffering from acute myocardial infarction (MI). After four months, significant enhancements were found in ventricular ejection fraction, cardiac geometry, coronary blood flow reserve, and myocardial viability (Shantsila, Watson, & Lip). A similar study looked at the therapeutic effects of EPCs on leg ischemia caused by severe peripheral artery disease. The study injected a sample of EPC rich blood into the gastrocnemius muscles of 25 patients. After 24 weeks an increased number of collateral vessels and improved recovery in blood perfusion was observed. Rest pain and pain-free walking were also noted to have improved [24]

The role of endothelial progenitor cells in wound healing remains unclear. Blood vessels have been seen entering ischemic tissue in a process driven by mechanically forced ingress of existing capillaries into the avascular region, and importantly, instead of through sprouting angiogenesis. These observations contradict sprouting angiogenesis driven by EPCs. Taken together with the inability to find bone-marrow derived endothelium in new vasculature, there is now little material support for postnatal vasculogenesis. Instead, angiogenesis is likely driven by a process of physical force.[25]

In endometriosis, it appears that up to 37% of the microvascular endothelium of the ectopic endometrial tissue originates from endothelial progenitor cells.[26]

Read more here:
Endothelial progenitor cell - Wikipedia

wbur Commentary

April 28, 2017

By Dr. Julie Losman

Dr. Julie Losman, a physician-scientist at Dana-Farber Cancer Institute and Brigham and Womens Hospital, told a memorable tale of sickle cell anemia and science at a Harvard rally before Boston's March for Science. It echoed a common theme, that support for basic science is crucial because it's not clear where the next great cure will come from. Her speech, lightly edited:

Sickle cell anemia has a very special place in the history of medicine: It was the first human disease that was understood on a molecular level.

Sickle cell anemia is caused by a single mutation in a gene, the hemoglobin gene, that produces a mutant protein with an abnormal structure. This abnormal hemoglobin disrupts the function of red blood cells.

The mutation was discovered in 1949 by a scientist named Linus Pauling. Pauling was not a medical doctor. He was a chemical engineer, a basic scientist. In fact, he won the Nobel Prize in 1954 for helping to invent the field of quantum chemistry, which is the study of how atoms and molecules interact. He was as fundamental and "basic" a scientist as you can be.

And yet it was Pauling's work on how small molecules bond together that led him to study how very big molecules, like proteins, bond together. This, in turn, led him to try and understand how a mutation in a gene could change the structure of a protein and alter the way that the protein bonds to other proteins.

That is how a chemical engineer who began his career studying protons and electrons made the first discovery of a human disease caused by a specific mutation.

The importance of this discovery to modern medicine cannot be overstated. Linus Paulings work laid the foundation for the entire field of medical genetics, which has absolutely revolutionized how we think about human disease.

For many, many, years, and even today, for many, many patients, the treatment for sickle cell anemia is palliative: Avoid things that trigger pain crises, treat pain crises when they happen, and try to protect organs from the damage that a crisis can cause. That is basically it.

A very few people with sickle cell anemia have successfully been cured with a transplant. Stem cell transplants are complicated, dangerous and very, very expensive. Undergoing a stem cell transplant requires absolute dedication from the patient, their families, their friends, their communities and their medical teams. Unfortunately, not everyone with sickle cell anemia has that kind of support or the access to exceptional medical care. A stem cell transplant for them is simply not an option.

But there is basic research going on right now --here in Boston and in labs across the United States and around the world --that has the potential to revolutionize how we treat sickle cell anemia. Right now, scientists are working on how to use an extraordinary new discovery called CRISPR to fix genetic mutations like the mutation that causes sickle cell anemia.

When this technique is perfected --not if it is perfected, but when it is perfected --it will be possible to take the stem cells of a patient, correct their mutation, and give them back their own stem cells. Because these reinfused stem cells would be perfectly at home in the patients body, there would be no need for months and months of post-transplant recovery.

Instead of being a leap of faith, a transplant would be a simple and safe procedure. It could even be done in young children with sickle cell anemia, before they ever have their first excruciating pain crisis.

The discovery of CRISPR and gene editing was not made by a geneticist or a stem cell biologist. CRISPR was discovered by a bunch of microbiologists, scientists who study bacteria and viruses.

In fact, much of the foundational work in CRISPR was done by nutritional microbiologists who wanted to understand how the bacteria we use to make cheese and yogurt are able to fight off viral infections. Imagine that! The future of gene therapy began in a yogurt vat.

The lesson we need to take away from Linus Pauling and these yogurt scientists is that basic fundamental research --the kind of research that is being done not just by the National Institutes of Health, but also by the National Science Foundation, the Department of Energy, NASA, the Environmental Protection Agency, the Department of Defense --is all absolutely crucial to advancing human health.

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How Yogurt Science Could Lead To A Cure For Sickle Cell Anemia - WBUR

We have anti-arthritis drugs. What we lack is the ability to deploy them when and where they are needed in the body. The drugs would be far more effective, and occasion fewer side effects, if they were to appear only in response to inflammation, and only in the joints. If the drugs could be delivered so painstakinglyso smartlythey wouldnt have to be administered systemically.

Although conventional drug delivery systems may be unable to respond to arthritic flares with such adroitness, cells may have better luckif they are suitably modified. Stem cells, for example, have been rewired by means of gene-editing technology to fight arthritis. These stem cells, known as SMART cells (Stem cells Modified for Autonomous Regenerative Therapy), develop into cartilage cells that produce a biologic anti-inflammatory drug. Ideally, the new cartilage cells will replace arthritic cartilage, and the biologic will protect against chronic inflammation, preserving joints and other tissues.

SMART cells of this sort were prepared by scientists based at Washington University School of Medicine in St. Louis. The scientists initially worked with skin cells taken from the tails of mice and converted those cells into stem cells. Then, using the gene-editing tool CRISPR in cells grown in culture, they removed a key gene in the inflammatory process and replaced it with a gene that releases a biologic drug that combats inflammation.

Details of this work appeared April 27 in the journal Stem Cell Reports, in an article entitled Genome Engineering of Stem Cells for Autonomously Regulated, Closed-Loop Delivery of Biologic Drugs. The article describes how modified stem cells grew into cartilage and produced cartilage tissue. The engineered cartilage, the scientists reported, was protected from inflammation.

Using the CRISPR/Cas9 genome-engineering system, we created stem cells that antagonize IL-1- [interleukin-1] or TNF-- [tumor necrosis factor-] mediated inflammation in an autoregulated, feedback-controlled manner, wrote the authors of the Stem Cell Reports article. Our results show that genome engineering can be used successfully to rewire endogenous cell circuits to allow for prescribed input/output relationships between inflammatory mediators and their antagonists, providing a foundation for cell-based drug delivery or cell-based vaccines via a rapidly responsive, autoregulated system.

Many current drugs used to treat arthritisincluding Enbrel (etanercept), Humira (adalimumab), and Remicade (infliximab)attack TNF-, an inflammation-promoting molecule. But the problem with these drugs is that they are given systemically rather than targeted to joints. As a result, they interfere with the immune system throughout the body and can make patients susceptible to side effects such as infections.

"We want to use our gene-editing technology as a way to deliver targeted therapy in response to localized inflammation in a joint, as opposed to current drug therapies that can interfere with the inflammatory response through the entire body," said Farshid Guilak, Ph.D., the paper's senior author and a professor of orthopedic surgery at Washington University School of Medicine. "If this strategy proves to be successful, the engineered cells only would block inflammation when inflammatory signals are released, such as during an arthritic flare in that joint."

Dr. Guilak's team encoded the stem/cartilage cells with genes that made the cells light up when responding to inflammation, so the scientists easily could determine when the cells were responding. Recently, the team began testing the engineered stem cells in mouse models of rheumatoid arthritis and other inflammatory diseases.

If the work can be replicated in animals and then developed into a clinical therapy, the engineered cells or cartilage grown from stem cells would respond to inflammation by releasing a biologic drugthe TNF- inhibitorthat would protect the synthetic cartilage cells that Dr. Guilak's team created and the natural cartilage cells in specific joints.

"When these cells see TNF-, they rapidly activate a therapy that reduces inflammation," Dr. Guilak explained. "We believe this strategy also may work for other systems that depend on a feedback loop. In diabetes, for example, it's possible we could make stem cells that would sense glucose and turn on insulin in response. We are using pluripotent stem cells, so we can make them into any cell type, and with CRISPR, we can remove or insert genes that have the potential to treat many types of disorders."

Excerpt from:
CRISPR-SMART Cells Regenerate Cartilage, Secrete Anti-Arthritis Drug - Genetic Engineering & Biotechnology News