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Category Archives: Massachusetts Stem Cells

Asymmetrex Will Present a New Test for Therapeutic Stem Cell Potency at the ISSCR 2021 Annual Meeting – PRNewswire

Posted: June 23, 2021 at 2:15 am

Potency tests assure doctors that a medicine has good quality and will be effective for treatment. Although potency tests are common for drug medicines, developing them for stem cell treatments has been difficult. For stem cell treatments, no reliable potency tests have been available.

At the June 21-26, 2021 Annual Meeting of the International Society for Stem Cell Research, stem cell biotechnology company Asymmetrex will present data and examples for a new test for evaluation of the potency of tissue stem cell treatments. The technology, called kinetic stem cell (KSC) counting, can tell doctors the number of live tissue-renewing stem cells in a treatment sample.

The President & CEO of Asymmetrex, James L. Sherley, M.D., Ph.D., explains, "Stem cell medicine has needed a quality and effectiveness index like drug specific activity for pharmaceuticals. What could work better than knowing the number of live tissue stem cells that can restore other tissue cells? That's what our KSC counting TORTOISE TestTM platform can tell doctors: the number of live stem cells in a treatment that can renew an organ or tissue."

Asymmetrex is currently focused on conducting preclinical and clinical evaluations of how well its tissue stem cell-specific data indicate the effectiveness of stem cell treatments in different patients. In his company's presentations at ISSCR 2021, Sherley says that he will also introduce the immediate benefits of KSC counting to stem cell scientists for their tissue stem cell research. "It's a no brainer that now knowing how many tissue stem cells are in experiments will greatly improve stem cell researchand, as a consequence, stem cell medicine."

About Asymmetrex

Asymmetrex, LLC is a Massachusetts life sciences company with a focus on developing technologies to advance stem cell medicine. Asymmetrex is a member company of the Advanced Regenerative Manufacturing Institute BioFabUSA (ARMI)and the Massachusetts Biotechnology Council (MassBio).

Media Contact: James L Sherley, [emailprotected]

SOURCE Asymmetrex, LLC

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Infertility: Men account for at least half of cases. So why have women shouldered the blame? – The Irish Times

Posted: at 2:15 am

Male scientists have long waxed poetic on the contents of their testes. Sperm is a drop of brain, wrote the ancient Greek writer Diogenes Laertius. Leonardo da Vinci drew the penis with a sperm duct that connected directly to the spinal cord. The 17th-century microscopist Antonie van Leeuwenhoek claimed that each sperm cell contained within it a folded-up human being waiting patiently to unfurl.

For nearly as long, scientists have fretted about sperms seemingly inevitable decline. Most recently, a series of alarming headlines as well as a new book by a public health researcher at Mount Sinai Medical Center in New York warned that falling sperm counts might threaten the future of the human race. Its a global existential crisis, saysShanna H Swan, author of the book Count Down.

Most of these headlines can be traced to an influential 2017 meta-analysis by Swan and others, which found that sperm counts in Europe, North America, Australia and New Zealand had plummeted by nearly 60 per cent since 1973. The authors screened 7,500 sperm-count studies from around the world, weeded out most of them and ultimately analysed 185 studies on 43,000 men worldwide.

They called the decline a canary in the coal mine for waning male reproductive health worldwide. Today, the authors would revise that statement. There is clear and present alarm now, says Dr Hagai Levine, a public-health researcher at Hebrew University-Hadassah School of Public Health and an author of the 2017 review. The canary is in trouble now. Swan agrees.

Now a group of interdisciplinary researchers from Harvard and Massachusetts Institute of Technology contend that fears of an impending Spermageddon have been vastly overstated. In a study published in May in the journal Human Fertility, they re-evaluated the 2017 review and found that it relied on flawed assumptions and failed to consider alternate explanations for the apparent decline of sperm.

Sarah Richardson, a Harvard scholar on gender and science and the senior author ofthe new study, calls the conclusion of the 2017 review an astonishing and terrifying claim that, were it to be true, would justify the apocalyptic tenor of some of the writing. Fortunately, she and her coauthors argue, there is little evidence that this is the case.

The 2017 authors were methodologically rigorous in screening sperm-count studies for quality and consistency, Richardson and her colleagues write. But even the data that passed muster was geographically sparse and uneven and often lacked basic criteria such as the age of the men. Moreover, its authors took for granted that a single metric sperm count was an accurate predictor of male fertility and overall health.

No one knows what an optimal sperm count is. The World Health Organisation sets a range of normal sperm count as from 15 million to 250 million sperm per millilitre. (Men produce about 2ml to 5ml per ejaculation.) But it isnt clear that more is better. Above a certain threshold 40 million per millilitre, according to the WHO a higher count does not mean a man is more fertile.

Doubling your sperm count from 25 million to 50 million doesnt double your chances, says Allan Pacey, an andrologist at the University of Sheffield, in England, and the editor of Human Fertility. Doubling it from 100 million to 200 million doesnt double your chances in fact it flattens off, if anything.

Germaine M Buck Louis, a reproductive-public-health researcher at George Mason University, in the United States, agrees that sperm count is a poor indicator of fertility. We dont see it predicting much of anything, especially in the context of a partner with a healthy female pelvis, says Buck Louis, who was not involved in the sperm-count studies.

The authors of the 2017 study inferred that lower sperm counts equated to lower fertility even though the sperm-count declines they documented all took place within the normal range, Richardson notes. Its similar to the whole conversation around testosterone more is better, and more is manlier, she says. Thats really a point we make, that there is no known normal or baseline for average population sperm counts.

Sperm count has other limitations as a metric. It takes about two months for stem cells in the testes to develop into new sperm, meaning that any single count is merely a snapshot of an evolving landscape.

Something thats going on in a mans body one month may be totally different from whats happening the next month, and the effects on sperm count might be changing also, says Meredith Reiches, an author ofthe 2021 paper and a biological anthropologist at the University of Massachusetts,Boston.

It also overlooks a vital piece of the infertility puzzle: women. Focusing only on the male metric leaves out key interactions between sperm, the female reproductive tract and the egg. Its very important, actually, to look at the couple, says Dr Bradley D Anawalt, a reproductive endocrinologist at the University of Washington school of medicine.

In her book, Swan suggests that sperm counts have plummeted largely because of the rise of endocrine disrupters, a class of hormone-mimicking chemicals found in everything from shampoo to TV-dinner packaging. (She also cites lifestyle factors such as obesity, alcoholand smoking.)

Richardson and her coauthors suggested an alternative: perhaps sperm levels naturally rise and fall over time and within populations. The question has not been explored by reproductive researchers and cannot be answered easily, as global sperm counts before 1970 are largely unknown.

There are other possible explanations, as well. Sperm-counting is a tricky business and notoriously prone to human error, Pacey says. (I say it from the point of view of someone who spent 30 years counting sperm and knows how difficult it is, he adds.) In a 2013 review article, he notes that as methodologies for counting had improved and been standardised since the 1980s, sperm counts had appeared to fall. In other words, it may simply be that earlier scientists were overcounting sperm.

Swan and Levine agree that exploring these alternative hypotheses was important, so that threats to reproductive health could be prevented. We showed evidence for decline, and raised alarm, Levine writes in an email. We need to study the causes, including the unlikely possibility of non-pathological decline.

There is one point that every author agrees on: mens reproductive health matters. And until nowit has been surprisingly neglected.

Male infertility contributes to at least half of all cases of infertility worldwide. Yet, historically, women have shouldered most of the blame for the inability to conceive. And with the rise of reproductive technologies such as in-vitro fertilisation, womens bodies are the ones that have been meticulously measured and tracked by reproductive medicine.

As a result, science still lacks basic knowledge when it comes to sperm, says Rene Almeling, a sociologist of medicine and author of GUYnecology: The Missing Science of Mens Reproductive Health.

We have built up such a medical infrastructure around the fertility and reproductivity of womens bodies that we havent asked some of the basic questions about mens reproductive health, Almeling says. There is just so, so much basic research still to be done about sperm.

The main qualities of sperm that infertility specialists look at nowadays how many, what shape and how they swim have not changed in the past 40 years, says Dr Abraham Morgentaler, a urologist and founder of Mens Health Boston.

Morgentaler, who worked at a semen-analysis lab at Beth Israel Deaconess Medical Center, in Boston, in the 1980s, attributes this stagnation to the rise of IVF and other technologies, which have become frontline treatments for almost any male-factor fertility problem. It almost doesnt even matter whats wrong with the sperm, he says.

These knowledge gaps radiate out to all bodies. Swan says part of her motivation for writing the book was that she wanted to see men and women become more proactive about their reproductive health.

Its invisible, she says. People dont talk about it. You talk about, Oh, Ive got a high cholesterol measure, or My blood pressures up. But you never would say, My egg count is down, or My sperm count is down.

Richardson agrees that the effect of reproductive toxins on fertility deserved further investigation. To say that we think these are alarmist and apocalyptic claims, and theyre not well founded, is not to say that we think it isnt an important research agenda, she says. There is a need to centre on mens reproductive health and understand their bodies as reproductive and as porous to the environment as anyones bodies. New York Times

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On systemic sources of early life stress, and empathetic responses – MIT News

Posted: June 6, 2021 at 2:00 am

A powerful series of speakers at the Picower Institute for Learning and Memorys biennial Spring Symposium, Early Life Stress and Mental Health, blended personal stories and rigorous research to demonstrate that while remedying the lifelong toxic stress and disadvantage many people incur during childhood can be difficult, it is by no means intractable.

Picower Institute Director Li-Huei Tsai opened the symposium, co-produced with the JPB Foundation led by Barbara Picower, with the observation that while problems such as poverty, racism, injustice, and child abuse have been around for a long time, finding and implementing ways to fight the health problems that can result has become increasingly urgent.

This feels especially so right now, as we grapple with a time in which many of us have seen young people endure historic stresses, she said. The many tragedies and disruptions of the Covid-19 pandemic and stark examples of racial and social injustice have made this a particularly difficult time to grow up.

Stories of systemic stress

Educator Geoffrey Canada, founder and president of the Harlem Childrens Zone, emphasized that the current moment is especially crucial in the Black community.

If I am right about what I suspect is going to happen in this country, I can just say for those of us who care about toxic stress we haven't seen nothing yet, he said. What's coming, in my opinion, is sort of unprecedented.

Early Life Stress and Mental Health - Geoffrey Canada

Canada, who grew up in the impoverished South Bronx, New York, recounted several episodes in which generations of his family encountered racism, sometimes at the hands of police and health care providers. Many Black people have come to regard such stresses as the price of living in America, he said. But after observing the disproportionately terrible impacts of Covid-19 in his and other communities of color, his concern is heightened further.

I think it's very clear in this country, your race determines largely whether you lived or died, whether you got sick, whether you ended up working at home or being on the front lines, he said, whether your children got an education, and whether or not you're going to have anything that looks like a recovery from this experience.

Moreover, the murder of George Floyd and other police killings were seared into the psyche, adding even more to the stresses black children now face.

Lawyer Bryan Stevenson, founder of the Equal Justice Initiative, called out other harms the justice system has inflicted, particularly on women and children. But he also recommended a prescription for the nation to reconsider policies that have led to mass incarceration and prosecution of children as adults.

Over the last 25 years, the percentage of women going to jails and prisons has increased 800 percent, he said. Eighty percent of the women that we put in our jails and prisons are single parents with minor children, which means that the lives of a generation of children are being disrupted by these carceral policies.

Moreover, in a country where one-in-three Black and one-in-six Latino boys are projected to be in prison during their lives, Stevenson said that when he sits down with preteens in poor communities, theyll say things that break my heart. Ive talked to too many children who tell me that they expect to be in jail.

He called for more people to get proximate to families struggling with poverty, addiction, and other difficulties because proximity promotes understanding and empathy and provides an opportunity to provide the affirmation, care, safety, and opportunity that children growing up among violence need. Proximity, for instance, can help undo the discredited but persistent narrative that juveniles accused of crimes are somehow super predators and not still children. It can combat the politics of fear and anger, he said, that led the country to treat addiction disorders through the legal system rather than as a health care problem. And it can dispel, he said, a sense in America, lingering since slavery and the genocide of Indigenous Americans, of a racial hierarchy.

Jose Antonio Vargas put a similar emphasis on inspiring empathy through storytelling. The organization he founded, Define American, is a culture change organization that uses the power of narrative to humanize conversations about immigrants. Vargas, who came to the United States from the Philippines as a child, discovered his undocumented status when he was a teenager. As difficult as living undocumented can be under typical circumstances he drew a parallel between limitations on travel many felt during the Covid pandemic with the restrictions undocumented people consistently face becoming a public advocate amid intense policy debate can add to that stress.

Early Life Stress and Mental Health - Jose Antonio Vargas

Define American has therefore spearheaded research with the University of Massachusetts at Amherst, funded by the National Geographic Society, to survey immigration advocates for signs of post-traumatic stress disorder, stress, depression, and other signs of mental health troubles, as well as resilience. Full results, he said, will be published this summer, but reflect high rates of both trauma and resilience.

Science begets solutions

Several symposium speakers emphasized that much as personal stories and proximity can aid reveal the roots of toxic stress, scientific data and research can also lead to remedies by discovering the mechanisms that underlie health problems.

Picower Institute neuroscientist Gloria Choi, associate professor in the MIT Department of Brain and Cognitive Sciences (BCS), for example, shared her research tracing a long-observed but never explained link between pregnant women getting sick from infection and the emergence of autism-like symptoms in their children. Her research in mouse models showed that when specific bacteria are in the gut microbiome of pregnant dams, infection during a specific time of pregnancy stimulates the release of cytokine molecules from immune cells. Those cytokines reach neurons in the S1DZ region of the cortex of the fetus, disrupting the development of inhibitory neurons. That in turn leads to hyperactivity of circuits governing social behaviors, causing the autism-like neurodevelopmental disorder.

By achieving this kind of detailed, causal understanding, Choi said, scientists pinpoint targets for therapeutic interventions.

We scientists, to be able to help children, I think we need to understand at mechanistic levels as to how mother's health can shape that of her child, she said.

At a population level, as well, extracting cause and effect from data can help guide public health and policy remedies, said social epidemiologist Mariana Arcaya, associate professor in MITs Department of Urban Studies and Planning. She made the case that while many researchers have shown that neighborhood characteristics such as poverty and violence can undermine health, fewer have studied what may be an equally important link existing health conditions can make it harder for families to move. Appreciating this bidirectional relationship between health and geography should not be overlooked in devising interventions, she said. Her research has helped to document it.

If poor health is a factor that is going to limit socioeconomic and geographic mobility, and we know that there's huge baseline disparities in health in the United States, Arcaya said, then we really need to be concerned about the co-production of health and neighborhood and housing conditions and how some families may be in a kind of cyclical disadvantage for both health outcomes and socioeconomic and neighborhood outcomes.

As the first surgeon general of the State of California, physician Nadine Burke Harris has galvanized a science-based statewide response to the public health crisis of adverse childhood experiences (ACEs), such as abuse, neglect, or disruptions in home life. More than 60 percent of adults have experienced at least one ACE and 15.8 percent have experienced four or more. Research shows that ACEs accumulate to raise the risk of serious health problems, including Alzheimers disease and suicide. In all, ACE-related health problems, she said, add $112.5 billion to annual health-care costs in California and more than $1 trillion across North America and Europe as a whole. On top of those, poverty and racism are also risk factors for future health difficulties.

Early Life Stress and Mental Health - Nadine Burke Harris

Over the last several decades weve begun to explore the biological mechanisms for how this happens, she said. Weve heard that trauma, especially in childhood, is damaging to our physical health, our mental health, but now we want to understand why, because when we understand the mechanism, that gives us tools to be able to unpack this.

In affected people, she said, ACEs trigger toxic stress an abnormally sustained stress hormone and immune system response as well as epigenetic changes that alter expression of genes. These factors, many of which act directly on the brain, lead to health risks. They can be mitigated, however, by providing safe, stable, and nurturing relationships and environments, as well as with stress management and medication.

So California has launched programs that have trained more than 17,000 primary care providers to screen more than 300,000 patients for ACEs and toxic stress risk. From there, doctors can help families with strategies to better manage the response. Moreover, the state has invested more than $30 million this year in grants covering 27 counties to link medical, social, educational, and community service providers together in trauma-informed networks of care that support families more broadly.

Extending opportunities

In a panel discussion moderated by Laura Schulz, a professor in BCS and the departments associate head for Diversity, Equity Inclusion and Justice Initiatives, the symposium also highlighted another dimension of harmful inequity that prevents people from reaching their full potential: the lack of diversity in science, technology, engineering, and mathematics, or STEM. Mirroring the focus other speakers put on seeking solutions, the panel featured people at MIT who are working to improve diversity in STEM, and participants in some of those programs who described what involvement has meant for them.

Picower Institute postdoc Hctor De Jess-Corts, a member of Picower Professor Mark Bears lab, for example, described how his participation as a student in Puerto Rico in the NIH-funded Minority Access for Research Careers program enabled him to do full-time research and to launch his scientific career. That and other opportunities inspired him to co-found the Sagrado MIT Neuroscience Pre-College Program, which helps high school students all over Puerto Rico to gain more exposure to science and knowledge about science careers. Of the 11 juniors who participated last year, many are now headed for colleges such as Stanford University, Yale University, Emory University, Cornell University, and Georgia Tech, he said.

Early Life Stress and Mental Health - Panel

The MIT Office of Engineering Outreachs three programs are currently serving about 365 high-achieving pre-college students from underrepresented groups and disadvantaged backgrounds. In all, OEOP has served more than 5,000 students, said Executive Director Eboney Hearn. About 80 percent have gone on to earn at least bachelors degrees in STEM fields, she said, including many at MIT.

Our alumni tell us that our programs have helped to level the playing field and helped them to get to places in their academic and personal journeys that didnt seem possible, she said.

Schulzs lab has been an active locus within BCS for inspiring and mentoring students at various stages. Graduate student Junyi Chu, for instance, described how last year she helped to launch the labs high school internship program, in partnership with Somerville High School and Black Girls Code. The lab has already engaged 17 students in the labs work studying cognition in babies. Interns also learn about science careers and publishing.

Panelist Liora Jones, from Torrington, Connecticut, was a Schulz lab intern. She just graduated high school and will study cognitive science at Wellesley College in the fall. Inspired by the fields of human-computer interaction, psychology, and artificial intelligence, she said she saw the internship as a way to learn more about cognition and to gain research skills. She did, and in the process met a mentor, new friends, and attended her first research conference.

Chu has also mentored college students in the MIT Summer Research Program. Among them is Kailande Cassamajor, who just graduated from Howard University with a degree in biology and psychology, and will attend a masters program in data science at Columbia University in the fall. Cassamajor said she enjoyed the chance to meet fellow MSRP students from other schools as well as to work with graduate students, like Junyi, who exposed her to cognitive and computational neuroscience. She greatly expanded her experience using a new programming language, for example.

In his remarks, panelist Tyler Bonnen provided vivid, personal representation of many of the themes of the day. Now a fifth-year neuroscience graduate student at Stanford, he described his adolescence in Miami Dade County, Florida, as mired within the criminal justice system: rehabs, hospitals, jail cells, psych wards, detention centers. But he had a good judge and was lucky enough to be picked for a study in which he and his family were helped. He got out of the institutions in which he was being harmed, he said, did social justice work, and then found his way to community college, where he encountered a program that would finance his education if he would study science.

After earning a degree at Columbia, he studied at MIT as a BCS postbaccalaureate scholar with Schulz and Professor Rebecca Saxe. Now hes dedicating his multidisciplinary research to studying how memory works, with the goal of better understanding trauma and helping people overcome it. Hes bringing his stories and science together to help others overcome acute stresses of their own.

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How Coronavirus Damages Lung Cells Within Mere Hours And What Drugs Could Halt COVID-19 Infection – SciTechDaily

Posted: February 1, 2021 at 8:54 am

Human lung cells (blue) infected with SARS-CoV-2 (red). Courtesy of Hekman, et al. Credit: Courtesy of Hekman, et al.

Multipronged BU research team finds 18 FDA-approved drugs that could halt coronavirus infection earlier.

What if scientists knew exactly what impact the SARS-CoV-2 virus had inside our lung cells, within the first few hours of being infected? Could they use that information to find drugs that would disrupt the virus replication process before it ever gets fully underway? The discovery that several existing FDA-approved drugsincluding some originally designed to fight cancercan stop coronavirus in its tracks indicates the answer is a resounding yes.

A team of Boston University researchershailing from BUs National Emerging Infectious Diseases Laboratories (NEIDL), the Center for Regenerative Medicine (CReM) at BUs Medical Campus, and BUs Center for Network Systems Biology (CNSB)embarked on a months-long, collaborative and interdisciplinary quest, combining multiple areas of expertise in virology, stem cellderived lung tissue engineering, and deep molecular sequencing to begin answering those questions. They simultaneously infected tens of thousands of human lung cells with the SARS-CoV-2 virus, and then tracked precisely what happens in all of those cells during the first few moments after infection. As if that was not complicated enough, the team had to cool their entire high-containment research facility inside the NEIDL to a brisk 61 degrees Fahrenheit.

The result of that challenging and massive undertaking? The BU team has revealed the most comprehensive map to date of all the molecular activities that are triggered inside lung cells at the onset of coronavirus infection. They also discovered there are at least 18 existing, FDA-approved drugs that could potentially be repurposed to combat COVID-19 infections shortly after a person becomes infected. Experimentally, five of those drugs reduced coronavirus spread in human lung cells by more than 90 percent. Their findings were recently published in Molecular Cell.

Now, academic and industry collaborators from around the world are in contact with the team about next steps to move their findings from bench to bedside, the researchers say. (Although COVID-19 vaccines are starting to be rolled out, its expected to take the better part of a year for enough people to be vaccinated to create herd immunity. And there are no guarantees that the current vaccine formulations will be as effective against future SARS-CoV-2 strains that could emerge over time.) More effective and well-timed therapeutic interventions could help reduce the overall number of deaths related to COVID-19 infections.

What makes this research unusual is that we looked at very early time points [of infection], at just one hour after the virus infects lung cells. It was scary to see that the virus already starts to damage the cells so early during infection, says Elke Mhlberger, one of the studys senior investigators and a virologist at BUs NEIDL. She typically works with some of the worlds most lethal viruses like Ebola and Marburg.

The most striking aspect is how many molecular pathways are impacted by the virus, says Andrew Emili, another of the studys senior investigators, and the director of BUs CNSB, which specializes in proteomics and deep sequencing of molecular interactions. The virus does wholesale remodeling of the lung cellsits amazing the degree to which the virus commandeers the cells it infects.

Viruses cant replicate themselves because they lack the molecular machinery for manufacturing proteinsthats why they rely on infecting cells to hijack the cells internal machinery and use it to spread their own genetic material. When SARS-CoV-2 takes over, it completely changes the cells metabolic processes, Emili says, and even damages the cells nuclear membranes within three to six hours after infection, which the team found surprising. In contrast, cells infected with the deadly Ebola virus dont show any obvious structural changes at these early time points of infection, and even at late stages of infection, the nuclear membrane is still intact, Mhlberger says.

The nuclear membrane surrounds the nucleus, which holds the majority of a cells genetic information and controls and regulates normal cellular functions. With the cell nucleus compromised by SARS-CoV-2, things rapidly take a bad turn for the entire cell. Under siege, the cellswhich normally play a role in maintaining the essential gas exchange of oxygen and carbon dioxide that occurs when we breathedie. As the cells die, they also emit distress signals that boost inflammation, triggering a cascade of biological activity that speeds up cell death and can eventually lead to pneumonia, acute respiratory distress, and lung failure.

I couldnt have predicted a lot of these pathways, most of them were news to me, says Andrew Wilson, one of the studys senior authors, a CReM scientist, and a pulmonologist at Boston Medical Center (BMC), BUs teaching hospital. At BMC, Bostons safety net hospital, Wilson has been on the front lines of the COVID-19 pandemic since March 2020, trying to treat and save the sickest patients in the hospitals ICU. Thats why our [experimental] model is so valuable.

Science is the answerif we use science to ask the lung cells what goes wrong when they are infected with coronavirus, the cells will tell us. Darrell Kotton

The team leveraged the CReMs organoid expertise to grow human lung air sac cells, the type of cell that lines the inside of lungs. Air sac cells are usually difficult to grow and maintain in traditional culture and difficult to extract directly from patients for research purposes. Thats why much coronavirus research to date by other labs has relied on the use of more readily available cell types, like kidney cells from monkeys. The problem with that is kidney cells from monkeys dont react the same way to coronavirus infection as lung cells from humans do, making them a poor model for studying the viruswhatever is learned from them doesnt easily translate into clinically relevant findings for treating human patients.

Our organoids, developed by our CReM faculty, are engineered from stem cellstheyre not identical to the living, breathing cells inside our bodies, but they are the closest thing to it, says Darrell Kotton, one of the studys senior authors. He is a director of the CReM and a pulmonologist at BMC, where he has worked alongside Wilson in the ICU treating COVID-19 patients. The two of them often collaborated with Mhlberger, Emili, and other members of their research team via Zoom calls that they managed to join during brief moments of calm in the ICU.

In another recent study using the CReMs engineered human lung cells, the research team confirmed that existing drugs remdesivir and camostat are effective in combating the virus, though neither is a perfect fix for controlling the inflammation that COVID-19 causes. Remdesivir, a broad-use antiviral, has already been used clinically in coronavirus patients. But based on the new studys findings that the virus does serious damage to cells within hours, setting off inflammation, the researchers say theres likely not much that antiviral drugs like remdesivir can do once an infection has advanced to the point where someone would need to be put on a ventilator in the ICU. [Giving remdesivir] cant save lives if the disease has already progressed, Emili says.

Seeing how masterfully SARS-CoV-2 commandeers human cells and subverts them to do the manufacturing work of replicating the viral genome, it reminded the researchers of another deadly invader.

I was surprised that there are so many similarities between cancer cells and SARS-CoV-2-infected cells, Mhlberger says. The team screened a number of cancer drugs as part of their study and found that several of them are able to block SARS-CoV-2 from multiplying. Like viruses, cancer cells want to replicate their own genomes, dividing over and over again. To do that, they need to produce a lot of pyrimidine, a basic building block for genetic material. Interrupting the production of pyrimidineusing a cancer drug designed for that purposealso blocks the SARS-CoV-2 genome from being built. But Mhlberger cautions that cancer drugs typically have a lot of side effects. Do we really want to use that heavy stuff against a virus? she says. More studies will be needed to weigh the pros and cons of such an approach.

The findings of their latest study took the four senior investigators and scientists, postdoctoral fellows, and graduate students from their laboratories almost four months, working nearly around the clock, to complete the research. Of critical importance to the teams leaders was making sure that the experimental setup had rock-solid foundations in mimicking whats actually happening when the SARS-CoV-2 virus infects people.

Science is the answerif we use science to ask the lung cells what goes wrong when they are infected with coronavirus, the cells will tell us, Kotton says. Objective scientific data gives us hints at what to do and has lessons to teach us. It can reveal a path out of this pandemic.

Hes particularly excited about the outreach the team has received from collaborators around the world. People with expertise in supercomputers and machine learning are excited about using those tools and the datasets from our publication to identify the most promising drug targets [for treating COVID-19], he says.

Kotton says the theme thats become obvious among COVID-19 clinicians and scientists is understanding that timing is key. Once a patient is on a ventilator in the ICU, we feel limited in what we can do for their body, he says. Timing is everything, its crucial to identify early windows of opportunity for intervention. You can keep guessing and hope we get luckyor you [do the research] to actually understand the infection from its inception, and take the guesswork out of drug development.

Reference: Actionable Cytopathogenic Host Responses of Human Alveolar Type 2 Cells to SARS-CoV-2 by Ryan M. Hekman, Adam J. Hume, Raghuveera Kumar Goel, Kristine M. Abo, Jessie Huang, Benjamin C. Blum, Rhiannon B. Werder, Ellen L. Suder, Indranil Paul, Sadhna Phanse, Ahmed Youssef, Konstantinos D. Alysandratos, Dzmitry Padhorny, Sandeep Ojha, Alexandra Mora-Martin, Dmitry Kretov, Peter E.A. Ash, Mamta Verma, Jian Zhao, J.J. Patten, Carlos Villacorta-Martin, Dante Bolzan, Carlos Perea-Resa, Esther Bullitt, Anne Hinds, Andrew Tilston-Lunel, Xaralabos Varelas, Shaghayegh Farhangmehr Ulrich Braunschweig, Julian H. Kwan, Mark McComb, Avik Basu, Mohsan Saeed, Valentina Perissi, Eric J. Burks, Matthew D. Layne, John H. Connor, Robert Davey, Ji-Xin Cheng, Benjamin L. Wolozin, Benjamin J. Blencowe, Stefan Wuchty, Shawn M. Lyons, Dima Kozakov, Daniel Cifuentes, Michael Blower, Darrell N. Kotton, Andrew A. Wilson, Elke Mhlberger and Andrew Emili, 18 November 2020, Molecular Cell.DOI: 10.1016/j.molcel.2020.11.028

This research was funded by the National Institutes of Health, the Australian National Health and Medical Research Council, the Pulmonary Fibrosis Foundation, the Massachusetts Consortium on Pathogen Readiness, the Digital Transformation Institute, the Canadian Institutes of Health Research, and Fast Grants.

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Orchard Therapeutics Outlines Comprehensive Presence at 2021 WORLDSymposium – GlobeNewswire

Posted: at 8:54 am

Nine abstracts accepted demonstrating potential of HSC gene therapy to treat multiple neurodegenerative disorders

New clinical data from all eight patients treated with OTL-203 for Mucopolysaccharidosis type I (MPS I)

Biomarker data from first three patients treated with OTL-201 for Mucopolysaccharidosis type IIIA (MPS-IIIA or Sanfilippo Syndrome Type A)

Multiple abstracts highlighting clinical and real-world data for OTL-200 and Metachromatic Leukodystrophy (MLD)

Company to host virtual investor webinar to review symposium data on Tuesday, February 9, 2021 at 4:30 p.m. ET

BOSTON and LONDON, Jan. 28, 2021 (GLOBE NEWSWIRE) -- Orchard Therapeutics(Nasdaq: ORTX), a global gene therapy leader, today outlined nine upcoming presentations from its neurodegenerative portfolio to be featured at the 17th Annual WORLDSymposium being held on February 8-12, 2021. Accepted abstracts include clinical data from three of its hematopoietic stem cell (HSC) gene therapy programs OTL-200 for MLD, OTL-203 for MPS-I and OTL-201 for MPS-IIIA as well as data supporting Orchards multi-pronged patient identification and market access strategies for eligible MLD patients in Europe.

Together with our clinical partners, were proud of our presence at the upcoming WORLDSymposium, which for the first time features clinical data on cognitive function and growth in all eight MPS-I patients treated with gene therapy, said Bobby Gaspar, M.D., Ph.D., chief executive officer of Orchard. Alongside emerging data in MPS-IIIA and our extensive body of clinical and real-world data in MLD, our programs are establishing a clear picture of the transformative potential of HSC gene therapy across multiple fatal neurodegenerative conditions.

The presentations are listed below and the full preliminary program is available online on the WORLDSymposium website. The ePosters will open at 2:30 p.m. ET on Monday, February 8, 2021 and will remain open throughout WORLDSymposium 2021.

Orchard is planning to host a virtual investor webinar on Tuesday, February 9th, 2021 at 4:30 p.m. ET to review the data from its neurodegenerative programs presented at the WORLDSymposium. A live webcast will be available under Events in the Investors & Media section of the companys website at and a replay of the webcast will be archived following the event.

Platform Oral Presentation Details:

Ex-vivo autologous stem cell gene therapy clinical trial for mucopolysaccharidosis type IIIA: Update on phase I/II clinical trialPresenting Author: Jane Kinsella, Royal Manchester Childrens Hospital 2021 Young Investigator Award RecipientDate/Time: Tuesday, February 9, 2021, 11:12 a.m. ET

Ex vivo hematopoietic stem cell gene therapy for mucopolysaccharidosis type I (Hurler syndrome)Presenting Author: Bernhard Gentner, San Raffaele Telethon Institute for Gene TherapyDate/Time: Tuesday, February 9, 2021, 11:24 a.m. ET

Lentiviral hematopoietic stem and progenitor cell gene therapy provides durable clinical benefit in early-symptomatic early juvenile metachromatic leukodystrophyPresenting Author: Francesca Fumagalli, San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific InstituteDate/Time: Wednesday, February 10, 2021, 11:36 a.m. ET

ePoster Presentation Details:

Lentiviral haematopoietic stem cell gene therapy for metachromatic leukodystrophy: Results in nine patients treated with a cryopreserved formulation of OTL-200Abstract Number: 25Presenting Author: Valeria Calbi, San Raffaele Telethon Institute for Gene TherapyDate/Time: Wednesday, February 10, 2021, 2:30 3:30 p.m. ET

Initial signs and symptoms of metachromatic leukodystrophy: A caregiver perspectiveAbstract Number: 64Presenting Author: Florian Eichler, Massachusetts General HospitalDate/Time: Thursday, February 11, 2021, 2:30 3:30 p.m. ET

Demographic and clinical characteristics of patients with metachromatic leukodystrophy in the United Kingdom: Interim results from an observational real-world studyAbstract Number: 110Presenting Author: Simon Jones, Manchester Centre for Genomic Medicine Date/Time: Thursday, February 11, 2021, 2:30 3:30 p.m. ET

Quality of life of patients with metachromatic leukodystrophy and their caregivers in the US, UK, Germany and FranceAbstract Number: 186Presenting Author: Francis Pang, Orchard TherapeuticsDate/Time: Thursday, February 11, 2021, 2:30 3:30 p.m. ET

Health-related quality of life in metachromatic leukodystrophy based on a societal utility study in the UKAbstract Number: 187Presenting Author: Francis Pang, Orchard TherapeuticsDate/Time: Thursday, February 11, 2021, 2:30 3:30 p.m. ET

Newborn screening for metachromatic leukodystrophy in Northern Germany - a prospective studyAbstract Number: 269Presenting Author: Thomas Wiesinger, ARCHIMEDlifeDate/Time: Thursday, February 11, 2021, 2:30 3:30 p.m. ET

About Libmeldy / OTL-200Libmeldy (autologous CD34+ cell enriched population that contains hematopoietic stem and progenitor cells (HSPC) transduced ex vivo using a lentiviral vector encoding the human arylsulfatase-A (ARSA) gene), also known as OTL-200, has been approved by the European Commission for the treatment of MLD in eligible early-onset patients characterized by biallelic mutations in the ARSA gene leading to a reduction of the ARSA enzymatic activity in children with i) late infantile or early juvenile forms, without clinical manifestations of the disease, or ii) the early juvenile form, with early clinical manifestations of the disease, who still have the ability to walk independently and before the onset of cognitive decline. Libmeldy is the first therapy approved for eligible patients with early-onset MLD.

The most common adverse reaction attributed to treatment with Libmeldy was the occurrence of anti-ARSA antibodies. In addition to the risks associated with the gene therapy, treatment with Libmeldy is preceded by other medical interventions, namely bone marrow harvest or peripheral blood mobilization and apheresis, followed by myeloablative conditioning, which carry their own risks. During the clinical studies, the safety profiles of these interventions were consistent with their known safety and tolerability.

For more information about Libmeldy, please see the Summary of Product Characteristics (SmPC) available on the EMA website.

Libmeldy is not approved outside of the European Union, UK, Iceland, Liechtenstein and Norway. OTL-200 is an investigational therapy in the US.

Libmeldy was developed in partnership with the San Raffaele-Telethon Institute for Gene Therapy (SR-Tiget) in Milan, Italy.

About OrchardOrchard Therapeutics is a global gene therapy leader dedicated to transforming the lives of people affected by rare diseases through the development of innovative, potentially curative gene therapies. Our ex vivo autologous gene therapy approach harnesses the power of genetically modified blood stem cells and seeks to correct the underlying cause of disease in a single administration. In 2018, Orchard acquired GSKs rare disease gene therapy portfolio, which originated from a pioneering collaboration between GSK and theSan Raffaele Telethon Institute for Gene Therapy in Milan, Italy. Orchard now has one of the deepest and most advanced gene therapy product candidate pipelines in the industry spanning multiple therapeutic areas where the disease burden on children, families and caregivers is immense and current treatment options are limited or do not exist.

Orchard has its global headquarters in London and U.S. headquarters in Boston. For more information, please visit, and follow us on Twitter and LinkedIn.

Availability of Other Information About OrchardInvestors and others should note that Orchard communicates with its investors and the public using the company website (, the investor relations website (, and on social media (Twitter andLinkedIn), including but not limited to investor presentations and investor fact sheets,U.S. Securities and Exchange Commissionfilings, press releases, public conference calls and webcasts. The information that Orchard posts on these channels and websites could be deemed to be material information. As a result, Orchard encourages investors, the media, and others interested in Orchard to review the information that is posted on these channels, including the investor relations website, on a regular basis. This list of channels may be updated from time to time on Orchards investor relations website and may include additional social media channels. The contents of Orchards website or these channels, or any other website that may be accessed from its website or these channels, shall not be deemed incorporated by reference in any filing under the Securities Act of 1933.

Forward-Looking StatementsThis press release contains certain forward-looking statements about Orchards strategy, future plans and prospects, which are made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. Forward-looking statements include express or implied statements relating to, among other things, Orchards business strategy and goals, and the therapeutic potential of Orchards product candidates, including the product candidate or candidates referred to in this release. These statements are neither promises nor guarantees and are subject to a variety of risks and uncertainties, many of which are beyond Orchards control, which could cause actual results to differ materially from those contemplated in these forward-looking statements. In particular, these risks and uncertainties include, without limitation: the risk that prior results, such as signals of safety, activity or durability of effect, observed from preclinical studies or clinical trials will not be replicated or will not continue in ongoing or future studies or trials involving Orchards product candidates, will be insufficient to support regulatory submissions or marketing approval in the US or EU, as applicable, or that long-term adverse safety findings may be discovered; the risk that any one or more of Orchards product candidates, including the product candidates referred to in this release, will not be approved, successfully developed or commercialized; the risk of cessation or delay of any of Orchards ongoing or planned clinical trials; the risk that Orchard may not successfully recruit or enroll a sufficient number of patients for its clinical trials; the delay of any of Orchards regulatory submissions; the failure to obtain marketing approval from the applicable regulatory authorities for any of Orchards product candidates or the receipt of restricted marketing approvals; the inability or risk of delays in Orchards ability to commercialize its product candidates, if approved, or Libmeldy in the EU; the risk that the market opportunity for Libmeldy, or any of Orchards product candidates, may be lower than estimated; and the severity of the impact of the COVID-19 pandemic on Orchards business, including on clinical development, its supply chain and commercial programs. Given these uncertainties, the reader is advised not to place any undue reliance on such forward-looking statements.

Other risks and uncertainties faced by Orchard include those identified under the heading "Risk Factors" in Orchards quarterly report on Form 10-Q for the quarter endedSeptember 30, 2020, as filed with theU.S. Securities and Exchange Commission(SEC), as well as subsequent filings and reports filed with theSEC. The forward-looking statements contained in this press release reflect Orchards views as of the date hereof, and Orchard does not assume and specifically disclaims any obligation to publicly update or revise any forward-looking statements, whether as a result of new information, future events or otherwise, except as may be required by law.


InvestorsRenee LeckDirector, Investor Relations+1

MediaChristine HarrisonVice President, Corporate Affairs+1

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NurOwn May Be Given to Early ALS Patients in US Who Finished Phase… – ALS News Today

Posted: December 20, 2020 at 5:00 pm

BrainStorm Cell Therapeutics has opened an expanded access program (EAP) in the U.S. to allow certain amyotrophic lateral sclerosis (ALS) patients to gain access to its investigational cell-based therapy NurOwn.

EAPs, also known as compassionate use programs, are intended to make investigational therapies available outside of a clinical trial to people whose serious or life-threatening conditions have few or no adequate treatments, when the therapys benefits are thought to outweigh potential risks.

Developed in partnership with the U.S. Food and Drug Administration (FDA), the program will allow clinicians to prescribe NurOwn, at no cost, to ALS patients who completed the therapys pivotal, placebo-controlled Phase 3 trial (NCT03280056) and who meet specific eligibility criteria.

Those with less advanced disease as measured by the ALS Functional Rating Scale(ALSFRS-R) will be the first to receive the treatment. This decision was based on the trials top-line data, which showed a superior treatment response in people in earlier stages of ALS.

Detailed, full data are expected to be presented at upcoming scientific conferences, and published in a peer-reviewed scientific journal.

We are pleased to have the opportunity to treat additional patients with NurOwn through this Expanded Access Program, which was strongly advocated for by members of the ALS advocacy community, Chaim Lebovits, BrainStorms CEO, said in a press release.

We recognize the urgency with which people with ALS want and need access to new potential treatments. This EAP is an important next step to providing an immediate option for some patients, Lebovits added.

Fred Fisher, president and CEO of The ALS Associations Golden West Chapter, said that enabling early access, while the data review continues, is an extraordinary gesture of support and compassion for those living with ALS, and reflects an understanding of the ALS communitys urgent need for an effective therapy. The Golden West Chapter represents the largest ALS community in the U.S.

I applaud Brainstorm for taking this important step, and I look forward to learning the results of their full data analysis, Fisher added.

Lebovits emphasized that BrainStorm remains committed to rapidly advancing NurOwn through clinical development and regulatory review in the hope that the greatest number of people living with ALS may benefit. The EAP will not interfere with data or regulatory timelines.

NurOwn involves collecting mesenchymal stem cells(MSCs) from a patientsown bone marrow, and expanding and maturating them into cells that produce high levels of neurotrophic factors molecules that promote nervous tissue growth and survival. MSCs are stem cells that can generate a variety of other cell types.

The mature cells called MSC-NTF cells are then injected into the patients spinal canal to promote and support nerve cell repair. Using a patients own cells minimizes the risk of an immune reaction, as might occur with cells from a donor.

NurOwn has been designated an orphan drug in both the U.S. and European Union, and given to fast track designation in the U.S.; all help to speed its clinical development and review.

Afterpromising Phase 2 resultsin people with fast-progressing ALS, BrainStorm launched a Phase 3 trial to confirm NurOwns benefits in a larger patient population.

The Phase 3 study evaluated the therapys safety and effectiveness in 189 people with rapidly progressing ALS, who wererandomly assigned to a total of three injections of either NurOwn or a placebo, given directly into the spinal canal, every other month.

Patients were recruited at six clinical sites in the U.S.: three in California, two in Massachusetts, and one in Minnesota. NurOwn will be available under the EAP at these six centers.

Top-line data showed that a greater proportion of NurOwn-treated patients (34.7%) had a slower disease progression as assessed with the ALSFRS-R compared with those given a placebo (27.7%).

However, this difference did not reach statistical significance. This was mainly due to unexpectedly good placebo group responses, exceeding those reported in other ALS trials, the company reported.

Also, no significant group differences were observed in ALSFRS-R score mean changes over the seven months of treatment (-5.52 in the NurOwn group vs. -5.88 in the placebo group), meaning that the trial failed to meet both its main and secondary effectiveness goals.

However, greater treatment responses were seen in a pre-specified group of participants with less advanced disease.

In this group, 34.6% of those given NurOwn showed a slower disease progression, compared with 15.6% of those in the placebo group. In addition, the mean decline in the ALSFRS-R total score was 1.77 with NurOwn and 3.78 with a placebo reflecting a 2.01-point improvement with the cell-based therapy.

Differences between these groups were also not statistically significant, but they were considered clinically meaningful. Based on these positive findings, BrainStorm is actively working with the FDA to identify regulatory pathways that may support NurOwn approval as an ALS treatment.

Biomarker analyses also confirmed that NurOwn was driving its intended biological effects. Its use significantly increased the levels of neurotrophic factors, and dropped those of neurodegenerative and neuroinflammatory biomarkers, in patients cerebrospinal fluid a finding not observed among placebo patients. (The cerebrospinal fluid is the liquid that surrounds the brain and spinal cord.)

This expanded access program is an appropriate and welcome next step in following up the exciting results of the Phase 3 study; it is widely anticipated and deeply appreciated by our ALS patients, said Robert Brown, MD, PhD, one of the trials principal investigators.

Brown is also the Leo P. and Theresa M. LaChance chair in medical research, and chair of the neurology department atUniversity of Massachusetts Medical Schooland UMass Memorial Medical Center.

NurOwn will initially be manufactured by the Dana Farber Cancer Institute, assisted by on-site BrainStorm personnel.

BrainStorm also is evaluating NurOwn as a potential therapy for other neurodegenerative diseases, such as multiple sclerosis, Parkinsons disease, Huntingtons disease, as well as for autism spectrum disorder.

Marta Figueiredo holds a BSc in Biology and a MSc in Evolutionary and Developmental Biology from the University of Lisbon, Portugal. She is currently finishing her PhD in Biomedical Sciences at the University of Lisbon, where she focused her research on the role of several signalling pathways in thymus and parathyroid glands embryonic development.

Total Posts: 45

Ins holds a PhD in Biomedical Sciences from the University of Lisbon, Portugal, where she specialized in blood vessel biology, blood stem cells, and cancer. Before that, she studied Cell and Molecular Biology at Universidade Nova de Lisboa and worked as a research fellow at Faculdade de Cincias e Tecnologias and Instituto Gulbenkian de Cincia. Ins currently works as a Managing Science Editor, striving to deliver the latest scientific advances to patient communities in a clear and accurate manner.

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Be Biopharma debuts with $52M to advance engineered B-cell therapies – FierceBiotech

Posted: October 24, 2020 at 8:57 pm

You may have heard of T cells, but Aleks Radovic-Moreno, Ph.D., Be Biopharmas co-founder, president and director, is betting on B cells as the future of cell therapies.

Our mission is to develop what we see as a new class of cell medicines that have a broad new pharmacology, he said of B cells potential. We think it's a big new white space that's enabled by the rich biology of these cells.

The Cambridge, Massachusetts-based company is capitalizingearly on research by scientists at the University of Washington School of Medicine. With a $52 million series A round in the bank, it'smaking a beeline for the clinic.

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Why the enthusiasm around B cells? The wayRadovic-Moreno sees it, they'rethe cellular gadget, if you will, that's really good at making large amounts of protein, and they also traffic to where you want them to go."

When we think about it from a drug development standpoint, now you have a system that can make a protein that you want in high quantities in places where you want it to be made, he added.

B cells may also be useful for targeting specific tissues and modulating microenvironments, or [talking] to the cells that are nearby, he said.

One of the biggest challenges to bringing Be Bio to fruition was making the products themselves. Theyre harder to engineer than other cell types thanksto their intrinsic biology, Radovic-Moreno said. Theyre also hard to make correctly and in large quantities, challenges the company only recently overcame.

Those two are the final two bottlenecks that were preventing B cells from being a viable stem cell therapy modality, he said.

RELATED: Q32 debuts with $46M to 'rebalance' innate and adaptive immunity

The applications of B cells include everything from autoimmune diseases to cancer and monogenic disorders, which are caused by variation in a single gene. B-cell therapy could eliminate the need for patients with monogenic disorders who are missing proteins to get biweekly four-hour infusions.

And that's not all. It couldalso eliminate the need for bone marrow transplants in these patients, as well asthe need for a pre-therapy round of chemotherapy, otherwise known as conditioning. For cancer patients who need conditioningahead of a stem cell treatment, the regimencan be deadly up to 10% of the time.

That's extraordinary if you think about a therapy killing patients 10% of the time, Radovic-Moreno said.

Beyond pushing Be'spipeline toward the clinic, the new fundingfrom Atlas Venture, RA Capital Management, Alta Partners, Longwood Fund and other investorswill bankroll potential partnerships and build out the company's team.

The most important thing is to build a great company, hire the best people. We want to be the best B-cell engineers in the world and in history, Radovic-Moreno said. We want to fully capitalize on the timing of this, given that it's a very kind of unusual place to be in this time and age of biotech, where you're sitting right in front of this massive blue wave, big blue ocean of possibilities so big.

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Targeted Therapy for Non-Hodgkin Lymphoma: Current Progress and Future Plans – Cancer Therapy Advisor

Posted: September 5, 2020 at 12:57 am

Non-Hodgkin lymphoma (NHL) is among the most common cancers in the United States. In 2020, an estimated 77,240 Americans will be diagnosed with the disease and about 20,000 people will die from it.1 Seventy-two percent of patients live for at least 5 years after diagnosis.2 However, the success of treatment varies widely across the many subtypes of NHL. Patients diagnosed with diffuse large B-cell lymphoma (DLBCL), the most common subtype, have a 5-year survival rate of 63% for all disease stages combined. By contrast, follicular lymphoma (FL) has a 5-year survival rate of 88% for all stages combined. Patients with mantle cell lymphoma, one of the more difficult-to-treat subtypes, have an average survival time of less than 5 years.3

But the treatment landscape is transforming across the entire spectrum of NHL. Novel immunotherapies and small molecule inhibitors are offering both previously treated and untreated patients entirely new options and new combinations. At the American Society of Clinical Oncology (ASCO) 2020 Virtual Scientific Program, researchers led by Jeremy Abramson, of Massachusetts General Hospital in Boston, provided a compelling overview of these new and upcoming treatments.4 Their overview, published in the ASCO Educational Book, offered a detailed and vital look at the present and future of NHL treatment.

CAR T-cell immunotherapy has been hailed as a major game-changer for some blood cancers.5 For aggressive B-cell lymphomas, such as DLBCL, anti-CD19 chimeric antigen receptor T cells (CAR-T) are a new option for patients who have relapsed following chemoimmunotherapy or autologous stem cell transplant (ASCT). For this patient group, which has a median overall survival of about 4 months, anti-CD19 CAR-T agents have elicited durable remissions in about 40% of patients.5-7 Clinical trial data has led to the approval of axicabtagene, ciloleucel, and tisagenlecleucel by both the US Food and Drug Administration and the European Medicine Agency. CAR T-cells offer curative intent therapy to patients with relapsed DLBCL who are not eligible for stem cell transplant, Dr Abramson told Cancer Therapy Advisor. Previously these patients only had palliative options available.

Some clinicians envision CAR-T as a potential first-line therapy for patients with DLBCL who relapsed after first-line chemoimmunotherapy. These patients, noted Anton Hagenbeek, MD, PhD, professor of Hematology at Amsterdam University Medical Centers, who was not involved with the review paper, represent one of the highest unmet needs in the treatment of lymphoma to date. And Helen Heslop, MD, who directs the Center for Cell and Gene Therapy at Baylor College of Medicine in Houston, Texas, noted that trials for first-line CAR-T therapy are already underway in acute lymphoblastic leukemia. Not everyone sees this potential. First-line treatment in NHL is generally very effective and much less expensive than CAR T-cells, explained Edward Copelan, MD, who chairs the Department of Hematologic Oncology and Blood Disorders at Carolinas Healthcare System in Charlotte, North Carolina, and who was not an author of the review. Though Dr Copelan emphasized that patients at extremely high risk of relapse following standard immunochemotherapy may respond well to CAR-T therapy.

Dr Abramson and co-authors highlighted a difficult conundrum with regard to DLBCL. Although the addition of rituximab to cyclophosphamide, doxorubicin, hydrochloride, and vincristine sulfate (CHOP) chemotherapy is curative for most patients, the number of patients who may be cured after relapse has declined. Thus improvements in second-line therapy are desperately needed. Several clinical trials are currently evaluating anti CD19 CAR-T for primary refractory or early relapsed aggressive B-cell lymphoma compared with traditional salvage therapy or ASCT. The same approach is being studied for relapsed DLBCL patients who are not transplant candidates.

Whether CAR-T therapy will find a place on the first line of care is another current question. The cost and logistics of CAR-T therapy make it unlikely that this approach will replace R-CHOP as the standard initial treatment, Dr Abramson and colleagues noted. I do not think CAR T-cells will replace frontline chemotherapy, Dr Abramson said. However, the authors note that for patients who do not respond well to initial treatment, such an approach may make sense a possibility that is now being examined in the clinical trial setting. Dr Hagenbeek is more certain about the first-line role for CAR-T therapy, based on the dismal prognosis of DLBCL that is refractory to R-CHOP.

On the subject of CAR-T therapy as first-line therapy, the authors pay special attention to so-called double-hit lymphomas (DHLs), also known as double expressor lymphomas. According to a multicenter study published in 2017, R-CHOP is curative for more patients than conventional wisdom has held.9 Clinical trials are currently investigating the use of anti-CD19 CAR-T early for patients who consistently test positive for disease on PET scans during initial therapy, though Dr Abramson and colleagues call for caution with this approach because the prognostic value of PET/CT scans is controversial. Dr Hagenbeek is optimistic about the potential for CAR-T therapy to improve the prognosis for patients with double- and even triple-hit lymphomas, if applied in the first complete, PET-negative metabolic remission. Because these patients have a relatively small tumor load, this approach could, said Dr. Hagenbeek, completely eradicate minimal residual disease. Its the double-hit patients who Dr Copelan sees as the likeliest candidates for first-line CAR T-cell treatment.

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Massachusetts Eye and Ear Enters Licensing Agreement with Biogen to Develop Treatment for Inherited Retinal Disorder – Newswise

Posted: July 2, 2020 at 7:44 pm

Newswise Massachusetts Eye and Ear, a member hospital of Mass General Brigham, is entering into an exclusive licensing agreement with Biogen to develop a potential treatment for inherited retinal degeneration due to mutations in the PRPF31 gene, which are among the most common causes for autosomal dominant retinitis pigmentosa.

Inherited retinal degenerations (IRDs), such as retinitis pigmentosa, are a group of blinding eye diseases caused by mutations in over 270 different genes. Mutations in the PRPF31 gene are the second most common cause of dominant IRD and lead to defects in the function of the retinal pigment epithelial (RPE) cells and photoreceptors of the retina. Previous lab-based research performed by members of the Ocular Genomics Institute at Harvard Ophthalmology, led by Eric A. Pierce, MD, PhD, demonstrated that adeno-associated virus (AAV)-mediated gene augmentation therapy for PRPF31 can restore normal function to PRPF31 mutant RPE cells.

Biogen (Nasdaq: BIIB), a biopharmaceutical company that discovers, develops, and delivers worldwide innovative therapies for people living with serious neurological and neurodegenerative diseases as well as related therapeutic adjacencies, will build upon this prior work, and conduct the studies needed for clinical development of PRPF31 gene therapy. This includes the pre-clinical studies needed to support progression to clinical trials of PRPF31 gene therapy. As part of the agreement, Biogen will receive an exclusive license to develop the product worldwide and will be responsible for all U.S. Food and Drug-Administration (FDA) required investigational new drug (IND) enabling studies, clinical development and commercialization.

The treatment of IRDs with highly effective AAV-based gene therapies is core to Biogens ophthalmology strategy, said Chris Henderson, Head of Research, Biogen. This agreement underscores our commitment to that strategy and builds off of our acquisition of Nightstar Therapeutics in 2019 and our active clinical trials of gene therapies for different genetic forms of IRD. We are excited to work with Massachusetts Eye and Ear and look forward to applying our preclinical and clinical experience to their leading PRPF31 program.

We are thrilled to work with Biogen, who will bring to this effort its deep experience with the clinical development process, as we work toward our goal of developing a gene therapy for people with PRPF31-related eye disease, added Dr. Pierce, who is the William F. Chatlos Professor of Ophthalmology at Harvard Medical School. My ultimate hope for patients with inherited retinal disorders due to mutations in PRPF31 is that a gene therapy will preserve and potentially restore some of their vision.

About the Ocular Genomics Institute

The Ocular Genomics Institute at Harvard Ophthalmology aims to translate genomic medicine into precision ophthalmic care for patients with inherited eye disorders. It is home to one of the leading centers for early-phase clinical trials of therapies for inherited retinal degenerations, with seven gene-based and one stem cell trial currently in progress. The group works in conjunction with other departments throughout Harvard Medical School and Mass. Eye and Ear, including the Bioinformatics Center and Grousbeck Gene Therapy Center.

Dr. Pierces lab, established in 2011, is dedicated to research in an effort to improve the understanding of the molecular bases of IRDs so that rational therapies can be developed for these diseases.

In 2018, Mass. Eye and Ear surgeons performed the first post-FDA approval gene therapy for patients with a form of inherited retinal blindness caused by mutations in the gene RPE65 by injecting an AAV-based drug treatment into a patients eye, which restored vision in a 13-year-old boy. This therapy, called Luxturna, is now being used to treat patients with RPE65-associated retinal degeneration around the world.

One of the exciting aspects of our collaboration with Biogen is that mutations in the PRPF31 gene affect approximately 10 to 20 times more people than mutations in the RPE65 gene, said Dr. Pierce. Success with PRPF31 gene therapy could provide visual benefit to more patients, which is our ultimate goal.

Mass. Eye and Ear was one of the first centers to offer life-changing gene therapies to patients with inherited retinal disease, and we are thrilled with this new opportunity to develop a translational retinal therapy that could help even more patients, said Joan W. Miller, MD, Chief of Ophthalmology at Mass. Eye and Ear, Massachusetts General Hospital, and Brigham and Womens Hospital, and Chair of Ophthalmology and the David Glendenning Cogan Professor of Ophthalmology at Harvard Medical School.

According to Chris Coburn, Chief Innovation Officer, Mass General Brigham, the collaboration with Biogen illustrates the importance of academia and industry teaming to solve problems for patients worldwide. We are eager to see this progress reach patients who are challenged by blinding, degenerative eye disease, said Coburn. We look forward to working with Biogen to advance this break-through innovation.

Patients with an inherited retinal disease require genetic testing prior to being considered for any gene therapy treatment.

About Massachusetts Eye and Ear

Massachusetts Eye and Ear, founded in 1824, is an international center for treatment and research and a teaching hospital of Harvard Medical School. A member of Mass General Brigham, Mass. Eye and Ear specializes in ophthalmology (eye care) and otolaryngologyhead and neck surgery (ear, nose and throat care). Mass. Eye and Ear clinicians provide care ranging from the routine to the very complex. Also home to the world's largest community of hearing and vision researchers, Mass. Eye and Ear scientists are driven by a mission to discover the basic biology underlying conditions affecting the eyes, ears, nose, throat, head and neck and to develop new treatments and cures. In the 20192020 Best Hospitals Survey,U.S. News & World Reportranked Mass. Eye and Ear #4 in the nation for eye care and #2 for ear, nose and throat care.For more information about life-changing care and research at Mass. Eye and Ear, visit our blog,Focus, and follow us onInstagram,TwitterandFacebook.

About Harvard Medical School Department of Ophthalmology

The Harvard Medical SchoolDepartment of Ophthalmologyis one of the leading and largest academic departments of ophthalmology in the nation. Composed of nine affiliates (Massachusetts Eye and Ear, which is home to Schepens Eye Research Institute; Massachusetts General Hospital; Brigham and Womens Hospital; Boston Childrens Hospital; Beth Israel Deaconess Medical Center; Joslin Diabetes Center/Beetham Eye Institute; Veterans Affairs Boston Healthcare System; Veterans Affairs Maine Healthcare System; and Cambridge Health Alliance) and several international partners, the department draws upon the resources of a global team to pursue a singular goaleradicate blinding diseases so that all children born today will see throughout their lifetimes. Formally established in 1871, the department is committed to its three-fold mission of providing premier clinical care, conducting transformational research, and providing world-class training for tomorrows leaders in ophthalmology.

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Startup targets glioblastoma tumors with CAR-T therapy – FierceBiotech

Posted: May 28, 2020 at 3:43 am

One of the major breakthroughs in cancer treatment is CAR-T technology, which involves genetically modifyinga patients own immune cells so they can recognize and attack cancer. But while the innovationhas benefited patients with certain blood malignancies, progress in solid tumors remains limited.

Now, scientists at McMaster University and the University of Toronto have developed a CAR-T therapy for the aggressive brain cancer glioblastoma. It helped reduce tumor burden and improved survival in mouse models, according to a new study published in the journal Cell Stem Cell.

The researchers were so encouraged by the findings that they launched a startup called Empirica Therapeutics, which aims to bring the CAR-T drug into clinical trials in recurrent glioblastoma patients by 2022.

For each CAR-T construct, T cells are modified to produce a special structure called a chimeric antigen receptor (CAR) that gives the cells the ability to recognize a specific protein on cancer cells. The two FDA-approved CAR-Ts, Novartis Kymriah and Gilead Sciences Yescarta, are directed toward CD19. TheCAR-T cell Empirica is developing targets CD133, also known as prominin-1.

In a 2003 Cancer Research study, a McMaster University team identified a group of neural stem cells from human brain tumors that bear CD133 on their surface. They found these CD133-expressing cells could differentiate into cells identical to the original tumor, suggesting these stem cells are necessary for glioblastoma tumor growth.

For the current study, the team tested three types of treatments in lab dishes and in mice. The first was a human IgG antibody that binds to CD133 on glioblastoma cells. The second was a bispecific T-cell engager antibody (BiTE), which can recruit cytotoxic T cells to kill tumor cells. The third was the CAR-T, known at Empirica as eCAR-133.

We found that the CAR-T therapy had enhanced activity compared to the other two therapeutics in preclinical models of human glioblastoma, Parvez Vora, the studys first author and director of preclinical development at Empirica, said in a statement.

Moreover, the CAR-T drug didnt induce any acute systemic toxicity in mice, showing it wouldnt disrupt hematopoiesis, a vital process in the human body that leads to the formation of blood cells, Vora said.

RELATED:Killing brain tumors with CAR-Ts built with scorpion venom

The potent clinical responses from CAR-T cells in blood cancers have sparked interest in exploring the approach in solid tumors, including hard-to-treat glioblastoma. A research team at City of Hope recently designed a novel CAR based on chlorotoxin, a toxin found in scorpion venom, and recorded promising results of the CAR-T cells in mice with glioblastoma xenografts.

There are many obstacles ahead. For one thing, the glioblastoma tumor microenvironment is notoriously immunosuppressive, which could dampen CAR-T cells activity once they arrive at the tumor site.

Besides CD133, other glioblastoma CAR-T targets that have been floated include IL-13Ra2 from City of Hope researchers, CSPG4froma team at the University of North Carolina, NKG2DL and EGFRvIII, among others.One possibility could be a combo of CAR-T and BiTEtechnologies. Last year, a team led by Massachusetts General Hospital designeda CAR-T that also expressed BiTE to activate bystander T cells against tumors. The CAR-T/BiTE cells eliminated tumors in mouse models of glioblastoma.

The Empirica scientists are also exploring combination strategies for their CD133-targeting CAR-T to treat glioblastoma."We hope that our work will now advance the development of really new and promising treatment options for these patients," said co-author Sheila Singh, professor in the department of surgery at McMaster and CEO of the startup.

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Startup targets glioblastoma tumors with CAR-T therapy - FierceBiotech

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