Stem Cell Clinic

Trials and Tribulations: Neurology Research During COVID-19 – Medscape

By adminApril 30, 2020Stem Cell Medical Center

With some pivotal trials on hold, the COVID-19 pandemic is slowing the pace of research in Alzheimer's disease (AD), stroke, and multiple sclerosis (MS).

However, researchers remain determined to forge ahead with many redesigning their studies, at least in part to optimize the safety of their participants and research staff.

Keeping people engaged while protocols are on hold; expanding normal safety considerations; and re-enlisting statisticians to keep their findings as significant as possible are just some of study survival strategies underway.

The pandemic is having a significant impact on Alzheimer's research, and medical research in general, says Heather Snyder, PhD, vice president, Medical & Scientific Relations at theAlzheimer's Association.

"Many clinical trials worldwide are pausing, changing, or halting the testing of the drug or the intervention," she told Medscape Medical News. "How the teams have adapted depends on the study," she added. "As you can imagine, things are changing on a daily basis."

The US Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (U.S. POINTER) trial, for example, is on hold until at least May 31. The Alzheimer's Association is helping to implement and fund the study along with Wake Forest University Medical Center.

"We're not randomizing participants at this point in time and the intervention which is based on a team meeting, and there is a social aspect to that has been paused," Snyder said.

Another pivotal study underway is the Anti-Amyloid Treatment in Asymptomatic Alzheimers study (the A4 Study). Investigators are evaluating if an anti-amyloid antibody, solanezumab (Eli Lilly and Co), can slow memory loss among people with amyloid on imaging but no symptoms of cognitive decline at baseline.

"The A4 Study is definitely continuing. However, in an effort tominimize risk to participants, site staff and study integrity, we have implemented an optional study hiatus for both the double-blind andopen-label extension phases," lead investigator Reisa Anne Sperling, MD, told Medscape Medical News.

"We wanted to prioritize the safety of our participants as well as theability of participants to remain in the studydespitedisruptions from the COVID-19 pandemic," said Sperling, who is professor of neurology at Harvard Medical School and director of the Center forAlzheimer Research andTreatment at Brigham and Women'sHospital andMassachusetts GeneralHospital in Boston.

The ultimate goal is for A4 participants to receive the full number of planned infusions and assessments, even if it takes longer, she added.

Many AD researchers outside the United States face similar challenges. "As you probably are well aware, Spain is now in a complete lockdown. This has affected research centers like ours, Barcelonaeta Brain Research Center, and the way we work," Jos Lus Molinuevo Guix, MD, PhD, told Medscape Medical News.

All participants in observational studies like the ALFA+ study and EPAD initiatives, as well as those in trials including PENSA and AB1601, "are not allowed, by law, to come in, hence from a safety perspective we are on good grounds," added Molinuevo Guix, who directs the Alzheimer's disease and other cognitive disorders unit at the Hospital Clinic de Barcelona.

The investigators are creating protocols for communicating with participants during the pandemic and for restarting visits safely after the lockdown has ended.

A similar situation is occurring in stroke trials. Stroke is "obviously an acute disease, as well as a disease that requires secondary prevention," Mitchell Elkind, MD, president-elect of the American Heart Association, told Medscape Medical News.

"One could argue that patients with stroke are going to be in the hospital anyway why not enroll them in a study? They're not incurring any additional risk," he said. "But the staff have to come in to see them, and we're really trying to avoid exposure."

One ongoing trial, the AtRial Cardiopathy and Antithrombotic Drugs In Prevention After Cryptogenic Stroke (ARCADIA), stopped randomly assigning new participants to secondary prevention with apixaban or aspirin because of COVID-19. However, Elkind and colleagues plan to provide medication to the 440 people already in the trial.

"Wherever possible, the study coordinators are shipping the drug to people and doing follow-up visits by phone or video," said Elkind, chief of the Division of Neurology Clinical Outcomes Research and Population Sciences at Columbia University in New York City.

Protecting patients, staff, and ultimately society is a "major driving force in stopping the randomizations," he stressed.

ARCADIA is part of the StrokeNet prevention trials network, run by the NIH's National Institute of Neurologic Disorders and Stroke (NINDS). Additional pivotal trials include the Carotid Revascularization Endarterectomy Versus Stenting Trial (CREST) and the Multi-arm Optimization of Stroke Thrombolysis (MOST) studies, he said.

Joseph Broderick, MD, director of the national NIH StrokeNet, agreed that safety comes first. "It was the decision of the StrokeNet leadership and the principal investigators of the trials that we needed to hold recruitment of new patients while we worked on adapting processes of enrollment to ensure the safety of both patients and researchers interacting with study patients," he told Medscape Medical News.

Potential risks vary based on the study intervention and the need for in-person interactions. Trials that include stimulation devices or physical therapy, for example, might be most affected, added Broderick, professor and director of the UC Gardner Neuroscience Institute at the University of Cincinnati in Ohio.

Nevertheless, "there are potential waysto move as much as possible toward telemedicine and digital interactions during this time."

At the national level, the COVID-19 pandemic has had an "unprecedented impact on almost all the clinical trials funded by NINDS," said Clinton Wright, MD, director of the Division of Clinical Research at NINDS. "Investigators have had to adapt quickly."

Supplementing existing grants with money to conduct research on COVID-19 and pursuing research opportunities from different institutes are "some of the creative approaches [that] have come from the NIH [National Institutes of Health] itself," Wright said. "Other creative approaches have come from investigators trying to keep their studies and trials going during the pandemic."

In clinical trials, "everything from electronic consent to in-home research drug delivery is being brought to bear."

"A few ongoing trials have been able to modify their protocols to obtain consent and carry out evaluations remotely by telephone or videoconferencing," Wright said. "This is especially critical for trials that involve medical management of specific risk factors or conditions, where suspension of the trial could itself have adverse consequences due to reduced engagement with research participants."

For participants already in MS studies, "each upcoming visit is assessed for whether it's critical or could be done virtually or just skipped. If a person needs a treatment that cannot be postponed or skipped, they come in," Jeffrey Cohen, MD, director of the Experimental Therapeutics Program at theMellen Center for Multiple Sclerosis Treatment and Researchat the Cleveland Clinic, Ohio, told Medscape Medical News.

New study enrollment is largely on hold and study visits for existing participants are limited, said Cohen, who is also president of the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).

Some of the major ongoing trials in MS are "looking at very fundamental questions in the field," Cohen said. The Determining the Effectiveness of earLy Intensive Versus Escalation Approaches for RRMS (DELIVER-MS) and Traditional Versus Early Aggressive Therapy for Multiple Sclerosis (TREAT-MS) trials, for example, evaluate whether treatment should be initiated with one of the less efficacious agents with escalation as needed, or whether treatment should begin with a high-efficacy agent.

Both trials are currently on hold because of the pandemic, as is the Best Available Therapy Versus Autologous Hematopoietic Stem Cell Transplant for Multiple Sclerosis (BEAT-MS) study.

"There has been a lot of interest in hematopoietic stem cell transplants and where they fit into our overall treatment strategy, and this is intended to provide a more definitive answer," Cohen said.

"The pandemic has been challenging" in terms of ongoing MS research, said Benjamin M. Segal, MD, chair of the Department of Neurology and director of the Neuroscience Research Institute at The Ohio State University Wexner Medical Center, Columbus.

"With regard to the lab, our animal model experiments have been placed on hold.We have stopped collecting samples from clinical subjects for biomarker studies.

"However, my research team has been taking advantage of the time that has been freed up from bench work by analyzing data sets that had been placed aside, delving more deeply into the literature, and writing new grant proposals and articles," he added.

Two of Segal's traineesare writing review articles on the immunopathogenesis of MS and its treatment. Another postdoctoral candidate is writing a grant proposal to investigate how coinfection with a coronavirus modulates CNS pathology and the clinical course of an animal model of MS.

"I am asking my trainees to plan out experiments further in advance than they ever have before, so they are as prepared as possible to resume their research agendas once we are up and running again," Segal said.

Confronting current challenges while planning for a future less disrupted by the pandemic is a common theme that emerges.

"The duration of this [pandemic] will dictate how we analyze the data at the end [for the US POINTER study]. There is a large group of statisticians working on this," Snyder said.

Harvard Medical School's Sperling also remains undeterred.

"This is definitely a challenging time, as we must not allow the COVID-19 to interfere with our essential mission to find a successful treatment to prevent cognitive decline in AD. We do need, however, to be asflexible as possible to protect our participants and minimize the impact to our overall study integrity," she said.

Molinuevo Guix, of the Barcelonaeta Brain Research Center, is also determined to continue his AD research.

"I am aware that after the crisis, there will be less [risk] but still a COVID-19 infection risk, so apart from trying to generate part of our visits virtually, we want to make sure we have all necessary safety measures in place. We remain very active to preserve the work we have done to keep up the fight against Alzheimer's and dementia," he said

Such forward thinking also applies to major stroke trials, said University of Cincinnati's Broderick.

"As soon as we shut down enrollment in stroke trials, we immediately began to make plans about how and when we can restart our stroke trials," he explained. "One of our trials can do every step of the trial process remotely without direct in-person interactions and will be able to restart soon."

An individualized approach is needed, Broderick added.

"For trials involving necessary in-person and hands-on assessments, we will need to consider how best to use protective equipment and expanded testing that will likely match the ongoing clinical care and requirements at a given institution.

"Even if a trial officially reopens enrollment, the decision to enroll locally will need to follow local institutional environment and guidelines. Thus, restart of trial enrollment will not likely be uniform, similar to how trials often start in the first place," Broderick added.

The NIH published uniform standards for researchers across its institutes to help guide them during the pandemic.

Future contingency plans also are underway at the NINDS.

"As the pandemic wanes and in-person research activities restart, it will be important to have in place safety measures that prevent a resurgence of the virus, such as proper personal protective equipment for staff and research participants, said Wright, the clinical research director at NINDS.

For clinical trials, NINDS is prepared to provide supplemental funds to trial investigators to help support additional activities undertaken as a result of the pandemic.

"This has been an instructive experience.The pandemic will end, and we will resume much of our old patterns of behavior," said Ohio State's Segal."But some of the strategies that we have employed to get through this time will continue to influence the way we communicate information, plan experiments, and prioritize research activities in the future, to good effect."

Snyder, Sperling, Molinuevo Guix, Elkind, Broderick, Wright, Cohen, and Segal have disclosed no relevant disclosures.

Follow Damian McNamara on Twitter: @MedReporter. For more Medscape Neurology news, join us on Facebook and Twitter.

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Trials and Tribulations: Neurology Research During COVID-19 - Medscape

Into the Lungs and Beyond – Harvard Medical School

By adminApril 30, 2020Stem Cell Medical Center

This article is part of Harvard Medical Schoolscontinuing coverageof medicine, biomedical research, medical education and policy related to the SARS-CoV-2 pandemic and the disease COVID-19.

What makes SARS-CoV-2, the virus behind COVID-19, such a threat?

A new study in Cell led by researchers at Harvard Medical School, Boston Children's Hospital and MIT pinpoints the likely cell types the virus infects.

Get more HMS news here

The study also unexpectedly showed that one of the bodys main defenses against viral infections may actually help the virus infect those very cells.

The study, published as a peer-reviewed pre-proof, will help focus efforts to understand what SARS-CoV-2 does in the body, why some people are more susceptible, and how best to search for treatments, the researchers say.

Multiple research models

When news broke about a new coronavirus in China, Jose Ordovas-Montanes, assistant professor of pediatrics at HMS and Boston Childrens, and colleague Alex Shalek at MIT had already been studying different cell types from throughout the human respiratory system and intestine. They also had gathered data from primates and mice.

In February, they began diving into these data.

We started to look at cells from tissues such as the lining of the nasal cavity, the lungs and gut, based on reported symptoms and where the virus has been detected, said Ordovas-Montanes, who is co-senior author of the new study along with Shalek. We wanted to provide the best information possible across our entire spectrum of research models.

COVID-19-susceptible cells

Recent research had found that SARS-CoV-2, like the closely related SARS-CoV that caused the SARS pandemic, uses a receptor called ACE2 to gain entry into human cells, aided by an enzyme called TMPRSS2.

That led Ordovas-Montanes, Shalek and colleagues to ask a simple question: Which cells in respiratory and intestinal tissue express both ACE2 and TMPRSS2?

To get the answer, the team turned to single-cell RNA sequencing. This identifies which of roughly 20,000 genes are on in individual cells.

They found that only a tiny percentage of human respiratory and intestinal cellsoften well below 10 percentmake both ACE2 and TMPRSS2.

Those cells fall into three types: goblet cells in the nose that secrete mucus; lung cells known as type II pneumocytes that help maintain the alveoli (the sacs where oxygen is taken in); and one type of so-called enterocytes that line the small intestine and are involved in nutrient absorption.

Sampling from non-human primates showed a similar pattern of susceptible cells.

Many existing respiratory cell lines may not contain the full mix of cell types, and may miss the types that are relevant, said Ordovas-Montanes. Once you understand which cells are infected, you can start to ask, How do these cells work? Is there anything within these cells that is critical for the viruss life cycle?

"With more refined cellular models, we can perform better screens to find what existing drugs target that biology, providing a stepping stone to go into mice or non-human primates.

Interferon: Helpful or harmful?

But it was the studys second finding that most intrigued the scientists.

They discovered that the ACE2 gene, which encodes the receptor SARS-CoV-2 uses to enter human cells, is stimulated by interferonone of the bodys main defenses when it detects a virus.

Interferon actually turned on the ACE2 gene at higher levels, potentially giving the virus new portals to get in.

ACE2 is also critical in protecting people during various types of lung injury, said Ordovas-Montanes. When ACE2 comes up, thats usually a productive response. But since the virus uses ACE2 as a target, we speculate that it might be exploiting that normal protective response.

Interferons, in fact, are being tested as a treatment for COVID-19. Whether they would help or do more harm than good is not yet clear.

It might be that in some patients, because of the timing or the dose, interferon can contain the virus, while in others, interferon promotes more infection, said Ordovas-Montanes. We want to better understand where the balance lies, and how we can maintain a productive antiviral response without producing more target cells for the virus to infect.

ACE inhibitors and cytokine storms

The findings may also raise new lines of inquiry around ACE inhibitors. These drugs are commonly used to treat hypertension, which has been linked to more severe COVID-19 disease. Are ACE inhibitors affecting peoples risk?

ACE and ACE2 work in the same pathway, but they actually have different biochemical properties, Ordovas-Montanes said. Its complex biology, but it will be important to understand the impact of ACE inhibitors on peoples physiological response to the virus.

Its also too soon to try to relate the study findings to the cytokine storm, a runaway inflammatory response that has been reported in very sick COVID-19 patients.

Cytokines are a family of chemicals that rally the bodys immune responses to fight infections. Interferon is part of the family.

It might be that were seeing a cytokine storm because of a failure of interferon to restrict the virus to begin with, so the lungs start calling for more help," he said. "Thats exactly what were trying to understand right now.

Future directions

In addition, the team wants to explore what SARS-CoV-2 is doing in the cells it targets and to study tissue samples from children and adults to understand why COVID-19 is typically less severe in younger people.

Carly Ziegler, Samuel Allon and Sarah Nyquist of MIT and Harvard and Ian Mbano of the Africa Health Research Institute were co-first authors on the paper. The study was done in collaboration with the Human Cell Atlas Lung Biological Network.

This has been an incredible community effort not just within Boston, but also with collaborators around the world who have shared their unpublished data to try and make potentially relevant information available as rapidly as possible, said Shalek. Its inspiring to see how much can be accomplished when everyone comes together to tackle a problem.

This work was supported in part by the National Institutes of Health (U24AI118672, AI201700104, R56AI139053, R01GM081871, T32GM007753, AI078908, HL111113, HL117945, R37AI052353, R01AI136041, R01HL136209, U19AI095219, U19HL129902, UM1AI126623, U19AI051731, R01HL095791, R33AI116184, U19AI117945, UM1AI126617), Bill and Melinda Gates Foundation, MIT Stem Cell Initiative through Foundation MIT, Aeras Foundation, Damon Runyon Cancer Research Foundation (DRG-2274-16), Richard and Susan Smith Family Foundation, UMass Center for Clinical and Translational Science Project Pilot Program, Office of the Assistant Secretary of Defense for Health Affairs (W81XWH-15-1-0317), P.B. Fondation pour la Recherche Medicale (DEQ20180339158) and Agence Nationale pour la Recherche (ANR-19-CE14-0027).

Adapted from a post in Discoveries, the Boston Children's clinical and research innovation portal.

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Into the Lungs and Beyond - Harvard Medical School

AgeX Therapeutics: Revolutionary Potential But Extremely Early – Seeking Alpha

By adminApril 30, 2020Embryonic Stem Cells

AgeX Therapeutics (AGE) is an interesting company in the up-and-coming longevity space. This article will take a look at the science behind their current development programs as well as the leading figures and stakeholders in the company. AgeX is certainly a very risky bet, both because of the low probability of any preclinical asset eventually gaining approval and because it is unclear whether the company has the financial resources to develop their current pipeline assets. Despite that, I do believe the potential reward of success could be tremendous for investors, and the continued vote of confidence from a major longevity investment company is meaningful in my opinion. At this time, my model does justify potentially taking a small, speculative position in the company while it is trading under $1/share, but nothing more than that until AgeXs outlook becomes clearer.

AgeX was founded in 2017 as a subsidiary of BioTime, Inc., a cell therapy biotech now known as Lineage Cell Therapeutics (LCTX). In 2018, AgeX was spun out from BioTime in connection with a public offering for AgeX, with BioTime shareholders receiving 1 share of AgeX for every 10 shares of BioTime they owned. Since that time, AgeX has operated as an independent, publicly-traded company.

AgeXs focus as a company is to develop therapies that target biological aging. AgeX intends to do this primarily through 2 major technologiesPureStem and inducible tissue regeneration ((iTR)). PureStem is a technology platform used to generate young pluripotent stem cell-derived cellular therapies for use in treating the degenerative diseases of aging. iTR is literally intended to reverse the age of human cells back to the very beginning of life by restoring the capacity of tissues to regenerate following injury, a process which is lost with aging.

Although AgeX is less than 3 years old, several members of its management have been involved in research related to AgeXs developmental technology for decades. For example, the companys CEO, Michael D. West, Ph.D., invented the PureStem and iTR technologies which are based on over 25 years of his research. Dr. West has written multiple books and scientific papers on stem cells and aging in general and is widely considered a pioneer in the field.

In addition to Dr. West, noted longevity researcher Aubrey de Grey, Ph.D., is also involved as the VP for New Technology Development. Dr. de Grey is the Chief Scientific Officer for the SENS Research Foundation which has spun out numerous anti-aging companies over the years, and he commonly appears in mainstream media outlets discussing longevity research. Dr. de Grey is perhaps most widely known for his ideas about the longevity escape velocity, the idea that at some point in the future, technology may reach a point where for each year you are alive, longevity research is able to add more than one additional year to your lifespan, essentially rendering humans immortal aside from accidents, homicides, etc.

AgeXs 3 current assets in the pipelineeach of which utilizes PureStem or iTRare all still in preclinical workup. This means a tremendous amount of cash will be required before any of these therapies even have the potential of bringing in revenue.

Figure 1: AgeXs Pipeline (source: AgeX website)

Even if successful, each of these preclinical assets could still be a decade and $100+ million away from FDA approval (source: The Pharmagellan Guide to Biotech Forecasting & Valuation). Given that at year-end 2019 the company only had $2.35 million in cash and equivalents, AgeX has a lot of capital raising to do to have any shot at realizing their technologys potential.

AgeX has several possible ways to get this much-needed capital. AgeX could certainly raise capital by selling additional shares on the open market, diluting current shareholders. Im sure some of this will take place but given the companys current market cap is barely over $32 million, it might be difficult for the company to get even close to the necessary amount through this method alone. That being said, anyone considering an investment in AgeX needs to be soberly aware of the likelihood of substantial dilution over the coming years.

For its part, AgeX is clearly aware of its current capital constraints and has made several moves aimed towards alleviating at least some of their near-term liquidity problems. In late 2019, AgeX incorporated a subsidiary specifically for the development of iTR, Reverse Bioengineering, Inc. This structural change is interesting, primarily because AgeX explicitly says in their corporate presentation regarding the creation of Reverse Bioengineering that the new company may take on third-party equity investment. If Reverse Bioengineering does take on early-stage venture funding, it could help AgeX to afford the development of iTR, but its again another obvious potential way that an investor in AgeX may have their interest in future iTR profits diluted.

A possible source of ongoing financial support for AgeX is its relationship with Juvenescence Limited, a holding company for biotechs involved in the longevity space. Juvenescence bought a 45.8% stake in AgeX shortly before the company was spun out from BioTime. This transaction was for 14.4 million shares at $3 each its certainly not a bad sign that a company with as much experience in longevity as Juvenescence thought AgeX shares were worth more than 3x the level at which they are currently trading. Thus, Juvenescence has a clear and significant interest in the success of AgeX. In 2019, Juvenescence agreed to provide AgeX with a $2 million unsecured loan. With a 2019 full year loss of over $12.5 million though, AgeX was still in need of money.

Accordingly on March 30, 2020, AgeX entered into another loan agreement with Juvenescence, with an immediate $500 thousand being disbursed to AgeX. There are 2 big differences with this loan facility though. First, the loan could be for as much as $8 million. Second, however, any amount loaned in excess of the first $500 thousand will this time be secured by AgeXs assets as well as the fact that Juvenescence can force AgeX to implement a cost reduction plan that could entail significant reductions in staffing and research and development activities. Further loans could even cause AgeX to have to issue additional shares to Juvenescence.

This sort of loan would cause me substantial concern if Juvenescence didnt have a large equity interest in AgeX. As it is though, Juvenescence stands to benefit too much from AgeXs potential success to use the terms of such a loan facility for its short-term benefit and AgeXs detriment. Its also worth noting that the CEO of Juvenescence is on AgeXs board. While AgeXs cash situation is certainly something to watch closely, my fears are assuaged somewhat that a well-funded company like Juvenescence is incentivized to help AgeX develop and commercialize its technology.

One early way AgeX could potentially monetize its technology is through licensing and partnerships. In fact, this is listed as item number 1 in the business strategy section of the companys recent 10-K, where AgeX says they hope to bring in early revenue streams this way. There is already some limited evidence of this strategy bearing fruit.

First, AgeX has partnered with ImStem Biotechnology, Inc. for the use of its pluripotent stem cell lines in developing an investigational therapy for multiple sclerosis. Imstem recently announced that an FDA clinical hold had been lifted and their IND was accepted. This should lead to the initiation of a Phase 1 trial for the therapy this year.

Also, involvement by Juvenescence may help to cross-pollinate AgeX technology with that of its other portfolio companies. One such example of this already taking place is with Lygenesis, a company focused on organ regeneration. Lygenesis is apparently exploring the use of AgeX technology to eliminate the need for immunosuppression in recipients of Lygenesis organ therapies. This is exactly the type of use that will hopefully increase demand for AgeXs UniverCyte technology.

AgeX will also realize some near-term income from its LifeMap Sciences subsidiary. This subsidiary sells the rights on a subscription basis to the GeneCards Database Suite, which is an integrated biomedical knowledgebase of human genes, variants, proteins, cells, biological pathways, diseases, and the relationships between them. The service currently has over 3.5 million users including users from more than 45 major biopharma companies. This income, however, will likely never offset more than a fraction of the companys total expenses, as it only brought in $1.3 million and $1.2 million in subscription revenue in 2019 and 2018 respectively.

Garnering a substantial amount of partnerships and accompanying revenue is certainly something that could de-risk the value proposition for AgeX. While nothing you can really hang your hat on, its worth noting that management said in their November letter to shareholders that they hope to announce several collaborations in the coming months.

AgeX has a number of cell-based technologies that, from the outside looking in, appear to be a little further along in the development process than iTR. As discussed immediately above, AgeXs stem cell technology looks ripe for partnerships, and each such partnership would provide critical additional data and experience to help move along AgeXs own proprietary assets.

The first of their cell-based technologies is PureStem, AgeXs allogeneic cell therapy platform that is based on human embryonic progenitors, cells in state of development between stem cells and adult cells. The company says these PureStem cells are distinct from competitors stem cell products because they would be commercialized as off-the-shelf products, be pure and industrially scalable, have lower cost of goods per unit, be amenable to traditional pharma supply chain logistics, and have the potential for acceptable reimbursement prices.

Figure 2: Diagram Depicting PureStem Clinical Use (source: corporate presentation)

AgeX says PureStem could have higher clinical adoption because of these expected cost savings and more simplified processes than with autologous stem cell technologies, where an individual is treated only with their own stem cells.

A second AgeX technology, UniverCyte, is what would allow for universal, off-the-shelf stem cell products. Based on the mechanism by which a fetus is protected from its hosts immune system, UniverCyte is a proprietary method for making cell that are off-the-shelf compatible with basically any recipient. The licensing possibilities for such a technology seem virtually endless, and I will certainly be watching for any such developments in the coming months.

AgeX is developing 2 proprietary assets utilizing their stem cell technology. Their lead pipeline asset, AGEX-BAT1, looks to brown fat to help with type 2 diabetes. Brown fat or brown adipose tissue (BAT) is thought to be prevalent in young people but slowly goes away as they age. BAT is far more metabolically active than the typical white fat that has negative consequences for the body, and experimental evidence in mice has shown that increased levels of BAT in older mice led to weight loss and increased insulin sensitivity.

AgeX intends to create BAT with its PureStem technology and use it as a therapy in diabetic patients. The metabolic activity of brown fat is a popular idea and research topic currently, so this idea has some support outside of just AgeX. It certainly would be a big deal to AgeX if successful because the overall diabetes therapy market is huge projected to be about $59 billion by 2025.

The second stem cell therapy currently in the pipeline is AGEX-VASC1, a program to develop vascular progenitors for use in treating ischemic heart disease. The idea is to deliver vascular progenitors made from AgeX pluripotent stem cells into ischemic heart tissue to regenerate collateral circulation in patients with coronary artery disease. AgeX is hoping to begin preclinical animal testing soon. Again this is a huge potential market, but as with most of AgeXs potential, it is years away from being realized if ever.

iTR would be revolutionary as this seems to be the first attempt at getting a true cellular regeneration or reprogramming technology into the clinic and then eventually onto market if all goes well. iTR would truly turn back the clock for treated cells to a non-diseased, younger state rather than just treating symptoms.

iTR utilizes small molecules to turn on regeneration of cells. The human body can only naturally regenerate certain cells and even then, only in a limited capacity. The novel approach taken by iTR may trigger complete regeneration of cells, and potentially organs and limbs. The premise behind iTR is that embryonic cells have a capacity for regeneration that is lost at the embryonic to fetal transition. With this loss, humans can no longer generate new cells or repair damaged cells to maintain a peak physical condition. The aim of iTR is to return an aged cell back to a youthful state, without crossing over to pluripotency, the point where stem cells have yet to differentiate or become a particular type of cell.

Company researchers and collaborators recently published that they reverted cells from a 114-year old back to pluripotent stems cells via iTR technology. Despite how promising it looks, iTR remains in the preclinical phase though. Its extremely hard to quantify the potential value of such a technology, but the one certain thing is that the road to a marketed iTR product will be a long and expensive one.

Even though any such value is incredibly speculative given that AgeX having an approved drug is likely a decade or more away, I attempted to assign a present value to the potential future cash flows AgeX could receive from their 3 current pipeline assets. All of the markets for these potential therapies are extremely competitive ones with numerous current therapies and doubtless many others that will come out long before AgeXs do.

Accordingly, I modeled a fairly low 10% peak market share despite how transformative AgeXs therapies could ultimately be. Also, I only gave AgeXs therapies a 5% overall chance of reaching the market given their extremely early and novel nature and especially the fact that none of them have reached the clinic yet. Below are charts showing my models for each of these pipeline therapies:

Figure 3: My Present Value Estimates for AGEX-BAT1, AGEX-VASC1, and AGEX-iTR1547 (source: data from AgeXs 10-K and my calculations based on them)

As you can see in Figure 3, even though any cash flow from the pipeline is many years away, there is still a good bit of present value to each of these assets because of how large potential market size is likely to be. I then subtracted out my estimates of expenses, which were $117 million each for R&D for the 3 main therapies and SG&A expenses scaled up from the current level to eventually being 35% of revenue once these therapies hit the market.

Figure 4: My Fair Value Estimate for AgeX (source: data from AgeXs 10-K and my calculations based on them)

My best attempt at a fair value estimate for AgeX at present is about $1.31 per share. Although this is now 50% above current levels, as you can see from Figure 5 AgeX was trading at roughly my fair value estimate before the recent broader market sell-off.

Figure 5: AgeX Stock Chart (source: finviz)

In theory, this suggests the company is presently undervalued and could even have meaningful short-term upside. Its worth noting though the far higher risk of loss of capital though when trading a company with no assets in the clinic and as little cash as AgeX versus the later stage biopharma stocks I more commonly invest in and write about. Although I have a great deal of respect for many of those involved in the company and personally find this area of development fascinating and compelling, I'm holding off on it as an investment at this time while I continue to watch the company with great interest.

AgeX has an extremely long road ahead of it. While my model does suggest some potential upside, I consider the company to be in the ballpark of fair value even at these low levels because of the high amount of uncertainty in their pipeline and their cash-strapped balance sheet. The only reason in my mind that justifies holding any position here is that AgeX seems to have novel and potentially lucrative technology that could result in partnerships which might quickly change the companys outlook. Any substantial rise in the share price though without a partnership, improvement to the balance sheet, or major pipeline progress would be a reason to sell in my opinion.

Disclosure: I/we have no positions in any stocks mentioned, and no plans to initiate any positions within the next 72 hours. I wrote this article myself, and it expresses my own opinions. I am not receiving compensation for it (other than from Seeking Alpha). I have no business relationship with any company whose stock is mentioned in this article.

Additional disclosure: Im not a registered investment advisor. Despite that I strive to provide the most accurate information, I neither guarantee the accuracy nor the timeliness. Past performance does NOT guarantee future results. I reserve the right to make any investment decision for myself without notification. The thesis that I presented may change anytime due to the changing nature of information itself. Investment in stocks and options can result in a loss of capital. The information presented should NOT be construed as a recommendation to buy or sell any form of security. My articles are best utilized as educational and informational materials to assist investors in your own due diligence process. You are expected to perform your own due diligence and take responsibility for your actions. You should also consult with your own financial advisor for specific guidance as financial circumstances are individualized.

Shares of Mesoblast Tumbled Over 20% Today After Doubling Last Week – The Motley Fool

By adminApril 29, 2020Stem Cell Doctors

What happened

Shares of Mesoblast (NASDAQ:MESO) fell as much as 22.3% today as investors decided to lock in gains. The stem-cell stock erupted for a 139% gain on Friday after data from a small study suggested the company's cell therapy might significantly improve outcomes for COVID-19 patients placed on mechanical ventilators.

The promising early stage results pushed the company's market cap to over $1.6 billion. Mesoblast had been valued at $450 million a few weeks earlier. Today's move suggests investors are taking the biopharma's inexperience and the preliminary nature of the study's data into account.

As of 3:58 p.m. EDT on Monday, the small-cap stock had settled to a 21.5% loss.

Image source: Getty Images.

In March and April, Mesoblast conducted a small study at New York City's Mount Sinai Hospital to evaluate if its lead drug candidate, remestemcel-L, could treat acute respiratory distress syndrome (ARDS) in individuals with COVID-19. Doctors administered two doses of the experimental therapy within five days of patients being placed on a mechanical ventilator. The study was conducted using an emergency compassionate-use order and was not considered a clinical trial.

Of the 12 individuals in the study, 10 survived and nine had been removed from ventilators at a median time of 10 days. That represents a survival rate of 83% and indicates 75% of patients improved enough to come off ventilator support relatively quickly.

All patients had received other experimental drugs, and the study was very small. But investors chose to focus on the remarkable outcome, especially when an observational study of 2,600 COVID-19 patients on ventilator support in New York City hospitals found that 88% died.

Mesoblast intends to use the 12-patient study to influence the design of a larger clinical trial studying remestemcel-L in the same patient population, with participation from medical centers across North America. It's plausible that some types of stem cells could help to relieve ARDS in COVID-19 patients, but investors need to remain cautious until the results are replicated in larger populations.

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Shares of Mesoblast Tumbled Over 20% Today After Doubling Last Week - The Motley Fool

THE BENEFITS OF TADALAFIL FOR ENLARGED PROSTATE AND ERECTILE DYSFUNCTION – RecentlyHeard.com

By adminApril 29, 2020Stem Cell Doctors

Tobacco kills and hurts people; therefore, you are always advised to quit smoking. Nowadays, some new options are available on the market. People can select a safe option that will not cause any health issue.

Smoking alternatives prove helpful for your quit smoking process. Visit a smoker supply shop to find out available substitutes. Here are six smoking tips to avoid health risks and other issues.

In the past, smoker believed that low-tar; light cigarettes had limited health risks. Studies prove that these cigarettes cant decrease dangerous health effects. The FDA (Food & Drug Administration) has barred these terms, such as low, mild and light in cigarette sales.

Some people prefer hand-rolled cigarettes because they consider them safe. Remember, these cigarettes have a maximum risk of cancers of esophagus, larynx, pharynx, and mouth. You may find them dangerous than machine-made cigarettes.

Nowadays, natural cigarettes are available in the market. Manufactures claim for selling cigarettes without additives and chemicals. These are rolled with cotton filters. Safety of these cigarettes may depend on the herbs in them. Remember, herbal cigarettes can be less dangerous if they are free from tobacco, carbon monoxide and tar.

E-cigarettes or electronic cigarettes can be a safe alternative to tobacco smoke. These are designed to convert the liquid into vapors to inhale. Other than tobacco, they depend on a liquid prepared from nicotine or other flavorings. However, the FDA doesnt endorse these products.

The advertisers of e-cigarettes claim that these options are safe and enable you to quit smoking. If you want a safe alternative of smoking, consult your doctor. With a battery-operated unit, you can enjoy non-nicotine solutions.

These look similar to cigarettes but work without burning any kind of tobacco. You can buy an e-cigarette as per your budget. Make sure to avoid overuse of these devices because it is dangerous for your health.

Studies show that vaping is safer than smoking. There is no need to worry about ash, tar or combustion. You will find them great for skin health, oral hygiene, and lung capacity, improved senses of taste and smell and circulation.

With the help of vaping, you can avoid noxious odors. These devices may have a particular aroma s per its flavor. The smell of vapors is hardly noticeable. Vaping enables you to enjoy maximum control on the nicotine dosage.

Along with vaporizers, you can get e-juices in different strengths. These devices offer you maximum control on vapors to exhale. Some tools, such as pod vapes are available to increase your convenience.

Get the advantage of endless options in terms of flavors. There are numerous new flavors in the market, such as tobacco, menthol, foods, beverages, desserts and fruits. You will find them great for instant satisfaction.

Bongs aka binger, billy or bubblers are water pipes to smoke marijuana. These are around for centuries to avoid possible problems of traditional smoking. You can buy them in different shapes and sizes.

A basic bong consists of a chamber and a bowl. Feel free to purchase a colorful bong that looks similar to a work of art. Bongs come with a small bowl to carry dried weed. Once you light this weed, it combusts and offers smoke. Remember, water in the base of bubbler will bubble while you inhale.

The smoke passes through water before entering your lungs and mouth. A bong is a good option to smoke weed as compared to dried weed bowled in a paper. Water in the bong can decrease the hazards of dry heat you may get from joints. You can enjoy cooler, smooth and creamy effect instead of harsh smoke.

If you want to decrease the hazards of smoking, you have to smoke in an open area. A room may have several things with probability to catch fire. Hot ashes or cigarette can make things dangerous. Moreover, an open environment will save you from possible troubles.

You can get rid of the smell of smoke easily in an open environment. It proves useful to get fresh oxygen immediately after smoking. After smoking, put your cigarettes out every time. Avoid walking away from smoking materials and lit cigarettes.

Immediately put water on the butts and ashes to make them cool before throwing them in the trash.

Remember, it is not safe to smoke after taking medication. You cant escape or prevent from fire if you are feeling sleepy. Carefully dispose of a burning cigarette before going to bed or taking medicines.

You should not smoke in your bed because bedding and mattresses can easily catch on fire. Moreover, you can sleep with a lit cigarette in your hand. Always put cigarettes out in ashtrays or buckets with sand. Keep lighters and matches away from children.

Alternatives to smoking are always useful for people interested in smoking cessation. You can try nicotine patches to apply on your body. Remember, these patches are designed with latex to apply on your skin. Heavy smokers can use them to get a stable dose of nicotine.

Lozenges are similar to candies and excellent for an instant nicotine fix. Feel free to put them in mouth and wait for ten minutes. You will feel its effects after a short period. These can dissolve in your mouth with 30 minutes. It can be an excellent choice to keep you busy.

Nicotine gums may start working within 5 to 10 minutes. You may find them in different flavors. Make sure to consult your doctor to learn about the right dose and its effects on your body. Some people may feel hiccups and nausea after consuming them.

Moreover, you cant ignore inhalers and nasal spray. It is a plastic tube similar to a pen. Inhalers can release nicotine with every puff. Nasal sprays are easy and convenient options to use. Keep it in mind that inhalers may become the reason for throat irritation and coughing. You have to consult your physician before trying any alternative.

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THE BENEFITS OF TADALAFIL FOR ENLARGED PROSTATE AND ERECTILE DYSFUNCTION - RecentlyHeard.com

Immunotherapy Before Surgery Could Advance Care of an Aggressive Form of Skin Cancer – Newswise

By adminApril 29, 2020Gene Therapy Clinics

Newswise In what is believed to be a first-of-its-kind study to evaluate the safety of a type of immunotherapy before surgery in patients with an aggressive form of skin cancer, researchers report that the treatment eliminated pathologic evidence of cancer in nearly half of the study participants undergoing surgery. In patients whose tumors respond, this treatment approach offers the potential to reduce the extent of surgery and may also slow or eliminate tumor relapses that often occur after surgery.

A report on the Merkel cell cancer trial, directed by investigators at the Johns Hopkins Bloomberg~Kimmel Institute for Cancer Immunotherapy and the Johns Hopkins Kimmel Cancer Center in collaboration with the University of Washington Seattle Cancer Care Alliance and 10 other medical centers across the U.S. and Europe, will be published April 23 in the Journal of Clinical Oncology. An additional review article by Bloomberg~Kimmel Institute experts, published Jan. 31 in the journal Science, also points to the potential strategic value of giving immune checkpoint inhibitor therapy earlier in the course of cancer treatment.

Merkel cell carcinoma is classified as an orphan disease by the National Cancer Institute, diagnosed in approximately 2,000 people annually in the U.S. It typically appears as a red, blue or flesh-colored lump on the skin in older people and those who have suppressed immune systems. About 80% of Merkel cell carcinomas are caused by a virus called the Merkel cell polyomavirus. The remaining cases are linked to sun or other ultraviolet light exposure and unknown factors. Merkel cell carcinoma can spread to the lymphatic system and other organs. Surgery, radiation therapy and chemotherapy have been the mainstays of treatment. However, for Merkel cell carcinomas advancing beyond the point of surgery, there were previously no treatment options that could prolong survival. Recently, drugs blocking the immune checkpoints PD-1 and PD-L1 were shown to be effective in advanced inoperable Merkel cell carcinomas, and were approved by the U.S. Food and Drug Administration in this treatment setting.

Merkel cell carcinoma appears to respond very rapidly to anti-PD-1 immunotherapy in some patients with advanced disease, says lead study author Suzanne Topalian, M.D., associate director of the Bloomberg~Kimmel Institute for Cancer Immunotherapy. This led us to test whether anti-PD-1 could be effective if given for a brief period before surgery, as so-called neoadjuvant therapy. Using this approach, we found that patients who had substantial tumor regressions on CT scans or in pathology studies of surgically removed tumor specimens had extended cancer recurrence-free survival that was statistically significant. Radiographic and pathologic tumor regressions following neoadjuvant anti-PD-1 therapy are therefore potential new, early markers that will help us predict what a patients long-term outcome will be. This is critical information for oncologists planning treatment strategies for their patients.

Nivolumab, the immunotherapy drug used in this study, works against cancers including Merkel cell carcinoma by blocking PD-1, a molecule on the surface of immune cells that suppresses immune responses. Cancer cells often manipulate PD-1 by expressing its partner molecule PD-L1, sending a stop signal to the immune system. Blocking that signal with a checkpoint inhibitor such as nivolumab initiates a go signal, unleashing immune cells to attack cancer cells.

In the phase I/II trial of nivolumab in virus-associated cancers called CheckMate 358, patients with operable Merkel cell cancers received 240 mg of the anti-PD-1 drug intravenously on days one and 15 of the study, with surgery planned for day 29.

The trial was designed primarily to assess the safety and tolerability of nivolumab in this treatment setting. Investigators also assessed tumor regression using CT and MRI scans; studied the presence of cancer cells microscopically in surgically removed tumors; and studied pretreatment tumor biopsies to measure the presence of the polyomavirus causing Merkel cell carcinoma, the mutational burden (the quantity of gene mutations found in a tumor) and expression of the PD-L1 protein.

Overall, 39 patients with stage IIA-IV Merkel cell cancer (locally advanced or having spread to lymph nodes or internal organs) received at least one dose of nivolumab between January 2016 and March 2019. Among 36 patients who underwent surgery, 17 (47%) achieved a pathologic complete response, meaning that there were no live tumor cells anywhere in the surgical tissue. Among 33 patients undergoing surgery who also had imaging scans, 18 (54.5%) had radiographic tumor reductions of at least 30%. Each of these findings correlated significantly with prolonged recurrence-free survival. Patients were followed for a median of 20 months.

These rates of pathologic and radiographic tumor regression after a brief four-week period of nivolumab therapy are very high compared to other cancer types in which anti-PD-1 treatment has been tried before surgery, Topalian says. For instance, in lung cancer, the published rate of complete pathologic response after neoadjuvant anti-PD-1 monotherapy is 15%, and in melanoma it is 19-25%. Furthermore, substantial radiographic tumor regression is not common within such a brief treatment period in other cancer types.

Overall, among 36 patients who underwent surgery, recurrence-free survival rates were 77.5% at 12 months and 68.5% at 24 months after surgery. However, those with a complete pathologic response had a recurrence-free survival of 100% at 12 months and 88.9% at 24 months, compared with those without a complete pathologic response, who had recurrence-free survivals of 59.6% and 52.2% at 12 and 24 months, respectively. Similarly, patients with substantial radiographic tumor regressions before surgery experienced prolonged recurrence-free survival, compared with the other patients in the study. These effects of neoadjuvant nivolumab on recurrence-free survival in some patients appear to offer an advantage compared to historical reports of conventional care.

Three of 39 patients (7.7%) did not undergo surgery, one because of tumor progression, and two because of adverse effects from nivolumab. Treatment-related adverse events occurred in 18 of 39 patients (46.2%) and most commonly included skin rashes. Three patients (7.7%) had a severe adverse event, including immune-related colitis. The characteristics of adverse events were similar to those previously reported for anti-PD-1 drugs in patients with other cancer types.

Topalian cautions that the study was a relatively small one, and did not have a control group for comparison. All patients received the same treatment. However, she says, We think these findings provide a rationale to conduct larger trials of neoadjuvant anti-PD-1 therapy in Merkel cell carcinoma, and have the potential to be practice-changing.

To our knowledge, this is the first attempt to look at the role of anti-PD-1 therapy before surgery in patients with Merkel cell carcinoma who are candidates for complete surgical removal of their tumor, Topalian says. We know that, historically, many of these patients would subsequently relapse after standard surgical and postoperative treatments. Even if we think were removing all of the existing tumor at the time of surgery, in many patients the tumor has already spread to other parts of the body, at microscopic sites of metastasis that are too tiny to be detected with scans.

Investigators from the Bloomberg~Kimmel Institute co-led this study with researchers from the University of Washington Seattle Cancer Care Alliance, in collaboration with 10 other medical centers in the U.S. and Europe. The Bloomberg~Kimmel Institute team included Topalian; William Sharfman, M.D.; Julie Stein, M.D.; Elizabeth Engle, M.S.; and Janis Taube, M.D., M.Sc.

Separately, in a review paper published in Science by Topalian and Johns Hopkins colleagues Taube and Drew M. Pardoll, M.D., Ph.D., director of the Bloomberg~Kimmel Institute for Cancer Immunotherapy, the researchers summarized scientific and medical knowledge about the use of immune checkpoint blockers before cancer surgery. This includes the first published report of neoadjuvant PD-1 pathway blocking antibodies, tested in non-small cell lung cancer at Johns Hopkins and described in the New England Journal of Medicine in 2018, and additional studies of immune checkpoint blockers in melanoma, bladder cancer and brain cancer from other research groups. There are many more neoadjuvant anti-PD-1 studies maturing now in other cancer types including breast and head and neck cancers, Topalian says.

When people talk about preventing cancer, they generally mean preventing cancer from forming, she says. However, these neoadjuvant immunotherapy studies speak to the possibility of preventing early-stage cancers from becoming end-stage. We think this is a very valuable approach. By using immune checkpoint blockers before definitive surgery for cancer, it may be possible in some patients to prevent to the disease from progressing to an inoperable stage. We look forward to a lot more information to come in this area.

Preliminary results of the Merkel cell carcinoma study were presented at the American Society of Clinical Oncology meeting in 2018. Other centers participating in that trial were the Levine Cancer Institute, Atrium Health, of Charlotte, N.C.; Winship Cancer Institute of Emory University, Atlanta; Universit de Paris, Saint Louis Hospital, Paris; Institut Claudius Regaud, Toulouse, France; Memorial Sloan Kettering Cancer Center, New York; H. Lee Moffitt Cancer Center and Research Institute, Tampa, Fla.; SLK-Clinics, MOLIT Institute, Heilbronn, Germany; University of Pittsburgh Medical Center Hillman Cancer Center; University Medical Center Utrecht, Cancer Center, the Netherlands; and the University of Michigan Comprehensive Cancer Center, Ann Arbor, Mich. Bristol Myers Squibb, which sponsored the trial, also had co-authors.

The work was supported by Bristol Myers Squibb and ONO Pharmaceutical Company Limited. Some of the scientific correlative work conducted at Johns Hopkins was supported by The Mark Foundation for Cancer Research and National Cancer Institute R01 grant CA142779. Authors received no financial support or compensation for publication of the study.

The Science review was supported by the Johns Hopkins Bloomberg~Kimmel Institute for Cancer Immunotherapy, the National Cancer Institute (R01 CA142779), the Cancer Research Institute/Stand Up To Cancer-Immunology Translational Cancer Research Grant, Bristol Myers Squibb, the Barney Family Foundation, Moving for Melanoma of Delaware, the Laverna Hahn Charitable Trust, the Melanoma Research Alliance, the Harry J. Lloyd Charitable Trust, the Emerson Collective Foundation, and the Mark Foundation for Cancer Research.

Topalian reported stock and other ownership interests for herself or an immediate family member from Aduro Biotech, DNAtrix, Dragonfly Therapeutics, Ervaxx, Five Prime Therapeutics, RAPT Therapeutics, Potenza Therapeutics, Tizona Therapeutics, Trieza Therapeutics and WindMIL; consulting or advisory roles with Amgen, Compugen, DNAtrix, Dragonfly Therapeutics, Dynavax, Ervaxx, Five Prime Therapeutics, RAPT Therapeutucs, Immunocore, Immunomic Therapeutics, Janssen Oncology, MedImmune, Merck, Tizona Therapeutics and WindMIL; research funding from Bristol Myers Squibb, Compugen and Potenza Therapeutics; travel, accommodations and expenses from Bristol Myers Squibb, Dragonfly Therapeutics, Five Prime Therapeutics and Merck; and patent royalties from Aduro Biotech, Arbor Pharmaceuticals, Bristol Myers Squibb, Immunomic Therapeutics, NexImmune, and WindMIL. These relationships are being managed by The Johns Hopkins University in accordance with its conflict of interest policies.

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Immunotherapy Before Surgery Could Advance Care of an Aggressive Form of Skin Cancer - Newswise

Institute for Stem Cell Science and Regenerative Medicine …

By adminApril 29, 2020Stem Cell Medicine

Institute for Stem Cell Science and Regenerative Medicine (inStem) is an autonomous research institute in Bangalore, dedicated to the study of stem cell science and regenerative medicine research. inStem is funded by Department of Biotechnology and well-supported, with access to facilities at both National Centre for Biological Sciences (NCBS) and Centre for Cellular and Molecular Platforms (C-CAMP).[1] Together these three institutions serve as part of the Bangalore Bio-Cluster.[2] The institute is also the umbrella organization for three initiatives: inStem itself, the Center for Stem Cell Research (CSCR) located at CMC Vellore, and an Extramural Program in Stem Cell Research (EPiSTEM), a funding initiative for support of stem cell research nationwide.[3]Institute for Stem Cell Science and Regenerative Medicine (inStem) is an autonomous research institute in Bangalore, dedicated to the study of stem cell science and regenerative medicine research. inStem is funded by Department of Biotechnology and well-supported, with access to facilities at both National Centre for Biological Sciences (NCBS) and Centre for Cellular and Molecular Platforms (C-CAMP).[1] Together these three institutions serve as part of the Bangalore Bio-Cluster.[2] The institute is also the umbrella organization for three initiatives: inStem itself, the Center for Stem Cell Research (CSCR) located at CMC Vellore, and an Extramural Program in Stem Cell Research (EPiSTEM), a funding initiative for support of stem cell research nationwide.[3]

Organoids: Exploring Liver Cancer Initiation and the Possibilities of Personalized Glioblastoma Treatment – Technology Networks

By adminApril 29, 2020Stem Cell Medicine

In the search for improved and high-throughput in vitro models, organoids have emerged as a promising 3D cell culture technology.1 Defined as a three-dimensional multicellular in vitro tissue construct, organoids are derived from cells that spontaneously self-organize into properly differentiated functional cell types to mimic at least some function of an organ.2 Organoid formation is driven by signaling cues in the extracellular matrix and medium, and is influenced by the particular cell types that are present.2 Compared with two-dimensional cultures, organoids incorporate more physiologically relevant cell-cell and cell-matrix interactions, and are a better reflection of the complex network found in vivo.With significant opportunities for studies of human-specific disease mechanisms, personalized medicine, drug discovery, pharmacokinetic profiling and regenerative medicine, organoids are being pursued across a range of disciplines. Many anticipate that these cell culture models will result in more efficient translation of research into clinical success. In this article, we explore the various types of organoids under development and shine a spotlight on some of the different approaches to organoids in cancer research.

Organoids can be derived from pluripotent stem cells (including embryonic stem cells or induced pluripotent stem cells) or neonatal or adult stem cells from healthy or diseased tissue.1,2 Cancer organoids have been generated from a range of human cancer tissues and cell lines including colon, pancreas, prostate, liver, breast, bladder and lung.6-12 This year, a research group led by Hongjun Song, Professor of Neuroscience at the Perelman School of Medicine at the University of Pennsylvania, published a report in Cell detailing methods for the rapid generation of patient-derived glioblastoma organoids.13Fresh tumor specimens were removed from 53 patient cases to produce microdissected tumor pieces that could survive, develop a spherical morphology and continuously grow in culture for at least two weeks (Figure 1). The production of glioblastoma organoids was achieved while maintaining a high level of similarity between the organoids and their parental tumors, with the expression levels of specific markers showing stability over long-term culture (48 weeks). Importantly, native cell-cell interactions were preserved by avoiding mechanical and enzymatic single-cell dissociation of the resected tumor. As Song explains, this was achieved on a clinically relevant timescale: Normally, the treatment for glioblastoma patients starts one month after surgery. The idea is that glioblastoma organoids can be generated within two weeks and subjected to testing of different treatment strategies to come up with the best option for a personalized treatment strategy.

Figure 1: Glioblastoma organoid generation, from fresh tumor pieces to frozen spherical organoids. Image used with permission from Jacob et al. 2020.One concern with organoid formation and expansion is the potential variability of the serum or Matrigel that can exist across batches and sources, creating variable exogenous factors that could cause the organoid to divert. This ultimately compromises reproducibility, a major bottleneck of current organoid systems.2,13 To avoid this source of error, Songs group used an optimized and defined medium devoid of variable factors that could contribute to the clonal selection of specific cell populations in culture.Glioblastoma is the most prevalent primary malignant brain tumor in adults,14 and having glioblastoma organoids available for research would present significant opportunities, explains Song: They can be used to test different drugs based on mutation profiles and to investigate mechanisms underlying tumor progression, drug sensitivity and resistance. While the accuracy of these predictions would need to be verified, researchers hope that patient-derived organoids will be used to help inform oncologists, accelerate drug discovery, and lead to better clinical trial design.Live-Cell Monitoring: Optimizing Workflows for Advanced Cell Models

As cell-based assays become technically more complex, the need to holistically capture dynamic and sometimes subtle cellular events becomes ever more important. By providing real-time imaging data of cellular events without disturbing the sample during the cell culture workflow, live-cell monitoring can support the optimization of these advanced models. Download this whitepaper to discover how live-cell monitoring can support such optimization, with a breadth of applications.

Scientists from Universities in Russia and Ukraine Collaborate to Research on New Approaches to Treat Obesity and Diabetes – QS WOW News

By adminApril 29, 2020Stem Cell Medicine

In the 21st century, the search for methods of treating noncommunicable diseases, such as obesity, metabolic syndrome, and diabetes are amongthe top priorities. Prevention and treatment of these diseases include changing and controlling lifestyle, diet, and the use of pharmaceuticals.

Despite the progress in medicine and pharmacology (developing new solutions for correcting metabolism) and biotechnologies, new effective approaches are still on demand in treating obesity, metabolic syndrome, and diabetes.

Researchers note that adipose tissue is one of the key players in the development of obesity and diabetes. Adipose tissue is classified both by anatomical location and by function (white and brown fat). So, the main functions of white adipose tissue are to save energy in the form of lipids, and it also has an endocrine function the secretion of hormones, growth factors, cytokines, chemokines, etc.

The function of brown adipose tissue is to generate heat during adaptive thermogenesis (the process of generating heat in response to cold stimulation). In humans, unlike rodents (laboratory animals most widely used in medical experiments, including modeling of obesity, metabolic syndrome and diabetes), brown adipose tissue is present in significant numbers only in newborns and infants. Recently, the existence of active thermogenic adipose tissue in adults has been shown, but this adipose tissue differs from classical brown adipose tissue in several aspects (development, morphology, gene expression, adipokine production, etc.). This adipose tissue is called brown.

All types of adipocytes (cells that make up adipose tissue mainly) arise from adipose stem cells during differentiation. Currently, the question of the origin of brown adipocytes (from the same stem cell as white adipocytes, or from the same stem cell as brown adipocytes, or from its own stem cell), as well as the ability of white adipose tissue to differentiate into brown adipose tissue.

The ability to control the formation of new adipose tissue, turn white adipose tissue into brown one, or determine the direction of adipocyte stem cell differentiation into a specific subtype is an attractive goal for the development of new pharmacological substances for the treatment of obesity, metabolic syndrome and diabetes.

In addition to the search for new pharmacological substances designed to control the functions of adipose tissue or various other biochemical aspects of energy homeostasis, it is also important to study the role of water in human health, metabolism and the pathogenesis of various diseases. Water is the most abundant chemical substance on Earth and makes up the largest mass fraction in living organisms as a percentage. Water is also a universal solvent in which the basic biochemical processes of living organisms occur.

An important component of a healthy diet is drinking water instead of sugar and soda. So, the modulation of the biological and physico-chemical properties of water is also a promising opportunity to increase the effectiveness of the treatment of said diseases.

Dr. Larisa Litvinova, Ph.D. in Medicine, Head of the Immunology and Cell Biotechnologies Laboratory says,One of the focuses of modern medicine is the development of deuterium-containing drugs. Another direction relates to the role of the D/H ratio of isotopology and its change in water, which will be used as an adjuvant in the treatment of cancer. A different D/H ratio manifests itself in the form of a kinetic isotope effect, which is characterized by a change in the rates of biotransformation and excretion of drugs. Moreover, methodological approaches to the quality control of medicines based on isotopology of water could reduce the toxic load on the body.

IKBFU Scientists Larisa Litvinova and Maria Wulf were conducting the research in cooperation with colleagues from Moscow and Kiev and the goal of the research was to find out whether deuterium is engaged in the differentiation of adipose tissue stem cells regulation. Adipogenic differentiation of mesenchymal stem cells was chosen as an in vitro model, where the efficiency of the formation of mature fat cells from precursor cells in media with different deuterium contents were evaluated.

The data on the effect of various concentrations of deuterium on the efficiency and direction (formation of brown/beige or white adipocytes) of differentiation of mesenchymal stem cells in an in vitro model system were obtained in the study. Naturally for the possible practical application of these results, additional studies are needed that would allow a more detailed description of the molecular mechanisms of the influence of various concentrations of deuterium at the cellular level, as well as studies at the body level.

The results of the study are published in the article The influence of deuterium on the effectiveness and type of adipogenic differentiation of stem cells of human adipose tissue in vitro in theScientific Reportsjournal.

The results can serve as the basis for the development of new approaches in the treatment of obesity, metabolic syndrome, and diabetes, by regulating the differentiation of fat stem cells and adipocyte functions.

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Scientists from Universities in Russia and Ukraine Collaborate to Research on New Approaches to Treat Obesity and Diabetes - QS WOW News

Chimerix Announces Initiation of a Phase 2/3 Study of DSTAT in Acute Lung Injury for Patients with Severe COVID-19 – BioSpace

By adminApril 29, 2020Stem Cell Medicine

DURHAM, N.C., April 29, 2020 (GLOBE NEWSWIRE) -- Chimerix (NASDAQ:CMRX), a biopharmaceutical company focused on accelerating the development of medicines to treat cancer and other serious diseases, today announced the Companys initiation of a Phase 2/3 study of dociparstat sodium (DSTAT) in COVID-19 patients with acute lung injury (ALI).

DSTAT is a glycosaminoglycan derivative of heparin with robust anti-inflammatory properties, including the potential to address underlying causes of coagulation disorders with substantially reduced risk of bleeding complications compared to commercially available forms of heparin.1

Given the severity of the COVID-19 pandemic, we have evaluated many potential targets to address the clinical manifestations associated with severe COVID-19,said Joseph Lasky, M.D., Professor of Medicine, Pulmonary and Critical Care Section Chief, John W. Deming, M.D. Endowed Chair in Internal Medicine at Tulane University Medical School. Based on the literature, we believe DSTAT has the potential to reduce the excessive inflammation, immune cell infiltration and hypercoagulation associated with poor outcomes in patients with severe COVID-19 infection.

DSTAT is well-suited to unlock the anti-inflammatory properties of heparin as it may be dosed at much higher levels than any available form of heparin without triggering bleeding complications, said Mike Sherman, Chief Executive Officer of Chimerix. We had planned to evaluate DSTAT in several indications of high unmet need, including ALI from different causes. The pandemic intensified our focus on ALI associated with COVID-19. Our team has worked closely with critical care physicians treating COVID-19 patients and with the U.S. Food and Drug Administration (FDA) to develop a Phase 2/3 protocol to determine if DSTAT can reduce the need for mechanical ventilation and improve the rate of survival in patients with severe COVID-19 infection.

Phase 2/3 Study Design

The study is a 1:1 randomized, double-blind, placebo-controlled, Phase 2/3 trial to determine the safety and efficacy of DSTAT in adults with severe COVID-19 who are at high risk of respiratory failure. Eligible subjects will be those with confirmed COVID-19 who require hospitalization and supplemental oxygen therapy. The primary endpoint of the study is the proportion of subjects who survive and do not require mechanical ventilation through day 28. Additional endpoints include time to improvement as assessed by the National Institute of Allergy and Infectious Disease ordinal scale, time to hospital discharge, time to resolution of fever, number of ventilator-free days, all-cause mortality, and changes in key biomarkers (e.g. interleukin-6 (IL-6), tumor necrosis factor- (TNF-), high mobility group box 1 (HMGB1), C-reactive protein and d-dimer).

The Phase 2 portion of the study will enroll 24 subjects to confirm the maximum safe dose and will then expand by an additional 50 patients (74 total) at the selected dose. A formal analysis of all endpoints, including supportive biomarkers will be performed at the conclusion of the phase 2 portion of the study. Contingent upon positive results, the Phase 3 portion of the study will enroll approximately 450 subjects.

Clinical Rationale for DSTAT in COVID-19 Patients with ALI

The clinical manifestations of COVID-19 range from mild, self-limited respiratory tract illness to severe alveolar damage and progressive respiratory failure, multiple organ failure, and death. Mortality in COVID-19 is associated with severe pulmonary disease and coagulation disorders such as disseminated intravascular coagulation (DIC).2,3

The mechanistic rationale supporting DSTATs potential in ALI patients with COVID-19 is two-fold:

In a recent Phase 2 Acute Myeloid Leukemia (AML) study DSTAT was well tolerated with adverse events similar across DSTAT and control groups. DSTAT is an investigational agent, not yet licensed or approved for use.

Conference Call and Webcast

Chimerix will host a conference call and live audio webcast today at 8:30 a.m. ET. To access the live conference call, please dial 877-354-4056 (domestic) or 678-809-1043 (international) at least five minutes prior to the start time and refer to conference ID 8263766.

A live audio webcast of the call will also be available on the Investors section of Chimerixs website, http://www.chimerix.com. An archived webcast will be available on the Chimerix website approximately two hours after the event.

About Chimerix

Chimerix is a development-stage biopharmaceutical company dedicated to accelerating the advancement of innovative medicines that make a meaningful impact in the lives of patients living with cancer and other serious diseases. Its two clinical-stage development programs are dociparstat sodium (DSTAT) and brincidofovir (BCV).

Dociparstat sodium is a potential first-in-class glycosaminoglycan compound derived from porcine heparin that has low anticoagulant activity In vitro and in vivo animal model data support DSTATs potential to reduce the inflammation and cellular infiltration associated with acute lung injury and address coagulation disorders associated with COVID-19 pathology. Separately, DSTAT inhibits the activities of several key proteins implicated in the viability of AML blasts and leukemic stem cells in the bone marrow during chemotherapy (e.g., CXCL12, selectins, HMGB1, elastase). Randomized Phase 2 data suggest that DSTAT may also accelerate platelet recovery post-chemotherapy via inhibition of PF4, a negative regulator of platelet production that impairs platelet recovery following chemotherapy. BCV is an antiviral drug candidate in development as a medical countermeasure for smallpox. For further information, please visit the Chimerix website, http://www.chimerix.com.

Forward Looking Statements

This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 that are subject to risks and uncertainties that could cause actual results to differ materially from those projected. Forward-looking statements include those relating to, among other things, the mechanism of action of DSTAT and its potential in ALI patients with COVID-19; Chimerixs ability to develop DSTAT, including the initiation of a Phase 2/3 clinical trial for DSTAT as a potential treatment for ALI associated with COVID-19; and Chimerixs ability to submit and/or obtain regulatory approvals for DSTAT. Among the factors and risks that could cause actual results to differ materially from those indicated in the forward-looking statements are risks that DSTAT may not achieve the endpoints of the Phase 2/3 clinical trial; risks that DSTAT may not obtain regulatory approval from the FDA or such approval may be delayed or conditioned; risks that development activities related to DSTAT may not be completed on time or at all; Chimerixs reliance on a sole source third-party manufacturer for drug supply; risks that ongoing or future trials may not be successful or replicate previous trial results, or may not be predictive of real-world results or of results in subsequent trials; risks and uncertainties relating to competitive products and technological changes that may limit demand for our drugs; risks that our drugs may be precluded from commercialization by the proprietary rights of third parties; and additional risks set forth in the Company's filings with the Securities and Exchange Commission. These forward-looking statements represent the Company's judgment as of the date of this release. The Company disclaims, however, any intent or obligation to update these forward-looking statements.

CONTACT:Investor Relations:Michelle LaSpaluto919 972-7115ir@chimerix.com

Will OConnorStern Investor Relationswill@sternir.com212-362-1200

Media:David SchullRusso Partners858-717-2310david.schull@russopartnersllc.com

note: DSTAT may be referred to as 2-O,3-O desulfated heparin, ODSH or CX-01 in these references.

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Chimerix Announces Initiation of a Phase 2/3 Study of DSTAT in Acute Lung Injury for Patients with Severe COVID-19 - BioSpace