Cell Reports

CIRM funding helps identify potential COVID-19 treatment

/ Yimy Villa / 1 Comment
The steps of the virus growth cycle that can be targeted with therapies: The virus enters a host cell (1), the virus’s genetic instructions are released, taking over cellular machinery (2), the virus is replicated within the cell (3) and copies of the virus exit the cell in search of new host cells to infect (4). Drugs like berzosertib might disrupt steps 2 and 3.  Image credit: Marc Roseboro/California NanoSytems Institute at UCLA

During the global pandemic, many researchers have responded to the needs of patients severely afflicted with COVID-19 by repurposing existing therapies being developed to treat patients.  CIRM responded immediately to the pandemic and to researchers wanting to help by providing $5 million in emergency funding for COVID-19 related projects. 

One of these grants ($349,999), awarded to Dr. Vaithilingaraja Arumugaswami at UCLA, has aided a study that has singled out a compound that shows promise for treating SARS-CoV-2, the virus that causes COVID-19.

In the spirit of banding together to help patients severely affected by COVID-19, the project was a collaboration among scientists from UCLA and other universities in California, Delaware and Germany, as well as a German pharmaceutical company.

The compound is named berzosertib and is licensed by the company Merck KGaA in Darmstadt, Germany.  Prior to the pandemic, it was developed for potential use, in combination with chemotherapy, as a possible treatment for small-cell lung cancer, ovarian cancer, and other types of solid tumors.

The team screened 430 drugs from among the approximately 200,000 compounds in CNSI’s Molecular Screening Shared Resource libraries before zeroing in on berzosertib as the most promising candidate.  They limited their search to compounds that either had been approved, or are already in the process of being evaluated, for safety in humans.

In a press release from UCLA, Dr. Arumugawami explains the rationale behind screening a potential drug candidate.

“That way, the compounds have cleared the first regulatory hurdle and could be deployed for further clinical trials on COVID-19 faster than drugs that have not been tested in humans.”

The researchers, led by Dr. Arumugaswami and Dr. Robert Damoiseaux from UCLA, conducted a series of experiments using different cell types in lab dishes to look at how effective the compound was at blocking SARS-CoV-2 from replicating.  Unlike other approaches which attack the virus directly, targeting replication could help better address the ability of the virus to mutate. 

For this study, the team used cells from the kidney, heart and lungs, all of which are organs that the virus is known to attack. The researchers pretreated cells with berzosertib, exposed the cells to SARS-CoV-2, allowed 48 hours for infection to set in, and then evaluated the results.

The team found that the compound consistently stalled SARS-CoV-2 replication without damaging the cells. The scientists also tested the drug against SARS and MERS, both of which are other types of coronaviruses that triggered deadly outbreaks earlier in the 2000s. They found that it was effective in stopping the replication of those viruses as well.

In the same press release from UCLA, Dr. Damoiseaux expressed optimism for what these findings could mean as a potential treatment.

“This is a chance to actually find a drug that might be broader in spectrum, which could also help fight coronaviruses that are yet to come.”

The next steps for this research would be to explore the mechanism through which the compound blocks coronavirus replication.  Understanding this and conducting preclinical studies are both necessary before the compound could be tested in clinical trials for COVID-19.

The full results of this study were published in Cell Reports.

The study’s co-corresponding author is Ulrich Betz of Merck KGaA, Darmstadt, Germany; the company also provided partial funding and clinical-grade berzosertib for the research. Other co-authors are from UCLA, Cedars-Sinai Medical Center, UC Irvine, University of Delaware, the Leibniz Institute for Experimental Virology in Germany, Heidelberg University in Germany and Scripps Research Institute.

In addition to CIRM, the study was also funded by CNSI, the Broad Stem Cell Research Center, the David Geffen School of Medicine at UCLA, the National Eye Institute, and the Bill and Melinda Gates Foundation.

De-stressing stem cells and the Bonnie & Clyde of stem cells

/ Kevin McCormack / 1 Comment
Dr. John Cashman

The cells in our body are constantly signalling with each other, it’s a critical process by which cells communicate not just with other cells but also with elements within themselves. One of the most important signalling pathways is called Wnt. This plays a key role in early embryonic and later development. But when Wnt signalling goes wrong, it can also help spur the growth of cancer.

Researchers at the Human BioMolecular Research Institute (HBRI) and Stanford University, have reported on a compound that can trigger a cascade of events that create stress and ultimately impact Wnt’s ability to control the ability of cells to repair themselves.

In a news release Dr. Mark Mercola, a co-author of a CIRM-funded study – published in the journal Cell Chemical Biology – says this is important: “because it explains why stressed cells cannot regenerate and heal tissue damage. By blocking the ability to respond to Wnt signaling, cellular stress prevents cells from migrating, replicating and differentiating.”

The researchers discovered a compound PAWI-2 that shows promise in blocking the compound that causes this cascade of problems. Co-author Dr. John Cashman says PAWI-2 could lead to treatments in a wide variety of cancers such as pancreatic, breast, prostate and colon cancer.

“As anti-cancer PAWI-2 drug development progresses, we expect PAWI-2 to be less toxic than current therapeutics for pancreatic cancer, and patients will benefit from improved safety, less side effects and possibly with significant cost-savings.”

Dr. Catriona Jamieson: Photo courtesy Moores Cancer Center, UCSD

Speaking of cancer….

Stem cells have many admirable qualities. However, one of their less admirable ones is their ability to occasionally turn into cancer stem cells. Like regular stem cells these have the ability to renew and replicate themselves over time, but as cancer stem cells they use that ability to help fuel the growth and spread of cancer in the body. Now, researchers at U.C. San Diego are trying to better understand how those regular stem cells become cancer stem cells, so they can stop that process.

In a CIRM-funded study Dr. Catriona Jamieson and her team identified two molecules, APOBEC3C and ADAR1, that play a key role in this process.

In a news release Jamieson said: “APOBEC3C and ADAR1 are like the Bonnie and Clyde of pre-cancer stem cells — they drive the cells into malignancy.”

So they studied blood samples from 54 patients with leukemia and 24 without. They found that in response to inflammation, APOBEC3C promotes the rapid production of pre-leukemia stem cells. That in turn enables ADAR1 to go to work, interfering with gene expression in a way that helps those pre-leukemia stem cells turn into leukemia stem cells.

They also found when they blocked the action of ADAR1 or silenced the gene in patient cells in the laboratory, they were able to stop the formation of leukemia stem cells.

The study is published in the journal Cell Reports.

“Mini” human liver made of stem cells successfully transplanted in rats

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Miniature liver made from human skin cells turned stem cells turned specialized liver cells Photo Credit: University of Pittsburgh School of Medicine

According to the American Liver Foundation website, almost 14,000 patients are on the waiting list for a liver transplant. But what if there was a way to generate a liver using your own cells so that you didn’t have to wait? Researchers at the University of Pittsburgh School of Medicine have gotten one step closer towards that goal.

Using human skin cells from volunteers, Dr. Alejandro Soto-Gutierrez and his team of researchers were able to create “mini” livers which were successfully transplanted into rats. In this proof of concept experiment, the “mini” livers survived inside the rats for four days. Additionally, they secreted bile acids and urea and produced proteins similar to a normal liver. Normally, liver maturation takes up to two years in a natural environment, but Dr. Soto-Gutierrez and his team were able to do this in under a month.

The researchers were able to do this by taking human skin cells and reprogramming them into induced pluripotent stem cells (iPSCs), a type of stem cell that has the ability to turn into virtually any other kind of cell. These newly formed iPSCs were then made into liver cells which were then seeded into a rat liver with all of its own cells removed. These newly formed “mini” livers were then transplanted into the rats.

In a press release, Dr. Soto-Gutierrez discusses what it was like observing the newly created “mini” livers.

“Seeing that little human organ there inside the animal – brown, looking like a liver – that was pretty cool. This thing that looks like a liver and functions like a liver came from somebody’s skin cells.”

Although these results were promising, there are still challenges that need to be addressed in future studies such as long-term survival and safety issues.

Even so, Dr. Soto-Gutierrez says his research could one-day benefit patients who are running out of options.

“The long-term goal is to create organs that can replace organ donation, but in the near future, I see this as a bridge to transplant. For instance, in acute liver failure, you might just need hepatic boost for a while instead of a whole new liver”.

The full results to this study were published in Cell Reports.

How quitting smoking helps your lungs regenerate; a discovery could lead to new ways to repair damaged lungs; and encouraging news in a stroke recovery trial

/ Kevin McCormack / Leave a comment
Photo courtesy Lindsay Fox

Smoking is one of the leading causes of preventable death not just in the US, but worldwide. According to the US Centers for Disease Control and Prevention tobacco causes an estimated seven million deaths around the world, every single year. And for every person who dies, another 30 live with a serious smoking-related illness. Clearly quitting is a good idea. Now a new study adds even more incentive to do just that.

Scientists at the Welcome Trust Sanger Institute and University College London in the UK, found that quitting smoking did more than just stop further damage to the lungs. They found that cells in the lining of the lungs that were able to avoid being damaged, were able to regrow and repopulate the lung, helping repair damaged areas.

In an article in Science Daily Dr Peter Campbell, a joint senior author of the study, said: “People who have smoked heavily for 30, 40 or more years often say to me that it’s too late to stop smoking — the damage is already done. What is so exciting about our study is that it shows that it’s never too late to quit — some of the people in our study had smoked more than 15,000 packs of cigarettes over their life, but within a few years of quitting many of the cells lining their airways showed no evidence of damage from tobacco.”

The study is published in the journal Nature.

Researchers at UCLA have also made a discovery that could help people with lung disease.

They examined the lungs of people with cancer and compared them to the lungs of healthy people. They were able to identify a group of molecules, called the Wnt/beta-catenin signaling pathway, that appear to influence the activity of stem cells that are key to maintaining healthy lungs. Too much activity can tilt the balance away from healthy lungs to ones with mutations that are more prone to developing tumors.

In a news release Dr. Brigitte Gomperts, the lead author of the study, says although this work has only been done in mice so far it has tremendous potential: “We think this could help us develop a new therapy that promotes airway health. This could not only inform the treatment of lung cancer, but help prevent its progression in the first place.”

The study is published in the journal Cell Reports.

CIRM has funded some of Dr. Gomperts earlier work in this area.

And there’s encouraging news for people trying to recover from a stroke. Results from ReNeuron’s Phase 2 clinical trial show the therapy appears to help people who have experienced some level of disability following a stroke.

ReNeuron says its CTX therapy – made from neural stem cells – was given to 23 people who had moderate to severe disability resulting from an ischemic stroke. The patients were, on average, seven months post stroke.

In the study, published in the Journal of Neurology, Neurosurgery & Psychiatry, researchers used the Modified Rankin Scale (mRS), a measure of disability and dependence to assess the impact of the therapy. The biggest improvements were seen in a group of 14 patients who had limited movement of one arm.

  • 38.5% experienced at least a one-point improvement on mRS six months after being treated.
  • 50% experienced a one-point improvement 12 months after being treated.

If that doesn’t seem like a big improvement, then consider this. Moving from an mRS 3 to 2 means that a person with a stroke regains their ability to live independently.

The therapy is now being tested in a larger patient group in the PISCES III clinical trial.

CIRM supported study finds that a gene associated with autism influences brain stem cells

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Dr. Bennett Novitch, UCLA Broad Stem Cell Research Center
Image Credit: UCLA Broad Stem Cell Research Center

In a previous blog post, we discussed new findings in a CIRM supported study at the Salk Institute for Autism Spectrum Disorder (ASD), a developmental disorder that comes in broad ranges and primarily affects communication and behavior.

This week, a new study, also supported by CIRM, finds that a gene associated with ASD, intellectual disability, and language impairment can affect brain stem cells, which in turn, influence early brain development. Dr. Bennett Novitch and his team at UCLA evaluated a gene, called Foxp1, which has been previously studied for its function in the neurons in the developing brain.

Image showing brain cells with lower levels of Foxp1 function (left) and higher levels (right). neural stem cells are stained in green; secondary progenitors and neurons in red.
Image Credit: UCLA Broad Stem Cell Research Center

In this study, Dr. Novitch and his team looked at Foxp1 levels in the brains of developing mouse embryos. What they discovered is that, in normal developing mice the gene was active much earlier than previous studies had indicated. It turns out that the gene was active during the period when neural stem cells are just beginning to expand in numbers and generate a subset of brain cells found deep within the developing brain.

When mice lacked the gene entirely, there were fewer neural stem cells at early stages of brain development, as well as fewer brain cells deep within the developing brain. Alternatively, when the levels of the gene were above normal, the researchers found significantly more neural stem cells and brain cells deep within the developing brain. Additionally, higher levels of the neural stem cells were observed in mice with high levels of the gene even after they were born.

In a press release from UCLA, Dr. Novitch explains how the different levels of the gene can be tied to the variation of Foxp1 levels seen in ASD patients.

“What we saw was that both too much and too little Foxp1 affects the ability of neural stem cells to replicate and form certain neurons in a specific sequence in mice. And this fits with the structural and behavioral abnormalities that have been seen in human patients.”

The full study was published in Cell Reports.

Genetic defect leads to slower production of brain cells linked to one form of autism

/ Kevin McCormack / Leave a comment
Child with Fragile X syndrome

Fragile X syndrome (FXS) is a genetic disorder that is the most common form of inherited intellectual disability in children, and has also been linked to a form of autism. Uncovering the cause of FXS could help lead to a deeper understanding of autism, what causes it and ultimately, it’s hoped, to treating or even preventing it.

Researchers at Children’s Hospital in Chicago looked at FXS at the stem cell level and found how a genetic defect has an impact on the development of neurons (nerve cells in the brain) and how that in turn has an impact on the developing brain in the fetus.

In a news release on Eurekalert, Dr. Yongchao Ma, the senior author of the study, says this identified a problem at a critical point in the development of the brain:

“During embryonic brain development, the right neurons have to be produced at the right time and in the right numbers. We focused on what happens in the stem cells that leads to slower production of neurons that are responsible for brain functions including learning and memory. Our discoveries shed light on the earliest stages of disease development and offer novel targets for potential treatments.”

The team looked at neural stem cells and found that a lack of one protein, called FMRP, created a kind of cascade that impacted the ability of the cells to turn into neurons. Fewer neurons meant impaired brain development. 

The findings, published in the journal Cell Reports, help explain how genetic information flows in cells in developing babies and, according to Dr. Ma, could lead to new ideas on how to treat problems.

“Currently we are exploring how to stimulate FMRP protein activity in the stem cell, in order to correct the timing of neuron production and ensure that the correct amount and types of neurons are available to the developing brain. There may be potential for gene therapy for fragile X syndrome.”

New study points to potential treatment for balance disorders

/ Yimy Villa / 2 Comments
Alan Cheng and his colleagues were able to regenerate hair cells inside the ears of mice — a first in mature mammals. Photo Courtesy of Steve Fisch

A sense of balance is important for a wide range of activities, from simple ones such as walking, running, and driving, to more intricate ones such as dancing, rock climbing, and tight-rope walking. A lack of physical balance in the body can lead to an inbalance in trying to live a normal everyday life.

One primary cause of balance disorders is a problem with hair cells located inside the inner ear, which play a role in maintaining balance, spatial orientation, and regulating eye movement. Damage to these cells can occur as a result from infections, genetic disorders, or aging. Unfortunately, in humans, hair cells in the inner ear regenerate on their own very minimally. In the United States alone, 69 million people experience balance disorders. Symptoms of this disorder include a “spinning” feeling, lack of balance, nausea, and difficulty tracking objects using the eyes.

However, a CIRM funded study has showed promising results for helping treat this disorder. Researchers at Stanford University have discovered a way to regenerate hair cells in the inner ear of mice, giving them a better sense of balance. To do this, the researchers impaired the hair cells in the inner ear of mice and measured how well they regenerated on their own to obtain a baseline measurement. They found that about a third of the cells regenerated on their own.

Next, the researchers manipulated Atoh1, a transcription factor that regulates hair cell formation in mice. By overexpressing Atoh1, the researchers found that as much as 70% of hair cells regenerated in the mice. Additionally, 70% of these mice also recovered their sense of balance. This simple proof of concept could potentially be applied in humans to treat similar disorders related to the loss of hair cells in the inner ear.

In a press release, Dr. Alan Cheng, senior author of this study, is quoted as saying,

“This is very exciting. It’s an important first step to find treatment for vestibular disorders. We couldn’t get sufficient regeneration to recover function before.”

The complete results of this study were published in Cell Reports.

Of Mice and Men, and Women Too; Stem cell stories you might have missed

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Mice brains can teach us a lot

Last week’s news headlines were dominated by one big story, the use of a stem cell transplant to effectively cure a person of HIV. But there were other stories that, while not quite as striking, did also highlight how the field is advancing.

A new way to boost brain cells (in mice!)

It’s hard to fix something if you don’t really know what’s wrong in the first place. It would be like trying to determine why a car is not working just by looking at the hood and not looking inside at the engine. The human brain is far more complex than a car so trying to determine what’s going wrong is infinitely more challenging. But a new study could help give us a new option.

Researchers in Luxembourg and Germany have developed a new computer model for what’s happening inside the brain, identifying what cells are not operating properly, and fixing them.

Antonio del Sol, one of the lead authors of the study – published in the journal Cell – says their new model allows them to identify which stem cells are active and ready to divide, or dormant. 

“Our results constitute an important step towards the implementation of stem cell-based therapies, for instance for neurodegenerative diseases. We were able to show that, with computational models, it is possible to identify the essential features that are characteristic of a specific state of stem cells.”

The work, done in mice, identified a protein that helped keep brain stem cells inactive in older animals. By blocking this protein they were able to help “wake up” those stem cells so they could divide and proliferate and help regenerate the aging brain.

And if it works in mice it must work in people right? Well, that’s what they hope to see next.

Deeper understanding of fetal development

According to the Mayo Clinic between 10 and 20 percent of known pregnancies end in miscarriage (though they admit the real number may be even higher) and our lack of understanding of fetal development makes it hard to understand why. A new study reveals a previously unknown step in this development that could help provide some answers and, hopefully, lead to ways to prevent miscarriages.

Researchers at the Karolinska Institute in Sweden used genetic sequencing to follow the development stages of mice embryos. By sorting those different sequences into a kind of blueprint for what’s happening at every stage of development they were able to identify a previously unknown phase. It’s the time between when the embryo attaches to the uterus and when it begins to turn these embryonic stem cells into identifiable parts of the body.

Qiaolin Deng, Karolinska Institute

Lead researcher Qiaolin Deng says this finding provides vital new evidence.

“Being able to follow the differentiation process of every cell is the Holy Grail of developmental biology. Knowledge of the events and factors that govern the development of the early embryo is indispensable for understanding miscarriages and congenital disease. Around three in every 100 babies are born with fetal malformation caused by faulty cellular differentiation.”

The study is published in the journal Cell Reports.

Could a new drug discovery reduce damage from a heart attack?

Every 40 seconds someone in the US has a heart attack. For many it is fatal but even for those who survive it can lead to long-term damage to the heart that ultimately leads to heart failure. Now British researchers think they may have found a way to reduce that likelihood.

Using stem cells to create human heart muscle tissue in the lab, they identified a protein that is activated after a heart attack or when exposed to stress chemicals. They then identified a drug that can block that protein and, when tested in mice that had experienced a heart attack, they found it could reduce damage to the heart muscle by around 60 percent.

Prof Michael Schneider, the lead researcher on the study, published in Cell Stem Cell, said this could be a game changer.

“There are no existing therapies that directly address the problem of muscle cell death and this would be a revolution in the treatment of heart attacks. One reason why many heart drugs have failed in clinical trials may be that they have not been tested in human cells before the clinic. Using both human cells and animals allows us to be more confident about the molecules we take forward.”

Coming up with a stem cell FIX for a life-threatening blood disorder

/ Pallavi Penumetcha / 1 Comment

Hemophilia

A promising new treatment option for hemophiliacs is in the works at the Salk Institute for Biological Sciences. Patients with Hemophilia B experience uncontrolled, and sometimes life threatening, bleeding due to loss or improper function of Factor IX (FIX), a protein involved in blood clotting. There is no cure for the disease and patients rely on routine infusions of FIX to prevent excessive blood loss. As you can imagine, this treatment regimen is both time consuming and expensive, while also becoming less effective over time.

Salk researchers, partially funded by CIRM, aimed to develop a more long-term solution for this devastating disease by using the body’s own cells to fix the problem.

In the study, published in the journal Cell Reports, They harvested blood cells from hemophiliacs and turned them into iPSCs (induced pluripotent stem cells), which are able to turn into any cell type. Using gene editing, they repaired the iPSCs so they could produce FIX and then turned the iPSCs into liver cells, the cell type that naturally produces FIX in healthy individuals.

One step therapy

To test whether these FIX-producing liver cells were able to reduce excess blood loss, the scientists injected the repaired human cells into a hemophiliac mouse. The results were very encouraging; they saw a greater than two-fold increase in clotting efficiency in the mice, reaching about a quarter of normal activity. This is particularly promising because other studies showed that increasing FIX activity to this level in hemophiliac humans significantly reduces bleeding rates. On top of that they also observed that these cells were able to survive and produce FIX for up to a year in the mice.

In a news release Suvasini Ramaswamy, the first author of the paper, said this method could eliminate the need for multiple treatments, as well as avoiding the immunosuppressive therapy that would be required for a whole liver transplant.

“The appeal of a cell-based approach is that you minimize the number of treatments that a patient needs. Rather than constant injections, you can do this in one shot.”

While these results provide an exciting new avenue in hemophilia treatment, there is still much more work that needs to be done before this type of treatment can be used in humans. This approach, however, is particularly exciting because it provides an important proof of principle that combining stem cell reprogramming with genetic engineering can lead to life-changing breakthroughs for treating genetic diseases that are not currently curable.