Taming the Zika virus to kill cancer stem cells that drive lethal brain tumor

An out of control flame can be very dangerous, even life-threatening. But when harnessed, that same flame sustains life in the form of warm air, a source of light, and a means to cook.

A similar duality holds true for viruses. Once it infects the body, a virus can replicate like wildfire and cause serious illness and sometimes death. But in the lab, researchers can manipulate viruses to provide an efficient, harmless method to deliver genetic material into cells, as well as to prime the immune system to protect against future infections.

In a Journal of Experimental Medicine study published this week, researchers from the University of Washington, St. Louis and UC San Diego also show evidence that a virus, in this case the Zika virus, could even be a possible therapy for a hard-to-treat brain cancer called glioblastoma.

Brain cancer stem cells (left) are killed by Zika virus infection (image at right shows cells after Zika treatment). Image: Zhe Zhu, Washington U., St. Louis.

Recent outbreaks of the Zika virus have caused microcephaly during fetal development. Babies born with microcephaly have a much smaller than average head size due to a lack of proper brain development. Children born with this condition suffer a wide range of devastating symptoms like seizures, difficulty learning, and movement problems just to name a few. In the race to understand the outbreak, scientists have learned that the Zika virus induces microcephaly by infecting and killing brain stem cells, called neural progenitors, that are critical for the growth of the developing fetal brain.

Now, glioblastoma tumors contain a small population of cells called glioblastoma stem cells (GSCs) that, like neural progenitors, can lay dormant but also make unlimited copies of themselves.  It’s these properties of glioblastoma stem cells that are thought to allow the glioblastoma tumor to evade treatment and grow back. The research team in this study wondered if the Zika virus, which causes so much damage to neural progenitors in developing babies, could be used for good by infecting and killing cancer stem cells in glioblastoma tumors in adult patients.

To test this idea, the scientists infected glioblastoma brain tumor samples with Zika and showed that the virus spreads through the cells but primarily kills off the glioblastoma stem cells, leaving other cells in the tumor unscathed. Since radiation and chemotherapy are effective at killing most of the tumor but not the cancer stem cells, a combination of Zika and standard cancer therapies could provide a knockout punch to this aggressive brain cancer.

Even though Zika virus is much more destructive to the developing fetal brain than to adult brains, it’s hard to imagine the US Food and Drug Administration ever approving the injection of a dangerous virus into the site of a glioblastoma tumor. So, the scientists genetically modified the Zika virus to make it more sensitive to the immune system’s first line of defense called the innate immunity. With just the right balance of genetic alterations, it might be possible to retain the Zika virus’ ability to kill off cancer stem cells without causing a serious infection.

The results were encouraging though not a closed and shut case: when glioblastoma cancer stem cells were infected with these modified Zika virus strains, the virus’ cancer-killing abilities were weaker than the original Zika strains but still intact. Based on these results, co-senior author and WashU professor, Dr. Michael S. Diamond, plans to make more tweaks to the virus to harness it’s potential to treat the cancer without infecting the entire brain in the process.

“We’re going to introduce additional mutations to sensitize the virus even more to the innate immune response and prevent the infection from spreading,” said Diamond in a press release. “Once we add a few more changes, I think it’s going to be impossible for the virus to overcome them and cause disease.”

 

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Stories that caught our eye last week: dying cells trigger stem cells, CRISPR videogames and an obesity-stem cell link

A dying cell’s last breath triggers stem cell division. Most cells in your body are in a constant state of turnover. The cells of your lungs, for instance, replace themselves every 2 to 3 weeks and, believe it or not, you get a new intestine every 2 to 3 days. We can thank adult stem cells residing in these organs for producing the new replacement cells. But with this continual flux, how do the stem cells manage to generate just the right number of cells to maintain the same organ size? Just a slight imbalance would lead to either too few cells or too many which can lead to organ dysfunction and disease.

The intestine turnovers every five days. Stem cells (green) in the fruit fly intestine maintain organ size and structure. Image: Lucy Erin O’Brien/Stanford U.

Stanford University researchers published results on Friday in Nature that make inroads into explaining this fascinating, fundamental question about stem cell and developmental biology. Studying the cell turnover process of the intestine in fruit flies, the scientists discovered that, as if speaking its final words, a dying intestinal cell, or enterocyte, directly communicates with an intestinal stem cell to trigger it to divide and provide young, healthy enterocytes.

To reach this conclusion, the team first analyzed young enterocytes and showed that a protein these cells produce, called E-cadherin, blocks the release of a growth factor called EGF, a known stimulator of cell division. When young enterocytes became old and begin a process called programmed cell death, or apoptosis, the E-cadherin levels drop which removes the inhibition of EGF. As a result, a nearby stem cell now receives the EGF’s cell division signal, triggering it to divide and replace the dying cell. In her summary of this research in Stanford’s Scope blog, science writer Krista Conger explains how the dying cell’s signal to a stem cell ensures that there no net gain or loss of intestinal cells:

“The signal emitted by the dying cell travels only a short distance to activate only nearby stem cells. This prevents an across-the-board response by multiple stem cells that could result in an unwanted increase in the number of newly generated replacement cells.”

Because E-cadherin and the EGF receptor (EGFR) are each associated with certain cancers, senior author Lucy Erin O’Brien ponders the idea that her lab’s new findings may explain an underlying mechanism of tumor growth:

Lucy Erin O’Brien Image: Stanford U.

“Intriguingly, E-cadherin and EGFR are each individually implicated in particular cancers. Could they actually be cooperating to promote tumor development through some dysfunctional version of the normal renewal mechanism that we’ve uncovered?”

 

How a videogame could make gene editing safer (Kevin McCormack). The gene editing tool CRISPR has been getting a lot of attention this past year, and for good reason, it has the potential to eliminate genetic mutations that are responsible for some deadly diseases. But there are still many questions about the safety of CRISPR, such as how to control where it edits the genome and ensure it doesn’t cause unexpected problems.

Now a team at Stanford University is hoping to use a videogame to find answers to some of those questions. Here’s a video about their project:

The team is using the online game Eterna – which describes itself as “Empowering citizen scientists to invent medicine”. In the game, “players” can build RNA molecules that can then be used to turn on or off specific genes associated with specific diseases.

The Stanford team want “players” to design an RNA molecule that can be used as an On/Off switch for CRISPR. This would enable scientists to turn CRISPR on when they want it, but off when it is not needed.

In an article on the Stanford News website, team leader Howard Chang said this is a way to engage the wider scientific community in coming up with a solution:

Howard Chang
Photo: Stanford U.

“Great ideas can come from anywhere, so this is also an experiment in the democratization of science. A lot of people have hidden talents that they don’t even know about. This could be their calling. Maybe there’s somebody out there who is a security guard and a fantastic RNA biochemist, and they don’t even know it. The Eterna game is a powerful way to engage lots and lots of people. They’re not just passive users of information but actually involved in the process.”

They hope up to 100,000 people will play the game and help find a solution.

Altered stem cell gene activity partly to blame for obesity. People who are obese are often ridiculed for their weight problems because their condition is chalked up to a lack of discipline or self-control. But there are underlying biological processes that play a key role in controlling body weight which are independent of someone’s personality. It’s known that so-called satiety hormones – which are responsible for giving us the sensation that we’re full from a meal – are reduced in obese individuals compared to those with a normal weight.

Stem cells may have helped Al Roker’s dramatic weight loss after bariatric surgery. Photo: alroker.com

Bariatric surgery, which reduces the size of the stomach, is a popular treatment option for obesity and can lead to remarkable weight loss. Al Roker, the weatherman for NBC’s Today Show is one example that comes to mind of a weight loss success story after having this procedure. It turns out that the weight loss is not just due to having a smaller stomach and in turn smaller meals, but researchers have shown that the surgery also restores the levels of satiety hormones. So post-surgery, those individuals get a more normal, “I’m full”, feedback from their brains after eating a meal.

A team of Swiss doctors wanted to understand why the satiety hormone levels return to normal after bariatric surgery and this week they reported their answer in Scientific Reports. They analyzed enteroendocrine cells – the cells that release satiety hormones into the bloodstream and to the brain in response to food that enters the stomach and intestines – in obese individuals before and after bariatric surgery as well as a group of people with normal weight. The results showed that obese individuals have fewer enteroendocrine cells compared with the normal weight group. Post-surgery, those cells return to normal levels.

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Cells which can release satiety hormones are marked in green. For obese patients (middle), the number of these cells is markedly lower than for lean people (top) and for overweight patients three months after surgery (bottom). Image: University of Basil.

A deeper examination of the cells from the obese study group revealed altered patterns of gene activity in stem cells that are responsible for generating the enteroendocrine cells. In the post-surgery group, the patterns of gene activity, as seen in the normal weight group, are re-established. As mentioned in a University of Basil press release, these results stress that obesity is more than just a problem of diet and life-style choices:

“There is no doubt that metabolic factors are playing an important part. The study shows that there are structural differences between lean and obese people, which can explain lack of satiation in the obese.”

 

Stem cell therapy for Parkinson’s disease shows promise in monkeys

Tremors, muscle stiffness, shuffling, slow movement, loss of balance. These are all symptoms of Parkinson’s disease (PD), a neurodegenerative disorder that progressively destroys the dopamine-producing neurons in the brain that control movement.

While there is no cure for Parkinson’s disease, there are drugs like Levodopa and procedures like deep brain stimulation that alleviate or improve some Parkinsonian symptoms. What they don’t do, however, is slow or reverse disease progression.

Scientists are still trying to figure out what causes Parkinson’s patients to lose dopaminergic neurons, and when they do, they hope to stop the disease in its early stages before it can cause the debilitating symptoms mentioned above. In the meantime, some researchers see hope for treating Parkinson’s in the form of stem cell therapies that can replace the brain cells that are damaged or lost due to the disease.

Dopaminergic neurons derived from induced pluripotent stem cells. (Xianmin Zeng, Buck Institute)

Promising results in monkeys

This week, a team of Japanese scientists reported in the journal Nature that they treated monkeys with Parkinson’s-like symptoms by transplanting dopaminergic neurons made from human stem cells into their brains. To prevent the monkeys from rejecting the human cells, they were treated with immunosuppressive drugs. These transplanted neurons survived for more than two years without causing negative side effects, like tumor growth, and also improved PD symptoms, making it easier for the monkeys to move around.

The neurons were made from induced pluripotent stem cells (iPSCs), which are stem cells that can become any cell type in the body and are made by transforming mature human cells, like skin, back to an embryonic-like state. The scientists transplanted neurons made from the iPSCs of healthy people and PD patients into the monkeys and saw that both types of neurons survived and functioned properly by producing dopamine in the monkey brains.

Experts in the field spoke to the importance of these findings in an interview with Nature News. Anders Bjorklund, a neuroscientist at Lund University in Sweden, said “it’s addressing a set of critical issues that need to be investigated before one can, with confidence, move to using the cells in humans,” while Lorenz Studer, a stem-cell scientist at the Memorial Sloan Kettering Cancer Center in New York City, said that “there are still issues to work out, such as the number of cells needed in each transplant procedure. But the latest study is ‘a sign that we are ready to move forward.’”

Next stop, human trials

Jun Takahashi

Looking ahead, Jun Takahashi, the senior author on the study, explained that his team hopes to launch a clinical trial testing this iPSC-based therapy by the end of 2018. Instead of developing personalized iPSC therapies for individual PD patients, which can be time consuming and costly, Takahashi plans to make special donor iPSC lines (called human leukocyte antigen or HLA-homozygous iPSCs) that are immunologically compatible with a larger population of patients.

In a separate study published at the same time in Nature Communications, Takahashi and colleagues showed that transplanting neurons derived from immune-matched monkey iPSCs improved their survival and dampened the immune response.

The Nature News article does a great job highlighting the findings and significance of both studies and also mentions other research projects using stem cells to treat PD in clinical trials.

“Earlier this year, Chinese researchers began a Parkinson’s trial that used a different approach: giving patients neural-precursor cells made from embryonic stem cells, which are intended to develop into mature dopamine-producing neurons. A year earlier, in a separate trial, patients in Australia received similar cells. But some researchers have expressed concerns that the immature transplanted cells could develop tumour-causing mutations.

Meanwhile, researchers who are part of a Parkinson’s stem-cell therapy consortium called GForce-PD, of which Takahashi’s team is a member, are set to bring still other approaches to the clinic. Teams in the United States, Sweden and the United Kingdom are all planning trials to transplant dopamine-producing neurons made from embryonic stem cells into humans. Previously established lines of embryonic stem cells have the benefit that they are well studied and can be grown in large quantities, and so all trial participants can receive a standardized treatment.”

You can read more coverage on these research studies in STATnews, The San Diego Union Tribune, and Scientific American.

For a list of projects CIRM is funding on Parkinson’s disease, visit our website.

From trauma to treatment: a Patient Advocate’s journey from helping her son battle a deadly disease to helping others do the same

Everett SCID 1

For every clinical trial CIRM funds we create a Clinical Advisory Panel or CAP. The purpose of the CAP is to make recommendations and provide guidance and advice to both CIRM and the Project Team running the trial. It’s part of our commitment to doing everything we can to help make the trial a success and get therapies to the people who need them most, the patients.

Each CAP consists of three to five members, including a Patient Advocate, an external scientific expert, and a CIRM Science Officer.

Having a Patient Advocate on a CAP fills a critical need for insight from the patient’s perspective, helping shape the trial, making sure that it is being carried out in a way that has the patient at the center. A trial designed around the patient, and with the needs of the patient in mind, is much more likely to be successful in recruiting and retaining the patients it needs to see if the therapy works.

One of the clinical trials we are currently funding is focused on severe combined immunodeficiency disease, or SCID. It’s also known as “bubble baby” disease because children with SCID are born without a functioning immune system, so even a simple virus or infection can prove fatal. In the past some of these children were kept inside sterile plastic bubbles to protect them, hence the name “bubble baby.”

Everett SCID family

Anne Klein is the Patient Advocate on the CAP for the CIRM-funded SCID trial at UCSF and St. Jude Children’s Research Hospital. Her son Everett was born with SCID and participated in this clinical trial. We asked Anne to talk about her experience as the mother of a child with SCID, and being part of the research that could help cure children like Everett.

“When Everett was born his disease was detected through a newborn screening test. We found out he had SCID on a Wednesday, and by  Thursday we were at UCSF (University of California, San Francisco). It was very sudden and quite traumatic for the family, especially Alden (her older son). I was abruptly taken from Alden, who was just two and a half years old at the time, for two months. My husband, Brian Schmitt, had to immediately drop many responsibilities required to effectively run his small business. We weren’t prepared. It was really hard.”

(Everett had his first blood stem cell transplant when he was 7 weeks old – his mother Anne was the donor. It helped partially restore his immune system but it also resulted in some rare, severe complications as a result of his mother’s donor cells attacking his body. So when, three years later, the opportunity to get a stem cell therapy came along Anne and her husband, Brian, decided to say yes. After some initial problems following the transplant, Everett seems to be doing well and his immune system is the strongest it has ever been.)

“It’s been four years, a lot of ups and downs and a lot of trauma. But it feels like we have turned a corner. Everett can go outside now and play, and we’re hanging out more socially because we no longer have to be so concerned about him being exposed to germs or viruses.

His doctor has approved him to go to daycare, which is amazing. So, Everett is emerging into the “normal” world for the first time. It’s nerve wracking for us, but it’s also a relief.”

Everett SCID in hospital

How Anne came to be on the CAP

“Dr. Cowan from UCSF and Dr. Malech from the NIH (National Institutes of Health) reached out to me and asked me about it a few months ago. I immediately wanted to be part of the group because, obviously, it is something I am passionate about. Knowing families with SCID and what they go through, and what we went through, I will do everything I can to help make this treatment more available to as many people as need it.

I can provide insight on what it’s like to have SCID, from the patient perspective; the traumas you go through. I can help the doctors and researchers understand how the medical community can be perceived by SCID families, how appreciative we are of the medical staff and the amazing things they do for us.

I am connected to other families, both within and outside of the US, affected by this disease so I can help get the word out about this treatment and answer questions for families who want to know. It’s incredibly therapeutic to be part of this wider community, to be able to help others who have been diagnosed more recently.”

The CAP Team

“They were incredibly nice and when I did speak they were very supportive and seemed genuinely interested in getting feedback from me. I felt very comfortable. I felt they were appreciative of the patient perspective.

I think when you are a research scientist in the lab, it’s easy to miss the perspective of someone who is actually experiencing the disease you are trying to fix.

At the NIH, where Everett had his therapy, the stem cell lab people work so hard to process the gene corrected cells and get them to the patient in time. I looked through the window into the hall when Everett was getting his therapy and the lab staff were outside, in their lab coats, watching him getting his new cells infused. They wanted to see the recipient of the life-saving treatment that they prepared.

It is amazing to see the process that the doctors go through to get treatments approved. I like being on the CAP and learning about the science behind it and I think if this is successful in treating others, then that would be the best reward.”

The future:

“We still have to fly back to the NIH, in Bethesda, MD, every three months for checkups. We’ll be doing this for 15 years, until Everett is 18. It will be less frequent as Everett gets older but this kind of treatment is so new that it’s still important to do this kind of follow-up. In between those trips we go to UCSF every month, and Kaiser every 1-3 weeks, sometimes more.

I think the idea of being “cured”, when you have been through this, is a difficult thing to think about. It’s not a word I use lightly as it’s a very weighted term. We have been given the “all clear” before, only to be dealt setbacks later. Once he’s in school and has successfully conquered some normal childhood illnesses, both Brian and I will be able to relax more.

One of Everett’s many doctors once shared with me that, in the past, he sometimes had to tell parents of very sick children with SCID that there was nothing else they could do to help them. So now to have a potential treatment like this, he was so excited about a stem cell therapy showing such promise.

One thing we think about Everett and Alden, is that they are both so young and have been through so much already. I’m hoping that they can forget all this and have a chance to grow up and lead a normal life.”

Extra dose of patience needed for spinal cord injury stem cell therapies, rat study suggests

2017 has been an exciting year for Asterias Biotherapeutics’ clinical trial which is testing a stem cell-based therapy for spinal cord injury. We’ve written several stories about patients who have made remarkable recoveries after participating in the trial (here and here).

But that doesn’t mean researchers at other companies or institutes who are also investigating spinal cord injury will be closing up shop. There’s still a long way to go with the Asterias trial and there’s still a lot to be learned about the cellular and molecular mechanisms of spinal cord injury repair, which could lead to alternative options for victims. Continued studies will also provide insights on optimizing the methods and data collection used in future clinical trials.

Human neuronal stem cells extend axons (green) three months after transplantation in rat model of spinal cord injury. Image: UCSD

In fact, this week a team of UC San Diego scientists report in the Journal of Clinical Investigation that, based on brain stem cell transplant studies in a rat model of spinal cord injury, recovery continues long after the cell therapy is injected. These findings suggest that collecting clinical trial data too soon may give researchers the false impression that their therapy is not working as well as they had hoped.

In this study, funded in part by CIRM, the researchers examined brain stem cells – or neural stem cells, in lab lingo – that were derived from human embryonic stem cells. These neural stem cells (NSCs) aren’t fully matured and give rise to nerve cells as well as support cells called glia. Previous studies have shown that when NSCs are transplanted into rodent models of spinal cord injury, the cells mature into nerve cells, make connections with nerves within the animal and can help restore some limb movement.

But the timeline for the maturation of the NSCs after transplantation into the injury site wasn’t clear because most studies only measured recovery for a few weeks or months. To get a clearer picture, the UCSD team analyzed the fate and impact of human NSCs in adult rats with spinal cord injury from 1 month to 1.5 years – the longest time such an experiment has been carried out so far. The results confirmed that the transplanted NSCs did indeed survive through the 18-month time point and led to recovery of movement in the animals’ limbs.

To their surprise, the researchers found that the NSCs continued to mature and some cell types didn’t fully specialize until 6 months or even 12 months after the transplantation. This timeline suggests that although the human cells are placed into the hostile environment of an injury site in an animal model, they still follow a maturation process seen during human development.

The researchers also focused on the fate of the nerve cells’ axons, the long, thin projections that relay nerve signals and make connections with other nerve cells. Just as is seen with normal human development, these axons were very abundant early in the experiment but over several months they went through a pruning process that’s critical for healthy nerve function.

Altogether, these studies provide evidence that waiting for the clinical trial results of stem cell-based spinal cord injury therapies will require an extra dose of patience. Team lead, Dr. Mark Tuszynski, director of the UC San Diego Translational Neuroscience Institute, summed it up this way in a press release:

Mark Tuszynski, UCSD

“The bottom line is that clinical outcome measures for future trials need to be focused on long time points after grafting. Reliance on short time points for primary outcome measures may produce misleadingly negative interpretation of results. We need to take into account the prolonged developmental biology of neural stem cells. Success, it would seem, will take time.”

Stem cell treatment helps puppies born with spina bifida walk again

Just when you thought puppies couldn’t get any cuter, this video appears in your twitter feed.

These adorable English bulldog puppies are named Darla and Spanky, and they were born with a birth defect called spina bifida where the bones and tissue surrounding the spinal cord fail to fuse completely. Spina bifida occurs in 1500-2000 children in the US each year and can cause serious problems such as paralysis and issues with walking, cognition, and bladder or bowel control. Dogs born with this condition usually cannot use their hind legs, and as a sad consequence, are typically put down at a young age.

Cutting edge research from UC Davis is now giving these unfortunate puppies hope. Diana Farmer, a fetal surgeon at UC Davis Health, and scientists from the university’s Veterinary Institute for Regenerative Cures have developed a combination surgery and stem cell transplant, using placenta-derived mesenchymal stromal cells (PMSCs), to treat puppies with spina bifida. Because prenatal screening for spina bifida is not done in dogs, Darla and Spanky received the treatment when they were ten weeks old.

With funding from a CIRM preclinical development award, Farmer has done similar surgeries in lambs that are still in the womb. A UC Davis news release provided historical background on Farmer’s work on spina bifida,

“Farmer pioneered the use of surgery prior to birth to improve brain development in children with spina bifida. She later showed that prenatal surgery combined with human placenta-derived mesenchymal stromal cells (PMSCs), held in place with a cellular scaffold, helped research lambs born with the disorder walk without noticeable disability.”

As you can see from the video, the surgeries were a success. Darla and Spanky are now able to live up to their full puppy potential and will live happily ever after with their adoptive family in New Mexico.

Looking forward, Farmer and her team would like to treat more dogs with spina bifida so they can improve another negative consequence of spina bifida called incontinence, or an uncontrollable bladder. The UC Davis release explained that, “while Darla and Spanky are very mobile and doing well on their feet, they still require diapers.” (Side note: this video proves that puppies can make anything look cute, even dirty diapers.)

Additionally, the team is hoping to receive regulatory approval from the US Food and Drug Administration to launch a clinical trial testing this therapy in humans. If this stem cell treatment proves to be both safe and effective in clinical trials, it could potentially prevent spina bifida from ever happening in animals and in humans.

English Bulldog undergoing spina bifida surgery at UC Davis Veterinary Medical Teaching Hospital. (Gregory Urquiaga/UC Davis)

Stem cell stories that caught our eye: bubble baby therapy a go in UK, in-utero stem cell trial and novel heart disease target

There were lots of CIRM mentions in the news this week. Here are two brief recaps written by Karen Ring to get you up to speed. A third story by Todd Dubnicoff summarizes an promising finding related to heart disease by researchers in Singapore.  

CIRM-funded “bubble baby” disease therapy gets special designation by UK.
Orchard Therapeutics, a company based in the UK and the US, is developing a stem cell-based gene therapy called OTL-101 to treat a primary immune disease called adenosine-deaminase deficient severe combined immunodeficiency (ADA-SCID), also known as “bubble baby disease”. CIRM is funding a Phase 1/2 clinical trial led by Don Kohn of UCLA in collaboration with Orchard and the University College in London.

In July, the US Food and Drug Administration (FDA) awarded OTL-101 Rare Pediatric Disease Designation (read more about it here), which makes the therapy eligible for priority review by the FDA, and could give it a faster route to being made more widely available to children in need.

On Tuesday, Orchard announced further good news that OTL-101 received “Promising Innovative Medicine Designation” by the UK’s Medicines and Healthcare Products Regulatory Agency (MHRA). In a news release, the company explained how this designation bodes well for advancing OTL-101 from clinical trials into patients,

“The designation as Promising Innovative Medicine is the first step of a two-step process under which OTL-101 can benefit from the Early Access to Medicine Scheme (“EAMS”). Nicolas Koebel, Senior Vice President for Business Operations at Orchard, added: “With this PIM designation we can potentially make OTL-101 available to UK patients sooner under the Early Access to Medicine Scheme”.

CIRM funded UCSF clinical trial mentioned in SF Business Times
Ron Leuty, reporter at the San Francisco Business Times, published an article about a CIRM-funded trial out of UCSF that is targeting a rare genetic blood disease called alpha thalassemia major, describing it as, “The world’s first in-utero blood stem cell transplant, soon to be performed at the University of California, San Francisco, could point the way toward pre-birth cures for a range of blood diseases, such as sickle cell disease.”

Alpha Thalassemia affects the ability of red blood cells to carry oxygen because of a reduction in a protein called hemoglobin. The UCSF trial, spearheaded by UCSF Pediatric surgeon Dr. Tippi MacKenzie, is hoping to use stem cells from the mother to treat babies in the womb to give them a better chance at surviving after birth.

In an interview with Leuty, Tippi explained,

“Our goal is to put in enough cells so the baby won’t need another transplant. But even if we fall short, if we can just establish 1 percent maternal cells circulating in the child, it will establish tolerance and then they can get the booster transplant.”

She also emphasized the key role that CIRM funded played in the development and launch of this clinical trial.

“CIRM is about more than funding for studies, MacKenzie said. Agency staff has provided advice about how to translate animal studies into work in humans, she said, as well as hiring an FDA consultant, writing an investigational new drug application and setting up a clinical protocol.”

“I’m a clinician, but running a clinical trial is different,” MacKenzie said. “CIRM’s been incredibly helpful in helping me navigate that.”

Heart, heal thyself: the story of Singheart
When you cut your finger or scrape a knee, a scab forms, allowing the skin underneath to regenerate and repair itself. The heart is not so lucky – it has very limited self-healing abilities. Instead, heart muscle cells damaged after a heart attack form scar tissue, making each heart beat less efficient. This condition can lead to chronic heart disease, the number one killer of both men and women in the US.

A mouse heart cell with 2 nuclei (blue) and Singheart RNA labelled by red fluorescent dyes.
Credit: A*STAR’s Genome Institute of Singapore

Research has shown that newborn mice retain the ability to completely regenerate and repair injuries to the heart because their heart muscle cells, or cardiomyocytes, are still able to divide and replenish damaged cells. But by adulthood, the mouse cardiomyocytes lose the ability to stimulate the necessary cell division processes. A research team in Singapore wondered what was preventing cardiomyocytes cell division in adult mice and if there was some way to lift that block.

This week in Nature Communications, they describe the identification of a molecule they call Singheart that may be the answer to their questions. Using tools that allow the analysis of gene activity in single cells revealed that a rare population of diseased cardiomyocytes are able to crank up genes related to cell division. And further analysis showed Singheart, a specialized genetic molecule called a long non-coding RNA, played a role in blocking this cell division gene.

As lead author Dr. Roger Foo, a principal investigator at Genome Institute of Singapore (GIS) and the National University Health System (NUHS), explained in a press release, these findings may lead to new self-healing strategies for heart disease,

“There has always been a suspicion that the heart holds the key to its own healing, regenerative and repair capability. But that ability seems to become blocked as soon as the heart is past its developmental stage. Our findings point to this potential block that when lifted, may allow the heart to heal itself.”

Confusing cancer to kill it

Kipps

Thomas Kipps, MD, PhD: Photo courtesy UC San Diego

Confusion is not a state of mind that we usually seek out. Being bewildered is bad enough when it happens naturally, so why would anyone actively pursue it? But now some researchers are doing just that, using confusion to not just block a deadly blood cancer, but to kill it.

Today the CIRM Board approved an investment of $18.29 million to Dr. Thomas Kipps and his team at UC San Diego to use a one-two combination approach that we hope will kill Chronic Lymphocytic Leukemia (CLL).

This approach combines two therapies, cirmtuzumab (a monoclonal antibody developed with CIRM funding, hence the name) and Ibrutinib, a drug that has already been approved by the US Food and Drug Administration (FDA) for patients with CLL.

As Dr. Maria Millan, our interim President and CEO, said in a news release, the need for a new treatment is great.

“Every year around 20,000 Americans are diagnosed with CLL. For those who have run out of treatment options, the only alternative is a bone marrow transplant. Since CLL afflicts individuals in their 70’s who often have additional medical problems, bone marrow transplantation carries a higher risk of life threatening complications. The combination approach of  cirmtuzumab and Ibrutinib seeks to offer a less invasive and more effective alternative for these patients.”

Ibrutinib blocks signaling pathways that leukemia cells need to survive. Disrupting these pathways confuses the leukemia cell, leading to its death. But even with this approach there are cancer stem cells that are able to evade Ibrutinib. These lie dormant during the therapy but come to life later, creating more leukemia cells and causing the cancer to spread and the patient to relapse. That’s where cirmtuzumab comes in. It works by blocking a protein on the surface of the cancer stem cells that the cancer needs to spread.

It’s hoped this one-two punch combination will kill all the cancer cells, increasing the number of patients who go into complete remission and improve their long-term cancer control.

In an interview with OncLive, a website focused on cancer professionals, Tom Kipps said Ibrutinib has another advantage for patients:

“The patients are responding well to treatment. It doesn’t seem like you have to worry about stopping therapy, because you’re not accumulating a lot of toxicity as you would with chemotherapy. If you administered chemotherapy on and on for months and months and years and years, chances are the patient wouldn’t tolerate that very well.”

The CIRM Board also approved $5 million for Angiocrine Bioscience Inc. to carry out a Phase 1 clinical trial testing a new way of using cord blood to help people battling deadly blood disorders.

The standard approach for this kind of problem is a bone marrow transplant from a matched donor, usually a family member. But many patients don’t have a potential donor and so they often have to rely on a cord blood transplant as an alternative, to help rebuild and repair their blood and immune systems. However, too often a single cord blood donation does not have enough cells to treat an adult patient.

Angiocrine has developed a product that could help get around that problem. AB-110 is made up of cord blood-derived hematopoietic stem cells (these give rise to all the other types of blood cell) and genetically engineered endothelial cells – the kind of cell that lines the insides of blood vessels.

This combination enables the researchers to take cord blood cells and greatly expand them in number. Expanding the number of cells could also expand the number of patients who could get these potentially life-saving cord blood transplants.

These two new projects now bring the number of clinical trials funded by CIRM to 35. You can read about the other 33 here.

 

 

 

Researchers, beware: humanized mice not human enough to study stem cell transplants

A researcher’s data is only as good as the experimental techniques used to obtain those results. And a Stanford University study published yesterday in Cell Reports, calls into question the accuracy of a widely used method in mice that helps scientists gauge the human immune system’s response to stem cell-based therapies. The findings, funded in part by CIRM, urge a healthy dose of caution before using promising results from these mouse experiments as a green light to move on to human clinical trials.

Humanized mice aren’t quite human. Illustration: Pascal Gerard

Immune rejection of stem cell-based products is a major obstacle to translating these therapies from cutting-edge research into everyday treatments for the general population for people. If the genetic composition between the transplanted cells and the patient are mismatched, the patient’s immune system will see that cell therapy as foreign and will attack it. Unlike therapies derived from embryonic stem cells or from another person, induced pluripotent stem cells (iPSC) are exciting because scientists can potentially develop stem cell-based therapies from a patient’s own cells which relieves most of the immune rejection fears.

But manufacturing iPSC-derived therapies for each patient can take months, not to mention a lot of money, to complete. Some patients with life-threatening conditions like a heart attack or stroke don’t have the luxury of waiting that long. So even with these therapies, many researchers are working towards developing non-matched cell products which would be available “off-the-shelf. In all of these cases, immune-suppressing drugs would be needed which have their own set of concerns due to dangerous side effects, like serious infection or cancer. So, before testing in humans begins, it’s important to be able to test various immune-suppressing drugs and doses in animals to understand how well a stem cell-based therapy will survive once transplanted.

But how do you test a human immune response to a human cell product in an animal? Believe it or not, researchers – some of whom are authors in this Cell Reports publication – developed “humanized mice” back in the 1980’s. These mice were engineered to lack their own immune system to allow the engraftment of a human immune system. Over the years, advances in this mouse experimental system has gotten it closer and closer to imitating a human immune system response to transplantation of mismatched cell product.

Close but no cigar, it seems.

The team in the current study performed a detailed analysis of the immune response in two different strains of humanized mice. Both groups of animals did not mount a normal, healthy immune response and so they could not completely reject transplants of various human stem cells or stem cell-based products. Now, if you didn’t know about the abnormally weak immune response in these humanized mice, you might conclude that very little immunosuppression would be needed for a given cell therapy to keep a patient’s immune system in check. But conclusively making that interpretation is not possible, according to team lead Dr. Joseph Wu, director of Stanford’s Cardiovascular Institute:

Joseph Wu. Photo: Steve Fisch/Stanford University

“In an ideal situation, these humanized mice would reject foreign stem cells just as a human patient would”, he said in a press release. “We could then test a variety of immunosuppressive drugs to learn which might work best in patients, or to screen for new drugs that could inhibit this rejection. We can’t do that with these animals.”

To uncover what was happening, the team took a step back and, rather than engrafting a human immune system into the mice, they engrafted immune cells from an unrelated mouse strain. Think of it as a mouse-ified mouse, if you will. When mouse iPSCs or human embryonic stem cells were transplanted into these mouse, the engrafted mouse immune system effectively rejected the stem cells. So, compared to these mice, some elements of the immune system in the humanized mouse strains are not quite capturing the necessary complexity to truly reproduce a human immune response.

More work will be needed to understand the underlying mechanisms of this difference. Other experiments in this study suggest that signals that inhibit the immune response may be elevated in the humanized mouse models. Dr. Leonard Shultz, a pioneer in the development of humanized mice at Jackson Laboratory and an author of this study, is optimistic about building a better model:

“The immune system is highly complex and there still remains much we need to learn. Each roadblock we identify will only serve as a landmark as we navigate the future. Already, we’ve seen recent improvements in humanized mouse models that foster enhancement of human immune function.”

Until then, the team urges other scientists to tread carefully when drawing conclusions from the humanized mice in use today.

New research suggests taking a daily dose of vitamin C could prevent leukemia

Did you take your vitamins today? It’s not always easy to remember with such busy lives, but after you read this blog, you’ll be sure to make vitamins part of your daily routine if you haven’t already!

Two recent studies, published in the journals Nature and Cell, reported that vitamin C has a direct impact on the function of blood forming, or hematopoietic stem cells, and can be used to protect mice from getting a blood cancer called leukemia.

Science reporter Bradley Fikes compared the findings of the two studies yesterday in the San Diego Union Tribune. According to Fikes, the Nature study, which was conducted by scientists at UT Southwestern, “found that human and mouse hematopoietic stem cells absorb unusually large amounts of vitamin C. When the cells were depleted of vitamin C, they were more likely to turn into leukemia cells.”

As for the Cell study, scientists from NYU Langone Health “found that high doses of vitamin C can cause leukemic cells to die, potentially making it a useful and safe chemotherapy agent.” For more details on this particular study, see our blog from last week and the video below.

Dr. Benjamin Neel, director of NYU Langone’s Perlmutter Cancer Center, discusses how vitamin C may “tell” faulty stem cells in the bone marrow to mature and die normally, instead of multiplying to cause blood cancers.

Vitamin C levels are crucial for preventing leukemia

The common factor between the two studies is a gene called Tet2, which is turned on in blood stem cells and protects them from over-proliferating and acquiring genetic mutations that transform them into leukemia cells. If one copy of the Tet2 gene is genetically mutated, treating blood stem cells with vitamin C can make up for this partial loss in Tet2 function. However, if both copies of Tet2 are mutated, its protective functions are completely lost and blood stem cells can turn cancerous.

Fikes reached out to Sean Morrison, senior author on the Nature study, for an explanation about the relationship between vitamin C and Tet2, and how it can be leveraged to prevent or treat leukemia:

Sean Morrison

“The Cell study showed that high doses of vitamin C can compensate for Tet2 mutations, restoring normal function, Morrison said. Usually, transformation of normal cells into leukemic cells is irreversible, but the study demonstrated that’s not true when the leukemia is driven by Tet2 mutations.”

“The Nature study demonstrated that vitamin C is a limiting factor in the proper function of Tet2, Morrison said. People have two copies of the gene, one from each parent. When one of the genes is disabled, it’s important to take the full recommended dose of vitamin C so the remaining gene can exert its full tumor-suppressing effect.”

Before you place your bulk order of vitamin C on amazon, you should be aware that Morrison and his colleagues found that giving mice super doses of the supplement failed to further reduce their risk of getting leukemia. Thus, it seems that having the right levels of vitamin C in blood stem cells and healthy copies of the Tet2 gene are vital for preventing leukemia.

Vitamin C, a panacea for cancer?

These two studies raise important questions. Do vitamin C levels play a role in the development of other cancer cells and could this supplement be used as a treatment for other types of cancers?

Since the 1970’s, scientists (including the famous American scientist Linus Pauling) and doctors have pursued vitamin C as a potential cancer treatment. Early stage research revealed that vitamin C plays a role in slowing the growth of various types of cancer cells including prostate, colon and brain cancer cells. More recently, some of this research has progressed to clinical trials that are testing high-doses of vitamin C either by itself or in combination with chemotherapy drugs in cancer patients. Some of these trials have reported an improved quality of life and increased average survival time in patients, but more research and trials are necessary to determine whether vitamin C is a truly effective anti-cancer therapy.

Now that Morrison and his team have a better understanding of how vitamin C levels affect cancer risk, they plan to address some of these outstanding questions in future studies.

“Our data also suggest that probably not all cancers are increased by vitamin C depletion. We particularly would predict that certain leukemias would be increased in the absence of vitamin C. We’re collaborating with the Centers for Disease Control right now to look more carefully at the epidemiological data that have been collected over decades, to understand more precisely which cancers are at increased risk in people that have lower levels of vitamin C.”