CIRM weekly stem cell roundup: stomach bacteria & cancer; vitamin C may block leukemia; stem cells bring down a 6’2″ 246lb football player

gastric

This is what your stomach glands looks like from the inside:  Credit: MPI for Infection Biology”

Stomach bacteria crank up stem cell renewal, may be link to gastric cancer.

The Centers for Disease Control and Prevention estimate that two-thirds of the world’s population is infected with H. pylori, a type of bacteria that thrives in the harsh acidic conditions of the stomach. Data accumulated over the past few decades shows strong evidence that H. pylori infection increases the risk of stomach cancers. The underlying mechanisms of this link have remained unclear. But research published this week in Nature suggests that the bacteria cause stem cells located in the stomach lining to divide more frequently leading to an increased potential for cancerous growth.

Tumors need to make an initial foothold in a tissue in order to grow and spread. But the cells of our stomach lining are replaced every four days. So, how would H. pylori bacterial infection have time to induce a cancer? The research team – a collaboration between scientists at the Max Planck Institute in Berlin and Stanford University – asked that question and found that the bacteria are also able to penetrate down into the stomach glands and infect stem cells whose job it is to continually replenish the stomach lining.

Further analysis in mice revealed that two groups of stem cells exist in the stomach glands – one slowly dividing and one rapidly dividing population. Both stem cell populations respond similarly to an important signaling protein, called Wnt, that sustains stem cell renewal. But the team also discovered a second key stem cell signaling protein called R-spondin that is released by connective tissue underneath the stomach glands. H. pylori infection of these cells causes an increase in R-spondin which shuts down the slowly dividing stem cell population but cranks up the cell division of the rapidly dividing stem cells. First author, Dr. Michal Sigal, summed up in a press release how these results may point to stem cells as the link between bacterial infection and increased risk of stomach cancer:

“Since H. pylori causes life-long infections, the constant increase in stem cell divisions may be enough to explain the increased risk of carcinogenesis observed.”

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Vitamin C may have anti-blood cancer properties

Vitamin C is known to have a number of health benefits, from preventing scurvy to limiting the buildup of fatty plaque in your arteries. Now a new study says we might soon be able to add another benefit: it may be able to block the progression of leukemia and other blood cancers.

Researchers at the NYU School of Medicine focused their work on an enzyme called TET2. This is found in hematopoietic stem cells (HSCs), the kind of stem cell typically found in bone marrow. The absence of TET2 is known to keep these HSCs in a pre-leukemic state; in effect priming the body to develop leukemia. The researchers showed that high doses of vitamin C can prevent, or even reverse that, by increasing the activity level of TET2.

In the study, in the journal Cell, they showed how they developed mice that could have their levels of TET2 increased or decreased. They then transplanted bone marrow with low levels of TET2 from those mice into healthy, normal mice. The healthy mice started to develop leukemia-like symptoms. However, when the researchers used high doses of vitamin C to restore the activity levels of TET2, they were able to halt the progression of the leukemia.

Now this doesn’t mean you should run out and get as much vitamin C as you can to help protect you against leukemia. In an article in The Scientist, Benjamin Neel, senior author of the study, says while vitamin C does have health benefits,  consuming large doses won’t do you much good:

“They’re unlikely to be a general anti-cancer therapy, and they really should be understood based on the molecular understanding of the many actions vitamin C has in cells.”

However, Neel says these findings do give scientists a new tool to help them target cells before they become leukemic.

Jordan reed

Bad toe forces Jordan Reed to take a knee: Photo courtesy FanRag Sports

Toeing the line: how unapproved stem cell treatment made matters worse for an NFL player  

American football players are tough. They have to be to withstand pounding tackles by 300lb men wearing pads and a helmet. But it wasn’t a crunching hit that took Washington Redskins player Jordan Reed out of the game; all it took to put the 6’2” 246 lb player on the PUP (Physically Unable to Perform) list was a little stem cell injection.

Reed has had a lingering injury problem with the big toe on his left foot. So, during the off-season, he thought he would take care of the issue, and got a stem cell injection in the toe. It didn’t quite work the way he hoped.

In an interview with the Richmond Times Dispatch he said:

“That kind of flared it up a bit on me. Now I’m just letting it calm down before I get out there. I’ve just gotta take my time, let it heal and strengthen up, then get back out there.”

It’s not clear what kind of stem cells Reed got, if they were his own or from a donor. What is clear is that he is just the latest in a long line of athletes who have turned to stem cells to help repair or speed up recovery from an injury. These are treatments that have not been approved by the Food and Drug Administration (FDA) and that have not been tested in a clinical trial to make sure they are both safe and effective.

In Reed’s case the problem seems to be a relatively minor one; his toe is expected to heal and he should be back in action before too long.

Stem cell researcher and avid blogger Dr. Paul Knoepfler wrote he is lucky, others who take a similar approach may not be:

“Fortunately, it sounds like Reed will be fine, but some people have much worse reactions to unproven stem cells than a sore toe, including blindness and tumors. Be careful out there!”

 

Brain stem cells unintentionally talk with brain tumors, allowing their spread

A stem cell’s capacity to lay quiet and, when needed, to self-renew plays a key role in restoring and maintaining the health of our organs. Unfortunately, cancer stem cells possess that same property allowing them to evade radiation and chemotherapy treatments which leads to tumor regrowth. And a CIRM-funded study published today in Cell shows the deviousness of these cancer cells goes even further. The Stanford research team behind the study found evidence that brain stem cells, which normally guide brain development and maintenance, unintentionally communicate with brain cancer cells in deadly tumors, called gliomas, providing them a means to invade other parts of the brain. But the silver lining to this scary insight is that it may lead to new treatment options for patients.

High grade gliomas do not end well
The most aggressive forms of glioma are called high grade gliomas and they carry devastating prognoses. For instance, the most common form of these tumors in children has a median survival of just 9 months with a 5-year survival of less than 1%. Surgery or anti-cancer therapies may help for a while but the tumor inevitably grows back.

MRI image of high grade glioma brain tumor (white mass on left). Image: Wikipedia

Researchers have observed that gliomas typically originate in the brain stem and very often invade a brain stem cell-rich area, called the subventrical zone (SVZ), that provides a space for the therapy-resistant cancer stem cells to hole up. This path of tumor spread is associated with a shorter time to relapse and poorer survival but the exact mechanism wasn’t known. The Stanford team hypothesized that SVZ brain stem cells release some factor that attracts the gliomas to preferentially invade that part of the brain.

To test this chemo-attraction idea, they mimicked cancer cell invasion in a specialized, dual compartment petri dish called a Boyden chamber. In the bottom compartment, they placed the liquid food, or media, that SVZ brain stem cells had been grown in. On the upper compartment, they placed the cancerous glioma cells. A porous, gelatin membrane between the two compartments acts as a barrier but allows the cells to receive signals from the lower compartment and migrate down into the media if a chemoattractant is present. And that’s what they saw: a significant glioma cell migration through the gelatin toward the brain stem cell media.

Boyden chamber assay. Image: Integr. Biol., 2009,1, 170-181

Pleiotrophin: an unintentional communicator with brain cancer cells
Something or somethings in the SVZ brain stem cell media had to be attracting the glioma cells. So, the Stanford team analyzed the composition of the media and identified four proteins that, when physically complexed together, had the same chemo-attraction ability as the media. They were pleased to find that one of the four proteins is pleiotrophin which is known to not only play a role in normal brain development and regeneration but also to increase glioma cell migration. And in this study, they showed that higher levels of pleiotrophin are present in the SVZ brain stem cell area compared to other regions of the brain. They went on to show that blocking the production of pleiotrophin in mice reduced the invasion of glioma cells into the SVZ region. This result suggests that blocking the release of pleiotrophin by brain stem cells in the SVZ could help prevent or slow down the spread of glioma in patients’ brains without the need of irradiating this important part of the brain.

The silver lining: hsp90 inhibitors have therapeutic promise

Michelle Monje, MD, PhD

To further explore this potential therapeutic approach, the team examined hsp90, one of the other three proteins complexed with pleiotrophin. Though it doesn’t have chemoattractant properties, it still is a necessary component and may act to stabilize pleiotrophin. It also turns out that inhibitors for hsp90 have already been developed in the clinic for treating various cancers. When the researchers in this study blocked hsp90 production in the SVZ region of mice, they observed a reduced invasion of glioma cells. Though clinical grade hsp90 inhibitors exist, team lead  Michelle Monje, MD, PhD – assistant professor of neurology, Stanford University – tells me that some tweaking of these drugs will be necessary to reach gliomas:

“Our challenge is to find an hsp90 inhibitor that penetrates the brain at effective concentrations.”

Once they find that inhibitor, it could provide new options, and hope, for people diagnosed with this dreadful cancer.

Treatments, cures and clinical trials: an in-person update on CIRM’s progress

Patients and Patient Advocates are at the heart of everything we do at CIRM. That’s why we are holding three free public events in the next few months focused on updating you on the stem cell research we are funding, and our plans for the future.

Right now we have 33 projects that we have funded in clinical trials. Those range from heart disease and stroke, to cancer, diabetes, ALS (Lou Gehrig’s disease), two different forms of vision loss, spinal cord injury and HIV/AIDS. We have also helped cure dozens of children battling deadly immune disorders. But as far as we are concerned we are only just getting started.

Over the course of the next few years, we have a goal of adding dozens more clinical trials to that list, and creating a pipeline of promising therapies for a wide range of diseases and disorders.

That’s why we are holding these free public events – something we try and do every year. We want to let you know what we are doing, what we are funding, how that research is progressing, and to get your thoughts on how we can improve, what else we can do to help meet the needs of the Patient Advocate community. Your voice is important in helping shape everything we do.

The first event is at the Gladstone Institutes in San Francisco on Wednesday, September 6th from noon till 1pm. The doors open at 11am for registration and a light lunch.

Gladstone Institutes

Here’s a link to an Eventbrite page that has all the information about the event, including how you can RSVP to let us know you are coming.

We are fortunate to be joined by two great scientists, and speakers – as well as being CIRM grantees-  from the Gladstone Institutes, Dr. Deepak Srivastava and Dr. Steve Finkbeiner.

Dr. Srivastava is working on regenerating heart muscle after it has been damaged. This research could not only help people recover from a heart attack, but the same principles might also enable us to regenerate other organs damaged by disease. Dr. Finkbeiner is a pioneer in diseases of the brain and has done ground breaking work in both Alzheimer’s and Huntington’s disease.

We have two other free public events coming up in October. The first is at UC Davis in Sacramento on October 10th (noon till 1pm) and the second at Cedars-Sinai in Los Angeles on October 30th (noon till 1pm). We will have more details on these events in the coming weeks.

We look forward to seeing you at one of these events and please feel free to share this information with anyone you think might be interested in attending.

CIRM weekly stem cell roundup: minibrain model of childhood disease; new immune insights; patient throws out 1st pitch

New human Mini-brain model of devastating childhood disease.
The eradication of Aicardi-Goutieres Syndrome (AGS) can’t come soon enough. This rare but terrible inherited disease causes the immune system to attack the brain. The condition leads to microcephaly (an abnormal small head and brain size), muscle spasms, vision problems and joint stiffness during infancy. Death or a persistent comatose state is common by early childhood. There is no cure.

Though animal models that mimic AGS symptoms are helpful, they don’t reflect the human disease closely enough to provide researchers with a deeper understanding of the mechanisms of the disease. But CIRM-funded research published this week may be a game changer for opening up new therapeutic strategies for the children and their families that are suffering from AGS.

Organoid mini-brains are clusters of cultured cells self-organized into miniature replicas of organs. Image courtesy of Cleber A. Trujillo, UC San Diego.

To get a clearer human picture of the disease, Dr. Alysson Muotri of UC San Diego and his team generated AGS patient-derived induced pluripotent stem cells (iPSCs). These iPSCs were then grown into “mini-brains” in a lab dish. As described in Cell Stem Cell, their examination of the mini-brains revealed an excess of chromosomal DNA in the cells. This abnormal build up causes various toxic effects on the nerve cells in the mini-brains which, according to Muotri, had the hallmarks of AGS in patients:

“These models seemed to mirror the development and progression of AGS in a developing fetus,” said Muotri in a press release. “It was cell death and reduction when neural development should be rising.”

In turns out that the excess DNA wasn’t just a bunch of random sequences but instead most came from so-called LINE1 (L1) retroelements. These repetitive DNA sequences can “jump” in and out of DNA chromosomes and are thought to be remnants of ancient viruses in the human genome. And it turns out the cell death in the mini-brains was caused by the immune system’s anti-viral response to these L1 retroelements. First author Charles Thomas explained why researchers may have missed this in their mouse models:

“We uncovered a novel and fundamental mechanism, where chronic response to L1 elements can negatively impact human neurodevelopment. This mechanism seems human-specific. We don’t see this in the mouse.”

The team went on to test the anti-retroviral effects of HIV drugs on their AGS models. Sure enough, the drugs decreased the amount of L1 DNA and cell growth rebounded in the mini-brains. The beauty of using already approved drugs is that the route to clinical trials is much faster and in fact a European trial is currently underway.

For more details, watch this video interview with Dr. Muotri:

New findings about immune cell development may open door to new cancer treatments
For those of you who suffer with seasonal allergies, you can blame your sniffling and sneezing on an overreaction by mast cells. These white blood cells help jump start the immune system by releasing histamines which makes blood vessels leaky allowing other immune cells to join the battle to fight disease or infection. Certain harmless allergens like pollen are mistaken as dangerous and can also cause histamine release which triggers tearing and sneezing.

Mast cells in lab dish. Image: Wikipedia.

Dysfunction of mast cells are also involved in some blood cancers. And up until now, it was thought a protein called stem cell factor played the key role in the development of blood stem cells into mast cells. But research reported this week by researchers at Karolinska Institute and Uppsala University found cracks in that previous hypothesis. Their findings published in Blood could open the door to new cancer therapies.

The researchers examine the effects of the anticancer drug Glivec – which blocks the function of stem cell factor – on mast cells in patients with a form of leukemia. Although the number of mature mast cells were reduced by the drug, the number of progenitor mast cells were not. The progenitors are akin to teenagers in that they’re at an intermediate stage of development, more specialized than stem cells but not quite mast cells. The team went on to confirm that stem cell factor was not required for the mast cell progenitors to survive, multiply and mature. Instead, their work identified two other growth factors, interleukin 3 and 6, as important for mast cell development.

In a press release, lead author Joakim Dahlin, explained how these new insights could lead to new therapies:

“The study increases our understanding of how mast cells are formed and could be important in the development of new therapies, for example for mastocytosis for which treatment with imatinib/Glivec is not effective. One hypothesis that we will now test is whether interleukin 3 can be a new target in the treatment of mast cell-driven diseases.”

Patient in CIRM-funded trial regains use of arms, hands and fingers will throw 1st pitch in MLB game.
We end this week with some heart-warming news from Asterias Biotherapeutics. You avid Stem Cellar readers will remember our story about Lucas Lindner several weeks back. Lucas was paralyzed from the neck down after a terrible car accident. Shortly after the accident, in June of 2016, he enrolled in Asterias’ CIRM-funded trial testing an embryonic stem cell-based therapy to treat his injury. And this Sunday, August 13th, we’re excited to report that due to regaining the use of his arms, hands and fingers since the treatment, he will throw out the first pitch of a Major League Baseball game in Milwaukee. Congrats to Lucas!

For more about Lucas’ story, watch this video produced by Asterias Biotherapeutics:

Reprogramming cells with a nanochip, electricity and DNA to help the body to heal itself

The axolotl, a member of the salamander family, has amazing regenerative abilities. You can cut off its limbs or crush its spinal cord and it will repair itself with no scarring. A human’s healing powers, of course, are much more limited.

To get around this unfortunate fact, the field of regenerative medicine aims to develop stem cell-based therapies that provide the body with that extra oomph of regenerative ability to rid itself of disease or injury. But most of the current approaches in development rely on complex and expensive manufacturing processes in clinical labs before the cells can be safely transplanted in a patient’s body. Wouldn’t it be nice if we could just give the cells already in our bodies some sort of spark to allow them to repair other diseased or damaged cells?

A research team at Ohio State University have taken a fascinating step toward that seemingly science fiction scenario. Reporting this week in Nature Nanotechnology, the scientists describe a technique that – with some DNA, a nanochip and an electric current placed on the skin – can help mice regrow blood vessels to restore dying tissue.

Researchers demonstrate a process known as tissue nanotransfection (TNT). In laboratory tests, this process was able to heal the badly injured legs of mice in just three weeks with a single touch of this chip. The technology works by converting normal skin cells into vascular cells, which helped heal the wounds. Photo: Wexner Medical Center/The Ohio State University

The foundation of this technique is cellular reprogramming. Induced pluripotent stem cells are the most well-known example of reprogramming in which adult cells, like skin or blood, are converted, in a lab dish, to an embryonic stem cell-like state by introducing a set of reprogramming genes into the cells. From there, the stem cells can be specialized into any cell type.

Now, you wouldn’t want to convert skin or blood cells inside the body into quasi embryonic stem cells because they could generate tumors due to their limitless ability to multiply. In this study, the researchers rely on a related method, direct reprogramming, that skips the stem cell step and uses a different set of genes to directly convert one cell type into another. They focused on the direct reprogramming of skin cells to endothelial cells, a key component of blood vessels, in mice that were given symptoms mimicking those seen in human injury-induced limb ischemia. This condition leads to a risk of gangrene and amputation when severely injured limbs deteriorate due to blocked blood vessels.

It’s one thing to introduce, or transfect, reprogramming genes into cells that are grown in the very controlled environment of a petri dish. But how the heck does one get DNA into skin cells on the leg of a mouse? That’s where the team’s tissue nano-transfection (TNT) approach comes into the picture. After rubbing off a small section of dead skin on the leg, the TNT device, composed of an nanochip electrode and tiny channels of liquid containing reprogramming DNA, is placed on the skin. A short pulse of electricity is applied which opens miniscule holes in the membranes of skin cells that are in contact with the electrode which allows the DNA to enter the cells. Here’s a short video describing the process:

Three weeks after the procedure, blood vessels had formed, blood flow was restored and the legs of the mice were saved. Team leader, Dr. Chandan Sen, described the results in an interview with National Public Radio:

“Not only did we make new cells, but those cells reorganized to make functional blood vessels that plumb with the existing vasculature and carry blood.”

It’s surprising that TNT reprogramming affects more than just the skin cells that were in contact with the device. But it appears the reprogramming instructions from the introduced DNA was somehow spread to other cells through tiny vesicles called exosomes. When Sen’s team extracted those exosomes and introduced them to skin cells in a petri dish, those cells specialized into blood vessel cells.

This result did attract some skepticism from the field. In the NPR story, stem cell expert Dr. Sean Morrison had this to say:

“There are all manners of claims of these vesicles. It’s not clear what these things are, and if it’s a real biological process or if it’s debris.”

Clearly, more work is needed before TNT is ready for clinical trials in humans. But if it holds up, the technique could bring us closer to the incredible self-healing powers of the axolotl.

How mice and zebrafish are unlocking clues to repairing damaged hearts

Bee-Gees

The Bee Gees, pioneers in trying to find ways to mend a broken heart. Photograph: Michael Ochs Archives

This may be the first time that the Australian pop group the Bee Gees have ever been featured in a blog about stem cell research, but in this case I think it’s appropriate. One of the Bee Gees biggest hits was “How can you mend a broken heart” and while it was a fine song, Barry and Robin Gibb (who wrote the song) never really came up with a viable answer.

Happily some researchers at the University of Southern California may succeed where Barry and Robin failed. In a study, published in the journal Nature Genetics, the USC team identify a gene that may help regenerate damaged heart tissue after a heart attack.

When babies are born they have a lot of a heart muscle cell called a mononuclear diploid cardiomyocyte or MNDCM for short. This cell type has powerful regenerative properties and so is able to rebuild heart muscle. However, as we get older we have less and less MNDCMs. By the time most of us are at an age where we are most likely to have a heart attack we are also most likely to have very few of these cells, and so have a limited ability to repair the damage.

Michaela Patterson, and her colleagues at USC, set out to find ways to change that. They found that in some adult mice less than 2 percent of their heart cells were MNDCMs, while other mice had a much higher percentage, around 10 percent. Not surprisingly the mice with the higher percentage of MNDCMs were better able to regenerate heart muscle after a heart attack or other injury.

So the USC team – with a little help from CIRM funding – dug a little deeper and did a genome-wide association study of these mice, that’s where they look at all the genetic variants in different individuals to see if they can spot common traits. They found one gene, Tnni3k, that seems to play a key role in generating MNDCMs.

Turning Tnni3K off in mice resulted in higher numbers of MNDCMs, increasing their ability to regenerate heart muscle. But when they activated Tnni3k in zebrafish it reduced the number of MNDCMs and impaired the fish’s ability to repair heart damage.

While it’s a long way from identifying something interesting in mice and zebrafish to seeing if it can be used to help people, Henry Sucov, the senior author on the study, says these findings represent an important first step in that direction:

“The activity of this gene, Tnni3k, can be modulated by small molecules, which could be developed into prescription drugs in the future. These small molecules could change the composition of the heart over time to contain more of these regenerative cells. This could improve the potential for regeneration in adult hearts, as a preventative strategy for those who may be at risk for heart failure.”

 

 

 

Stem cell stories that caught our eye: skin grafts fight diabetes, reprogramming the immune system, and Asterias expands spinal cord injury trial sites

Here are the stem cell stories that caught our eye this week.

Skin grafts fight diabetes and obesity.

An interesting new gene therapy strategy for fighting type 1 diabetes and obesity surfaced this week. Scientists from the University of Chicago made genetically engineered skin grafts that secrete a peptide hormone called glucagon-liked peptide-1 (GLP-1). This peptide is released by cells in the intestine and can lower blood sugar levels by stimulating pancreatic islet cells to secrete insulin (a hormone that promotes the absorption of glucose from the blood).

The study, which was published in the journal Cell Stem Cell, used CRISPR gene editing technology to introduce a mutation to the GLP-1 gene in mouse and human skin stem cells. This mutation stabilized the GLP-1 peptide, allowing it to hang around in the blood for longer. The team matured these stem cells into skin grafts that secreted the GLP-1 into the bloodstream of mice when treated with a drug called doxycycline.

When fed a high-fat diet, mice with a skin graft (left), genetically altered to secrete GLP-1 in response to the antibiotic doxycycline, gained less weight than normal mice (right). (Image source: Wu Laboratory, the University of Chicago)

On a normal diet, mice that received the skin graft saw a rise in their insulin levels and a decrease in their blood glucose levels, proving that the gene therapy was working. On a high fat diet, mice with the skin graft became obese, but when they were treated with doxycycline, GLP-1 secreted from their grafts reduced the amount of weight gain. So not only does their engineered skin graft technology look like a promising new strategy to treat type 1 diabetes patients, it also could be used to control obesity. The beauty of the technology is in its simplicity.

An article in Genetic Engineering and Biotechnology News that covered this research explained that Xiaoyang Wu, the senior author on the study, and his team “worked with skin because it is a large organ and easily accessible. The cells multiply quickly and are easily transplanted. And, transplanted cells can be removed, if needed. “Skin is such a beautiful system,” Wu says, noting that its features make it a perfect medium for testing gene therapies.”

Wu concluded that, “This kind of therapy could be potentially effective for many metabolic disorders.” According to GenBio, Wu’s team “is now testing the gene-therapy technique in combination with other medications.” They also hope that a similar strategy could be used to treat patients that can’t make certain proteins like in the blood clotting disorder hemophilia.

How to reprogram your immune system (Kevin McCormack)

When your immune system goes wrong it can cause all manner of problems, from type 1 diabetes to multiple sclerosis and cancer. That’s because an overactive immune system causes the body to attack its own tissues, while an underactive one leaves the body vulnerable to outside threats such as viruses. That’s why scientists have long sought ways to correct those immune dysfunctions.

Now researchers at the Gladstone Institutes in San Francisco think they have found a way to reprogram specific cells in the immune system and restore a sense of health and balance to the body. Their findings are published in the journal Nature.

The researchers identified a drug that targets effector T cells, which get our immune system to defend us against outside threats, and turns them into regulatory T cells, which control our immune system and stops it from attacking our own body.

Why would turning one kind of T cell into another be helpful? Well, in some autoimmune diseases, the effector T cells become overly active and attack healthy tissues and organs, damaging and even destroying them. By converting them to regulatory T cells you can prevent that happening.

In addition, some cancers can hijack regulatory T cells and suppress the immune system, allowing the disease to spread. By turning those cells into effector T cells, you can boost the immune system and give it the strength to fight back and, hopefully, kill the cancer.

In a news release, Gladstone Senior Investigator Sheng Ding, the lead scientists on the study, said their findings could have several applications:

“Our findings could have a significant impact on the treatment of autoimmune diseases, as well as on stem cell and immuno-oncology therapies.” 

Gladstone scientists Sheng Ding (right) and Tao Xu (left) discovered how to reprogram cells in our immune system. (Gladstone Institutes)

CIRM-funded spinal cord injury trial expands clinical sites

We have another update from CIRM’s clinical trial front. Asterias Biotherapeutics, which is testing a stem cell treatment for complete cervical (neck) spinal cord injury, is expanding its clinical sites for its CIRM-funded SCiStar Phase 1/2a trial. The company is currently treating patients at six sites in the US, and will be expanding to include two additional sites at Thomas Jefferson University Hospital in Philadelphia and the UC San Diego Medical Center, which is part of the UCSD Health CIRM Alpha Stem Cell Clinic.

In a company news release, Ed Wirth, Chief Medical Officer of Asterias said,

Ed Wirth

“We are excited about the clinical site openings at Thomas Jefferson University Hospital and UC San Diego Health. These sites provide additional geographical reach and previous experience with spinal cord injury trials to our SCiStar study. We have recently reported completion of enrollment in four out of five cohorts in our SCiStar study so we hope these institutions will also participate in a future, larger study of AST-OPC1.”

The news release also gave a recap of the trial’s positive (but still preliminary) results this year and their plans for completing trial enrollment.

“In June 2017, Asterias reported 9 month data from the AIS-A 10 million cell cohort that showed improvements in arm, hand and finger function observed at 3-months and 6-months following administration of AST-OPC1 were confirmed and in some patients further increased at 9-months. The company intends to complete enrollment of the entire SCiStar study later this year, with multiple safety and efficacy readouts anticipated during the remainder of 2017 and 2018.”

ViaCyte treats first patients in PEC-Direct stem cell trial for type 1 diabetes

Today, ViaCyte shared an update on its latest clinical trial for type 1 diabetes (T1D). The company is based in San Diego and is developing two stem cell-based products that attempt to replace the pancreatic beta islet cells that are attacked by the immune system of patients with T1D.

Their first product, called VC-01 or PEC-Encap, is an implantable device containing embryonic stem cells that develop into pancreatic progenitor cells, which are precursors to the islet cells destroyed by T1D. The hope is that when this device is transplanted under a patient’s skin, the progenitor cells will develop into mature insulin-secreting cells that can properly regulate the glucose levels in a patient’s blood. Because the cells are encapsulated in a protective semi-permeable membrane, hormones and nutrients can pass in and out of the device, but the implanted cells are guarded against the patient’s immune system. VC-01 is currently being tested in a Phase 1 clinical trial that is funded CIRM.

ViaCyte now has a second product called VC-02, or PEC-Direct, that also transplants pancreatic progenitors but in a device that allows a patient’s blood vessels to make direct contact with the implanted cells. This “direct vascularization” approach is being tested in patients that are at high risk for severe complications associated with T1D including hypoglycemia unawareness – a condition where patients fail to recognize when their blood glucose level drops to dangerously low levels because the typical symptoms of hypoglycemia fail to appear.

ViaCyte’s PEC-Direct device allows a patient’s blood vessels to integrate and make contact with the transplanted beta cells.

In May, ViaCyte announced that the US Food and Drug Administration (FDA) approved their Investigational New Drug (IND) application for PEC-Direct, which gave the company the green light to proceed with a Phase 1 safety trial to test the treatment in patients. ViaCyte’s pre-IND work on PEC-Direct was supported in part by a late stage preclinical grant from CIRM.

Today, the ViaCyte announced in a press release that it has treated its first patients with PEC-Direct in a Phase 1/2 trial at the University of Alberta Hospital in Edmonton, Alberta and at the UCSD Alpha Stem Cell Clinic in San Diego, California.

“The first cohort of type 1 diabetes patients is receiving multiple small-format cell-filled devices called sentinels in order to evaluate safety and implant viability.  These sentinel units will be removed at specific time points and examined histologically to provide early insight into the progression of engraftment and maturation into pancreatic islet cells including insulin-producing beta cells.”

The news release also revealed plans for enrollment of a larger cohort of patients by the end of 2017.

“A second cohort of up to 40 patients is expected to begin enrolling later this year to evaluate both safety and efficacy.  The primary efficacy measurement in the trial will be the clinically relevant production of insulin, as measured by the insulin biomarker C-peptide, in a patient population that has little to no ability to produce endogenous insulin at the time of enrollment.  Other important endpoints will be evaluated including injectable insulin usage and the incidence of hypoglycemic events.  ViaCyte’s goal is to demonstrate early evidence of efficacy in the first half of 2018 and definitive efficacy 6 to 12 months later.”

President and CEO of ViaCyte, Dr. Paul Laikind, is hopeful that PEC-Direct will give patients with high-risk T1D a better treatment option than what is currently available.

ViaCyte’s President & CEO, Paul Laikind

“There are limited treatment options for patients with high-risk type 1 diabetes to manage life-threatening hypoglycemic episodes. We believe that the PEC-Direct product candidate has the potential to transform the lives of these patients and we are excited to move closer to that goal with the initiation of clinical evaluation announced today.  This also represents a step towards a broader application of the technology.  We remain fully committed to developing a functional cure for all patients with insulin-requiring diabetes.  To that end, we are hard at work on next-generation approaches as well, and expect the work with PEC-Direct to further advance our knowledge and drive progress.”


Related links:

Family, faith and funding from CIRM inspire one patient to plan for his future

Caleb Sizemore speaks to the CIRM Board at the June 2017 ICOC meeting.

Having been to many conferences and meetings over the years I have found there is a really simple way to gauge if someone is a good speaker, if they have the attention of people in the room. You just look around and see how many people are on their phones or laptops, checking their email or the latest sports scores.

By that standard Caleb Sizemore is a spellbinding speaker.

Last month Caleb spoke to the CIRM Board about his experiences in a CIRM-funded clinical trial for Duchenne Muscular Dystrophy. As he talked no one in the room was on their phone. Laptops were closed. All eyes and ears were on him.

To say his talk was both deeply moving and inspiring is an understatement. I could go into more detail but it’s so much more powerful to hear it from  Caleb himself. His words are a reminder to everyone at CIRM why we do this work, and why we have to continue to do all that we can to live up to our mission statement and accelerate stem cell treatments to patients with unmet medical needs.

Video produced by Todd Dubnicoff/CIRM


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Stem Cell Stories that Caught our Eye: CRISPRing Human Embryos, brain stem cells slow aging & BrainStorm ALS trial joins CIRM Alpha Clinics

Here are the stem cell stories that caught our eye this week. Enjoy!

Scientists claim first CRISPR editing of human embryos in the US.

Here’s the big story this week. Scientists from Portland, Oregon claim they genetically modified human embryos using the CRISPR/Cas9 gene editing technology. While their results have yet to be published in a peer review journal (though the team say they are going to be published in a prominent journal next month), if they prove true, the study will be the first successful attempt to modify human embryos in the US.

A representation of an embryo being fertilized. Scientists can inject CRISPR during fertilization to correct genetic disorders. (Getty Images).

Steve Connor from MIT Technology Review broke the story earlier this week noting that the only reports of human embryo modification were published by Chinese scientists. The China studies revealed troubling findings. CRISPR caused “off-target” effects, a situation where the CRISPR machinery randomly introduces genetic errors in a cell’s DNA, in the embryos. It also caused mosaicism, a condition where the desired DNA sequences aren’t genetically corrected in all the cells of an embryo producing an individual with cells that have different genomes. Putting aside the ethical conundrum of modifying human embryos, these studies suggested that current gene editing technologies weren’t accurate enough to safely modify human embryos.

But a new chapter in human embryo modification is beginning. Shoukhrat Mitalipov (who is a member of CIRM’s Grants Working Group, the panel of scientific experts that reviews our funding applications) and his team from the Oregon Health and Science University said that they have developed a method to successfully modify donated human embryos that avoids the problems experienced by the Chinese scientists. The team found that introducing CRISPR at the same time an embryo was being fertilized led to successful correction of disease-causing mutations while avoiding mosaicism and “off-target” effects. They grew these embryos for a few days to confirm that the genetic modifications had worked before destroying them.

The MIT piece quoted a scientist who knows of Mitalipov’s work,

“It is proof of principle that it can work. They significantly reduced mosaicism. I don’t think it’s the start of clinical trials yet, but it does take it further than anyone has before.”

Does this discovery, if it’s true, open the door further for the creation of designer babies? For discussions about the future scientific and ethical implications of this research, I recommend reading Paul Knoepfler’s blog, this piece by Megan Molteni in Wired Magazine and Jessica Berg’s article in The Conversation.

Brain stem cells slow aging in mice

The quest for eternal youth might be one step closer thanks to a new study published this week in the journal Nature. Scientists from the Albert Einstein College of Medicine in New York discovered that stem cells found in an area of the brain called the hypothalamus can slow the aging process in mice.

The hypothalamus is located smack in the center of your brain near the brain stem. It’s responsible for essential metabolic functions such as making and secreting hormones, managing body temperature and controlling feelings of hunger and thirst. Because the body’s metabolic functions decline with age, scientists have suspected that the hypothalamus plays a role in aging.

The mouse hypothalamus. (NIH, Wikimedia).

In the current study, the team found that stem cells in the hypothalamus gradually disappear as mice age. They were curious whether the disappearance of these stem cells could jump start the aging process. When they removed these stem cells, the mice showed more advanced mental and physical signs of aging compared to untreated mice.

They also conducted the opposite experiment where they transplanted hypothalamic stem cells taken from baby mice (the idea being that these stem cells would exhibit more “youthful” qualities) into the brains of middle-aged mice and saw improvements in mental and physical functions and a 10% increase in lifespan.

So what is it about these specific stem cells that slows down aging? Do they replenish the aging brain with new healthy cells or do they secrete factors that keep the brain healthy? Interestingly, the scientists found that these stem cells secreted vesicles that contained microRNAs, which are molecules that regulate gene expression by turning genes on or off.

They injected these microRNAs into the brains of middle-aged mice and found that they reversed symptoms of aging including cognitive decline and muscle degeneration. Furthermore, when they removed hypothalamic stem cells from middle-aged mice and treated them with the microRNAs, they saw the same anti-aging effects.

In an interview with Nature News, senior author on the study, Dongsheng Cai, commented that hypothalamic stem cells could have multiple ways of regulating aging and that microRNAs are just one of their tools. For this research to translate into an anti-aging therapy, “Cai suspects that anti-ageing therapies targeting the hypothalamus would need to be administered in middle age, before a person’s muscles and metabolism have degenerated beyond a point that could be reversed.”

This study and its “Fountain of Youth” implications has received ample attention from the media. You can read more coverage from The Scientist, GenBio, and the original Albert Einstein press release.

BrainStorm ALS trial joins the CIRM Alpha Clinics

Last month, the CIRM Board approved $15.9 million in funding for BrainStorm Cell Therapeutic’s Phase 3 trial that’s testing a stem cell therapy to treat patients with a devastating neurodegenerative disease called amyotrophic lateral sclerosis or ALS (also known as Lou Gehrig’s disease).

The stem cell therapy, called NurOwn®, is made of mesenchymal stem cells extracted from a patient’s bone marrow. The stem cells are genetically modified to secrete neurotrophic factors that keep neurons in the brain healthy and prevent their destruction by diseases like ALS.

BrainStorm has tested NurOwn in early stage clinical trials in Israel and in a Phase 2 study in the US. These trials revealed that the treatment was “safe and well tolerated” and that “NurOwn also achieved multiple secondary efficacy endpoints, showing clear evidence of a clinically meaningful benefit.  Notably, response rates were higher for NurOwn-treated subjects compared to placebo at all time points in the study out to 24 weeks.”

This week, BrainStorm announced that it will launch its Phase 3 CIRM-funded trial at the UC Irvine (UCI) CIRM Alpha Stem Cell Clinic. The Alpha Clinics are a network of top medical centers in California that specialize in delivering high quality stem cell clinical trials to patients. UCI is one of four medical centers including UCLA, City of Hope, and UCSD, that make up three Alpha Clinics currently supporting 38 stem cell trials in the state.

Along with UCI, BrainStorm’s Phase 3 trial will also be conducted at two other sites in the US: Mass General Hospital in Boston and California Pacific Medical Center in San Francisco. Chaim Lebovits, President and CEO, commented,

“We are privileged to have UCI and Dr. Namita Goyal join our pivotal Phase 3 study of NurOwn. Adding UCI as an enrolling center with Dr. Goyal as Principal Investigator will make the treatment more accessible to patients in California, and we welcome the opportunity to work with this prestigious institution.”

Before the Phase 3 trial can launch at UCI, it needs to be approved by our federal regulatory agency, the Food and Drug Administration (FDA), and an Institutional Review Board (IRB), which is an independent ethics committee that reviews biomedical research on human subjects. Both these steps are required to ensure that a therapy is safe to test in patients.

With promising data from their Phase 1 and 2 trials, BrainStorm’s Phase 3 trial will likely get the green light to move forward. Dr. Goyal, who will lead the trial at the UCI Alpha Clinic, concluded:

“NurOwn is a very promising treatment with compelling Phase 2 data in patients with ALS; we look forward to further advancing it in clinical development and confirming the therapeutic benefit with Brainstorm.”