How a see-through fish could one day lead to substitutes for bone marrow transplants

Human blood stem cells

For years researchers have struggled to create human blood stem cells in the lab. They have done it several times with animal models, but the human kind? Well, that’s proved a bit trickier. Now a CIRM-funded team at UC San Diego (UCSD) think they have cracked the code. And that would be great news for anyone who may ever need a bone marrow transplant.

Why are blood stem cells important? Well, they help create our red and white blood cells and platelets, critical elements in carrying oxygen to all our organs and fighting infections. They have also become one of the most important weapons we have to combat deadly diseases like leukemia and lymphoma. Unfortunately, today we depend on finding a perfect or near-perfect match to make bone marrow transplants as safe and effective as possible and without a perfect match many patients miss out. That’s why this news is so exciting.

Researchers at UCSD found that the process of creating new blood stem cells depends on the action of three molecules, not two as was previously thought.

Zebrafish

Here’s where it gets a bit complicated but stick with me. The team worked with zebrafish, which use the same method to create blood stem cells as people do but also have the advantage of being translucent, so you can watch what’s going on inside them as it happens.  They noticed that a molecule called Wnt9a touches down on a receptor called Fzd9b and brings along with it something called the epidermal growth factor receptor (EGFR). It’s the interaction of these three together that turns a stem cell into a blood cell.

In a news release, Stephanie Grainger, the first author of the study published in Nature Cell Biology, said this discovery could help lead to new ways to grow the cells in the lab.

“Previous attempts to develop blood stem cells in a laboratory dish have failed, and that may be in part because they didn’t take the interaction between EGFR and Wnt into account.”

If this new approach helps the team generate blood stem cells in the lab these could be used to create off-the-shelf blood stem cells, instead of bone marrow transplants, to treat people battling leukemia and/or lymphoma.

CIRM is also funding a number of other projects, several in clinical trials, that involve the use of blood stem cells. Those include treatments for: Beta Thalassemia; blood cancer; HIV/AIDS; and Severe Combined Immunodeficiency among others.

Stem Cell Agency Board Approves 50th Clinical Trial

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Rich Lajara, the first patient treated in a CIRM-funded clinical trial

May 4th, 2011 marked a landmark moment for the California Institute for Regenerative Medicine (CIRM). On that day the Stem Cell Agency’s Board voted to invest in its first ever clinical trial, which was also the first clinical trial to use cells derived from embryonic stem cells. Today the Stem Cell Agency reached another landmark, with the Board voting to approve its 50th clinical trial.

“We have come a long way in the past seven and a half years, helping advance the field from its early days to a much more mature space today, one capable of producing new treatments and even cures,” says Jonathan Thomas, JD, PhD, Chair of the CIRM Board. “But we feel that in many ways we are just getting started, and we intend funding as many additional clinical trials as we can for as long as we can.”

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The project approved today awards almost $6.2 million to Angiocrine Bioscience Inc. to see if genetically engineered cells, derived from cord blood, can help alleviate or accelerate recovery from the toxic side effects of chemotherapy for people undergoing treatment for lymphoma and other aggressive cancers of the blood or lymph system.

“This is a project that CIRM has supported from an earlier stage of research, highlighting our commitment to moving the most promising research out of the lab and into people,” says Maria T. Millan, MD, President & CEO of CIRM. “Lymphoma is the most common blood cancer and the 6th most commonly diagnosed cancer in California. Despite advances in therapy many patients still suffer severe complications from the chemotherapy, so any treatment that can reduce those complications can not only improve quality of life but also, we hope, improve long term health outcomes for patients.”

The first clinical trial CIRM funded was with Geron, targeting spinal cord injury. While Geron halted the trial for business reasons (and returned the money, with interest) the mantle was later picked up by Asterias Biotherapeutics, which has now treated 25 patients with no serious side effects and some encouraging results.

Rich Lajara was part of the Geron trial, the first patient ever treated in a CIRM-funded clinical trial. He came to the CIRM Board meeting to tell his story saying when he was injured “I knew immediately I was paralyzed. I thought this was the end, little did I know this was just the beginning. I call it being in the wrong place at the right time.”

When he learned about the Geron clinical trial he asked how many people had been treated with stem cells. “Close to none” he was told. Nonetheless he went ahead with it. He says he has never regretted that decision, knowing it helped inform the research that has since helped others.

Since that first trial the Stem Cell Agency has funded a wide range of projects targeting heart disease and stroke, cancer, diabetes, HIV/AIDS and several rare diseases. You can see the full list on the Clinical Trials Dashboard page on our website.

Rich ended by saying: “CIRM has proven how much can be achieved if we invest in cutting-edge medical research. As most of you here probably know, CIRM’s funding from Proposition 71 is about to run out. If I had just one message I wanted people to leave with today it would be this, I will do everything I can to make sure the agency gets refunded and I hope that all of you will join me in that fight. I’m excited for the world of stem cells, particularly in California and can’t wait to see what’s on the horizon.”

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The CIRM Board also took time today to honor Dr. Bert Lubin, who is stepping down after serving almost eight years on the Board.

When he joined the Board in February, 2011 Dr. Lubin said: “I hope to use my position on this committee to advocate for stem cell research that translates into benefits for children and adults, not only in California but throughout the world.”

Over the years he certainly lived up to that goal. As a CIRM Board member he has supported research for a broad range of unmet medical needs, and specifically for curative treatments for children born with a rare life-threatening conditions such as Sickle Cell Disease and Severe Combined Immunodeficiency (SCID) as well as  treatments to help people battling vision destroying diseases.

As the President & CEO of Children’s Hospital Oakland (now UCSF Benioff Children’s Hospital Oakland) Dr. Lubin was a leader in helping advance research into new treatments for sickle cell disease and addressing health disparities in diseases such as asthma, diabetes and obesity.

Senator Art Torres said he has known Dr. Lubin since the 1970’s and in all that time has been impressed by his devotion to patients, and his humility, and that all Californians should be grateful to him for his service, and his leadership.

Dr. Lubin said he was “Really grateful to be on the Board and I consider it an honor to be part of a group that benefits patients.”

He said he may be stepping down from the CIRM Board but that was all: “I am going to retire the word retirement. I think it’s a mistake to stop doing work that you find stimulating. I’m going to repurpose the rest of my life, and work to make sure the treatments we’ve helped develop are available to everyone. I am so proud to be part of this. I am stepping down, but I am devoted to doing all I can to ensure that you get the resources you need to sustain this work for the future.”

Mechanical forces are the key to speedy recovery after blood cancer treatment

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Mesenchymal stem cells grown on a surface with specialized mechanical properties. Image courtesy of Krystyn Van Vliet at MIT.

Blood cancers, such as leukemia and lymphoma, are projected to be responsible for 10% of all new cancer diagnoses this year. These types of cancers are often treated by killing the patient’s bone marrow (the site of blood cell manufacturing), with a treatment called irradiation. While effective for ridding the body of cancerous cells, this treatment also kills healthy blood cells. Therefore, for a time after the treatment, patients are particularly vulnerable to infections, because the cellular components of the immune system are down for the count.

Now scientists at MIT have devised a method to make blood cells regenerate faster and  minimize the window for opportunistic infections.

Using multipotent stem cells (stem cells that are able to become multiple cell types) grown on a new and specialized surface that mimics bone marrow, the investigators changed the stem cells into different types of blood cells. When transplanted into mice that had undergone irradiation, they found that the mice recovered much more quickly compared to mice given stem cells grown on a more traditional plastic surface that does not resemble bone marrow as well.

This finding, published in the journal Stem Cell Research and Therapy, is particularly revolutionary, because it is the first time researchers have observed that mechanical properties can affect how the cells differentiate and behave.

The lead author of the study attributes the decreased recovery time to the type of stem cell that was given to mice compared to what humans are normally given after irradiation. Humans are given a stem cell that is only able to become different types of blood cells. The mice in this study, however, were give a stem cell that can become many different types of cells such as muscle, bone and cartilage, suggesting that these cells somehow changed the bone marrow environment to promote a more efficient recovery. They attributed a large part of this phenomenon to a secreted protein call ostepontin, which has previously been describe in activating the cells of the immune system.

In a press release, Dr. Viola Vogel, a scientist not related to study, puts the significance of these findings in a larger context:

“Illustrating how mechanopriming of mesenchymal stem cells can be exploited to improve on hematopoietic recovery is of huge medical significance. It also sheds light onto how to utilize their approach to perhaps take advantage of other cell subpopulations for therapeutic applications in the future.”

Dr. Krystyn Van Vliet, explains the potential to expand these findings beyond the scope of just blood cancer treatment:

“You could imagine that by changing their culture environment, including their mechanical environment, MSCs could be used for administration to target several other diseases such as Parkinson’s disease, rheumatoid arthritis, and others.”

 

New stem cell approach targeting deadly blood cancers

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Every four minutes someone in the US is diagnosed with a blood cancer. It might be lymphoma or leukemia, myeloma or myelodysplastic syndromes (MDS). While we have made great strides in treating some of these over the years, we still have a long way to go. Need proof? Well, every nine minutes someone in the US dies from a blood cancer.

Because of that need, the CIRM Board last week approved $3.5 million to help fund the search for a more effective, more efficient way to treat people suffering from blood cancer.

The Board funded a program by Angiocrine Biosciences, a San Diego-based company that is developing a new method for transplanting cord blood into patients.

Now cord blood transplants have been around for decades and they can be very effective. But they can also cause serious, even life-threatening complications. And they have limitations. For example some cord blood units are small and don’t have as many stem cells as the doctors would like. As a result, patients may need to spend longer in the hospital recovering from the procedure, putting them at increased risk of viral infections or pneumonia. Alternatively, doctors could use more than one cord blood unit for each transplant and while that seems to be an effective alternative, some studies suggest it can also carry an increased risk for serious complications such as Graft-versus-host disease (GVHD) where the newly transplanted cells attack the patient’s body.

To get around these issues, Angiocrine is developing a product called AB-110. This takes stem cells from cord blood, uses a specialized manufacturing facility to expand their numbers and then mixes them with genetically modified endothelial cells, the kind of cell that forms the lining of blood vessels.

It’s hoped that AB-110 will reduce the complications and increase the chances the transplanted cells will successfully engraft, meaning they start growing and creating new, healthy, blood cells.

In a news release CIRM’s President and CEO, C. Randal Mills, PhD, says this program fits in perfectly with our mission of accelerating stem cell treatments to patients with unmet medical needs:

“This project aims to do precisely that, speeding up the body’s ability to create new white blood cells and platelets – both essential qualities when treating deadly diseases like leukemia and lymphoma. Under CIRM 2.0, we are trying to create a pipeline of products that move out of the lab and into clinical trials in people, and we’re hopeful this program will demonstrate it’s potential and get approval from the Food and Drug Administration (FDA) to begin a clinical trial.”

Everyone at Angiocrine and CIRM will work as hard as we can to move this research toward a clinical trial as fast as we can. But in the meantime there are tens of thousands of critically ill people in desperate need of a life-saving transplant.

One way of helping those in need is for new parents to donate their child’s umbilical cord blood to the state’s umbilical cord blood collection program. This is a safe procedure that doesn’t harm the baby but could save someone’s life.

The cord blood program is housed at the UC Davis Institute for Regenerative Cures – a facility CIRM helped build and where we fund many great projects. This program is particularly important because it collects and stores cord blood units that reflect the state’s diverse communities, and that are available to all those in need of a transplant.

The bank also is a rich source of cord blood units for research, particularly for stem cell research, which will hopefully lead to even more effective therapies in the future.

Sonic Hedgehog provides pathway to fight blood cancers

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

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

For a lot of people Sonic Hedgehog is a video game. But for stem cell researcher Dr. Catriona Jamieson it is a signaling pathway in the body that offers a way to tackle and defeat some deadly blood cancers.

Dr. Jamieson – a researcher at the University of California, San Diego (UCSD) – has a paper published online today in The Lancet Haematology that highlights the safety and dosing levels for a new drug to treat a variety of blood cancers. CIRM funding helped Dr. Jamieson develop this work.

The drug targets cancer stem cells, the kind of cell that is believed to be able to lie dormant and evade anti-cancer therapies before springing back into action, causing a recurrence of the cancer. The drug coaxes the cancer stem cells out of their hiding space in the bone marrow and gets them to move into the blood stream where they can be destroyed by chemotherapy.

In a news release Dr. Jamieson says the drug – known by the catchy name of PF-04449913 – uses the sonic Hedgehog signaling pathway, an important regulator of the way we develop, to attack the cancer:

“This drug gets that unwanted house guest to leave and never come back. It’s a significant step forward in treating people with refractory or resistant myeloid leukemia, myelodysplastic syndrome and myelofibrosis. It’s a bonus that the drug can be administered as easily as an aspirin, in a single, daily oral tablet.”

The goal of this first-in-human study was to test the drug for safety; so 47 adults with blood and marrow cancer were given daily doses of the drug for up to 28 days. Those who were able to tolerate the dosage, without experiencing any serious side effects, were then given a higher dose for the next 28 days. Those who experienced problems were taken off the therapy.

Of the 47 people who started the trial in 2010, 28 experienced side effects. However, only three of those were severe. The drug showed signs of clinical activity – meaning it seemed to have an impact on the disease – in 23 people, almost half of those enrolled in the study.

Because of that initial promise it is now being tested in five different Phase 2 clinical trials. Dr. Jamieson says three of those trials are at UCSD:

“Our hope is that this drug will enable more effective treatment to begin earlier and that with earlier intervention, we can alter the course of disease and remove the need for, or improve the chances of success with, bone marrow transplantation. It’s all about reducing the burden of disease by intervening early.”

Stem cell stories that caught our eye: young blood, cord blood, and blood cancers

Here are some stem cell stories that caught our eye this past week. Some are groundbreaking science, others are of personal interest to us, and still others are just fun.

Pinning down young blood’s rejuvenating power. A trio of studies in the past week provided more evidence that giving older mice the blood of younger mice can rejuvenate some aspect of their function to a younger state. This has been shown for some years with various tissues, such as CIRM grantee Irina Conboy’s work at UC Berkeley looking at revitalizing older muscle. The recent studies all showed improvement in various aspects of brain function. Most important, the studies started to uncover some reasons for why the young blood could be beneficial when introduced into older animals. Conboy has suggested that one thing it does is provide an environment that lets muscle stem cells do a better job. The three current teams’ work suggests there are probably many factors at play in the young blood. The Boston Globe focused on the work of the Harvard team but puts all three projects in perspective. The San Francisco Business Times focused on the Stanford work and includes an extensive Q&A with the lead researcher.

Expanding cord blood could expand uses. The blood-forming stem cells found in umbilical cord blood have proven extremely valuable as a part of therapy for certain blood cancers. The problem with them is there just are not enough of them in a single cord to treat anyone large than a nine or 10-year-old child. That means when an adult needing a blood stem cell transplant can’t find a matching adult donor and has to resort to cord blood, they receive cells from two cords doubling the chance for severe side effect. Now, a team at Mount Sinai School of Medicine in New York has found a way to get cord blood stem cells to proliferate in the lab in greater numbers than anyone has in the past. They accomplished the trick by resetting the genetic switches that turn genes on and off. Genetic Engineering and Biotechnology News ran a description of the work.

Deciding on banking cord blood. I handle many desperate patient calls here at CIRM, and occasionally get a call from a parent wanting advice about banking their soon-to-be-born child’s cord blood. While I never offer specific advice, I do try to talk through a few factual issues for them to consider, such as the limitation on the number of cells in the cord discussed above. In this Huffington Post blog a mom walks through her family’s decision process for two different pregnancies that came to different, though pretty logical, conclusions for each. She raises many important considerations. However, note that toward the end when she talks about research “advancing” for several diseases, for all those diseases many more years of research will be needed before cord blood therapies become a reality if they ever do.

Blood cancers vs. blood stem cells. One of the difficulties of treating blood cancers is you often end up killing off the vital blood forming stem cells at the same time you destroy the cancer cells. A team at Dartmouth has developed a method to make it easier to distinguish between the stem cells and the cancer cells. Knowing this difference should help researchers find more specific cancer therapies that can destroy the cancer without harming the needed stem cells. Science Codex posted the press release from the medical school. You can read about projects CIRM funds in the field on our leukemia fact sheet.

Don Gibbons