Stories that caught our eye: How dying cells could help save lives; could modified blood stem cells reverse diabetes?; and FDA has good news for patients, bad news for rogue clinics

Gunsmoke

Growing up I loved watching old cowboy movies. Invariably the hero, even though mortally wounded, would manage to save the day and rescue the heroine and/or the town.

Now it seems some stem cells perform the same function, dying in order to save the lives of others.

Researchers at Kings College in London were trying to better understand Graft vs Host Disease (GvHD), a potentially fatal complication that can occur when a patient receives a blood stem cell transplant. In cases of GvHD, the transplanted donor cells turn on the patient and attack their healthy cells and tissues.

Some previous research had found that using bone marrow cells called mesenchymal stem cells (MSCs) had some success in combating GvHD. But it was unpredictable who it helped and why.

Working with mice, the Kings College team found that the MSCs were only effective if they died after being transplanted. It appears that it is only as they are dying that the MSCs engage with the individual’s immune system, telling it to stop attacking healthy tissues. The team also found that if they kill the MSCs just before transplanting them into mice, they were just as effective.

In a news article on HealthCanal, lead researcher Professor Francesco Dazzi, said the next step is to see if this will apply to, and help, people:

“The side effects of a stem cell transplant can be fatal and this factor is a serious consideration in deciding whether some people are suitable to undergo one. If we can be more confident that we can control these lethal complications in all patients, more people will be able to receive this life saving procedure. The next step will be to introduce clinical trials for patients with GvHD, either using the procedure only in patients with immune systems capable of killing mesenchymal stem cells, or killing these cells before they are infused into the patient, to see if this does indeed improve the success of treatment.”

The study is published in Science Translational Medicine.

Genetically modified blood stem cells reverse diabetes in mice

When functioning properly, the T cells of our immune system keep us healthy by detecting and killing off infected, damaged or cancerous cells in our body. But in the case of type 1 diabetes, a person’s own T cells turn against the body by mistakenly targeting and destroying perfectly normal islet cells in the pancreas, which are responsible for producing insulin. As a result, the insulin-dependent delivery of blood sugar to the energy-hungry organs is disrupted leading to many serious complications. Blood stem cell transplants have been performed to treat the disease by attempting to restart the immune system. The results have failed to provide a cure.

Now a new study, published in Science Translational Medicine, appears to explain why those previous attempts failed and how some genetic rejiggering could lead to a successful treatment for type 1 diabetes.

An analysis of the gene activity inside the blood stem cells of diabetic mice and humans reveals that these cells lack a protein called PD-L1. This protein is known to play an important role in putting the brakes on T cell activity. Because T cells are potent cell killers, it’s important for proteins like PD-L1 to keep the activated T cells in check.

Cell based image for t 1 diabetes

Credit: Andrea Panigada/Nancy Fliesler

Researchers from Boston Children’s Hospital hypothesized that adding back PD-L1 may prevent T cells from the indiscriminate killing of the body’s own insulin-producing cells. To test this idea, the research team genetically engineered mouse blood stem cells to produce the PD-L1 protein. Experiments with the cells in a petri dish showed that the addition of PD-L1 did indeed block the attack-on-self activity. And when these blood stem cells were transplanted into a diabetic mouse strain, the disease was reversed in most of the animals over the short term while a third of the mice had long-lasting benefits.

The researchers hope this targeting of PD-L1 production – which the researchers could also stimulate with pharmacological drugs – will contribute to a cure for type 1 diabetes.

FDA’s new guidelines for stem cell treatments

Gottlieb

FDA Commissioner Scott Gottlieb

Yesterday Scott Gottlieb, the Commissioner at the US Food and Drug Administration (FDA), laid out some new guidelines for the way the agency regulates stem cells and regenerative medicine. The news was good for patients, not so good for clinics offering unproven treatments.

First the good. Gottlieb announced new guidelines encouraging innovation in the development of stem cell therapies, and faster pathways for therapies, that show they are both safe and effective, to reach the patient.

At the same time, he detailed new rules that provide greater clarity about what clinics can do with stem cells without incurring the wrath of the FDA. Those guidelines detail the limits on the kinds of procedures clinics can offer and what ways they can “manipulate” those cells. Clinics that go beyond those limits could be in trouble.

In making the announcement Gottlieb said:

“To be clear, we remain committed to ensuring that patients have access to safe and effective regenerative medicine products as efficiently as possible. We are also committed to making sure we take action against products being unlawfully marketed that pose a potential significant risk to their safety. The framework we’re announcing today gives us the solid platform we need to continue to take enforcement action against a small number of clearly unscrupulous actors.”

Many of the details in the announcement match what CIRM has been pushing for some years. Randy Mills, our previous President and CEO, called for many of these changes in an Op Ed he co-wrote with former US Senator Bill Frist.

Our hope now is that the FDA continues to follow this promising path and turns these draft proposals into hard policy.

 

 

 

 

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Surprise findings about bone marrow transplants could lead to more effective stem cell therapies

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Bone marrow transplant: Photo courtesy FierceBiotech

Some medical therapies have been around for so long that we naturally assume we understand how they work. That’s not always the case. Take aspirin for example. It’s been used for more than 4,000 years to treat pain and inflammation but it was only in the 1970’s that we really learned how it works.

The same is now true for bone marrow transplants. Thanks to some skilled research at the Fred Hutchinson Cancer Research Center in Seattle.

Bone marrow transplants have been used for decades to help treat deadly blood cancers such as leukemia and lymphoma. The first successful bone marrow transplant was in the late 1950’s, involving identical twins, one of whom had leukemia. Because the twins shared the same genetic make-up the transplant avoided potentially fatal problems like graft-vs-host-disease, where the transplanted cells attack the person getting them. It wasn’t until the 1970’s that doctors were able to perform transplants involving people who were not related or who did not share the same genetic make-up.

In a bone marrow or blood stem cell transplant, doctors use radiation or chemotherapy to destroy the bone marrow in a patient with, say, leukemia. Then cancer-free donor blood stem cells are transplanted into the patient to help create a new blood system, and rebuild their immune system.

Surprise findings

In the study, published in the journal Science Translational Medicine, the researchers were able to isolate a specific kind of stem cell that helps repair and rebuild the blood and immune system.

The team found that a small subset of blood stem cells, characterized by having one of three different kinds of protein on their surface – CD34 positive, CD45RA negative and CD90 positive – did all the work.

In a news release Dr. Hans-Peter Kiem, a senior author on the study, says some of their initial assumptions about how bone marrow transplants work were wrong:

“These findings came as a surprise; we had thought that there were multiple types of blood stem cells that take on different roles in rebuilding a blood and immune system. This population does it all.”

Tracking the cells

The team performed bone-marrow transplants on monkeys and then followed those animals over the next seven years, observing what happened as the donor cells grew and multiplied.

They tracked hundreds of thousands of cells in the blood and found that, even though the cells with those three proteins on the surface made up just five percent of the total blood supply, they were responsible for rebuilding the entire blood and immune system.

Study co-author Dr. Jennifer Adair said they saw evidence of this rebuilding within 10 days of the transplant:

“Our ability to track individual blood cells that developed after transplant was critical to demonstrating that these really are stem cells.”

Hope for the future

It’s an important finding because it could help researchers develop new ways of delivering bone marrow transplants that are both safer and more effective. Every year some 3,000 people die because they cannot find a matching donor. Knowing which stem cells are specifically responsible for an effective transplant could help researchers come up with ways to get around that problem.

Although this work was done in monkeys, the scientists say humans have similar kinds of stem cells that appear to act in the same way. Proving that’s the case will obviously be the next step in this research.

 

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.”

Stem cell stories that caught our eye: lab-grown blood stem cells and puffer fish have the same teeth stem cells as humans

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.

Scientists finally grow blood stem cells in the lab!

Two exciting stem cell studies broke through the politics-dominated headlines this week. Both studies, published in the journal Nature, demonstrated that human hematopoietic or blood stem cells can be grown in the lab.

This news is a big deal because scientists have yet to make bonafide blood stem cells from pluripotent stem cells or other human cells. These stem cells not only create all the cells in our blood and immune systems, but also can be used to develop therapies for patients with blood cancers and genetic blood disorders.

But to do these experiments, you need a substantial source of blood stem cells – something that has eluded scientists for decades. That’s where these two studies come to the rescue. One study was spearheaded by George Daley at the Boston Children’s Hospital in Massachusetts and the other was led by Shahin Rafii at the Weill Cornell Medical College in New York City.

Researchers have made blood stem cells and progenitor cells from pluripotent stem cells. Credit: Steve Gschmeissner Getty Images

George Daley and his team developed a strategy that matured human induced pluripotent stem cells (iPS cells) into blood-forming stem and progenitor cells. It’s a two-step process that first uses a cocktail of chemicals to make hemogenic endothelium, the embryonic tissue that generates blood stem cells. The second step involved treating these intermediate cells with a combination of seven transcription factors that directed them towards a blood stem cell fate.

These modified human blood stem cells were then transplanted into mice where they developed into blood stem cells that produced blood and immune cells. First author on the study, Ryohichi Sugimura, explained the applications that their technology could be used for in a Boston Children’s Hospital news release,

“This step opens up an opportunity to take cells from patients with genetic blood disorders, use gene editing to correct their genetic defect and make functional blood cells. This also gives us the potential to have a limitless supply of blood stem cells and blood by taking cells from universal donors. This could potentially augment the blood supply for patients who need transfusions.”

The second study by Shahin Rafii and his team at Cornell used a different strategy to generate blood-forming stem cells. Instead of genetically manipulating iPS cells, they selected a more mature cell type to directly reprogram into blood stem cells. Using four transcription factors, they successfully reprogrammed mouse endothelial cells, which line the insides of blood vessels, into blood-forming stem cells that repopulated the blood and immune systems of irradiated mice.

Raffii believe his method is simpler and more efficient than Daley’s. In coverage by Nature News, he commented,

“Using the most efficient method to generate stem cells matters because every time a gene is added to a batch of cells, a large portion of the batch fails to incorporate it and must be thrown out. There is also a risk that some cells will mutate after they are modified in the lab, and could form tumors if they are implanted into people.”

To play devil’s advocate, Daley’s technique might appeal more to some because the starting source of iPS cells is much easier to obtain and culture in the lab than endothelial cells that have to be extracted from the blood vessels of animals or people. Furthermore, Daley argued that his team’s method could “be made more efficient, and [is] less likely to spur tumor growth and other abnormalities in modified cells.”

The Nature News article compares the achievements of both studies and concluded,

“Time will determine which approach succeeds. But the latest advances have buoyed the spirits of researchers who have been frustrated by their inability to generate blood stem cells from iPS cells.”

 

Humans and puffer fish have the same tooth-making stem cells.

Here’s a fun fact for your next blind date: humans and puffer fish share the same genes that are responsible for making teeth. Scientists from the University of Sheffield in England discovered that the stem cells that make teeth in puffer fish are the same stem cells that make the pearly whites in humans. Their work was published in the journal PNAS earlier this week.

Puffer fish. Photo by pingpogz on Flickr.

But if you look at this puffer fish, you’ll see a dramatic difference between its smile and ours – their teeth look more like a beak. Research has shown that the tooth-forming stem cells in puffer fish produce tooth plates that form a beak-like structure, which helps them crush and consume their prey.

So why is this shared evolution between humans and puffer fish important when our teeth look and function so differently? The scientists behind this research believe that studying the pufferfish could unearth answers about tooth loss in humans. The lead author on the study, Dr. Gareth Fraser, concluded in coverage by Phys.org,

“Our study questioned how pufferfish make a beak and now we’ve discovered the stem cells responsible and the genes that govern this process of continuous regeneration. These are also involved in general vertebrate tooth regeneration, including in humans. The fact that all vertebrates regenerate their teeth in the same way with a set of conserved stem cells means that we can use these studies in more obscure fishes to provide clues to how we can address questions of tooth loss in humans.”

Stem Cell Stories That Caught our Eye: Making blood and muscle from stem cells and helping students realize their “pluripotential”

Stem cells offer new drug for blood diseases. A new treatment for blood disorders might be in the works thanks to a stem cell-based study out of Harvard Medical School and Boston Children’s hospital. Their study was published in the journal Science Translational Medicine.

The teams made induced pluripotent stem cells (iPSCs) from the skin of patients with a rare blood disorder called Diamond-Blackfan anemia (DBA) – a bone marrow disease that prevents new blood cells from forming. iPSCs from DBA patients were then specialized into blood progenitor cells, the precursors to blood cells. However, these precursor cells were incapable of forming red blood cells in a dish like normal precursors do.

Red blood cells were successfully made via induced pluripotent stem cells from a Diamond-Blackfan anemia patient. Image: Daley lab, Boston Children’s

Red blood cells were successfully made via induced pluripotent stem cells from a Diamond-Blackfan anemia patient. Image: Daley lab, Boston Children’s

The blood progenitor cells from DBA patients were then used to screen a library of compounds to identify drugs that could get the DBA progenitor cells to develop into red blood cells. They found a compound called SMER28 that had this very effect on progenitor cells in a dish. When the compound was tested in zebrafish and mouse models of DBA, the researchers observed an increase in red blood cell production and a reduction of anemia symptoms.

Getting pluripotent stem cells like iPSCs to turn into blood progenitor cells and expand these cells into a population large enough for drug screening has not been an easy task for stem cell researchers.

Co-first author on the study, Sergei Doulatov, explained in a press release, “iPS cells have been hard to instruct when it comes to making blood. This is the first time iPS cells have been used to identify a drug to treat a blood disorder.”

In the future, the researchers will pursue the questions of why and how SMER28 boosts red blood cell generation. Further work will be done to determine whether this drug will be a useful treatment for DBA patients and other blood disorders.

 

Students realize their “pluripotential”. In last week’s stem cell stories, I gave a preview about an exciting stem cell “Day of Discovery” hosted by USC Stem Cell in southern California. The event happened this past Saturday. Over 500 local middle and high school students attended the event and participated in lab tours, poster sessions, and a career resource fair. Throughout the day, they were engaged by scientists and educators about stem cell science through interactive games, including the stem cell edition of Family Feud and a stem cell smartphone videogame developed by USC graduate students.

In a USC press release, Rohit Varma, dean of the Keck School of Medicine of USC, emphasized the importance of exposing young students to research and scientific careers.

“It was a true joy to welcome the middle and high school students from our neighboring communities in Boyle Heights, El Sereno, Lincoln Heights, the San Gabriel Valley and throughout Los Angeles. This bright young generation brings tremendous potential to their future pursuits in biotechnology and beyond.”

Maria Elena Kennedy, a consultant to the Bassett Unified School District, added, “The exposure to the Keck School of Medicine of USC is invaluable for the students. Our students come from a Title I School District, and they don’t often have the opportunity to come to a campus like the Keck School of Medicine.”

The day was a huge success with students posting photos of their experiences on social media and enthusiastically writing messages like “stem cells are our future” and “USC is my goal”. One high school student acknowledged the opportunity that this day offers to students, “California currently has biotechnology as the biggest growing sector. Right now, it’s really important that students are visiting labs and learning more about the industry, so they can potentially see where they’re going with their lives and careers.”

You can read more about USC’s Stem Cell Day of Discovery here. Below are a few pictures from the event courtesy of David Sprague and USC.

Students have fun with robots representing osteoblast and osteoclast cells at the Stem Cell Day of Discovery event held at the USC Health Sciences Campus in Los Angeles, CA. February 4th, 2017. The event encourages students to learn more about STEM opportunities, including stem cell study and biotech, and helps demystify the fields and encourage student engagement. Photo by David Sprague

Students have fun with robots representing osteoblast and osteoclast cells at the USC Stem Cell Day of Discovery. Photo by David Sprague

Dr. Francesca Mariana shows off a mouse skeleton that has been dyed to show bones and cartilage at the Stem Cell Day of Discovery event held at the USC Health Sciences Campus in Los Angeles, CA. February 4th, 2017. The event encourages students to learn more about STEM opportunities, including stem cell study and biotech, and helps demystify the fields and encourage student engagement. Photo by David Sprague

Dr. Francesca Mariana shows off a mouse skeleton that has been dyed to show bones and cartilage. Photo by David Sprague

USC masters student Shantae Thornton shows students how cells are held in long term cold storage tanks at -195 celsius at the Stem Cell Day of Discovery event held at the USC Health Sciences Campus in Los Angeles, CA. February 4th, 2017. The event encourages students to learn more about STEM opportunities, including stem cell study and biotech, and helps demystify the fields and encourage student engagement. Photo by David Sprague

USC masters student Shantae Thornton shows students how cells are held in long term cold storage tanks at -195 celsius. Photo by David Sprague

Genesis Archila, left, and Jasmine Archila get their picture taken at the Stem Cell Day of Discovery event held at the USC Health Sciences Campus in Los Angeles, CA. February 4th, 2017. The event encourages students to learn more about STEM opportunities, including stem cell study and biotech, and helps demystify the fields and encourage student engagement. Photo by David Sprague

Genesis Archila, left, and Jasmine Archila get their picture taken at the USC Stem Cell Day of Discovery. Photo by David Sprague

New stem cell recipes for making muscle: new inroads to study muscular dystrophy (Todd Dubnicoff)

Embryonic stem cells are amazing because scientists can change or specialize them into virtually any cell type. But it’s a lot easier said than done. Researchers essentially need to mimic the process of embryo development in a petri dish by adding the right combination of factors to the stem cells in just the right order at just the right time to obtain a desired type of cell.

Making human muscle tissue from embryonic stem cells has proven to be a challenge. The development of muscle, as well as cartilage and bone, are well characterized and known to form from an embryonic structure called a somite. Researches have even been successful working out the conditions for making somites from animal stem cells. But those recipes didn’t work well with human stem cells.

Now, a team of researchers at the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA has overcome this roadblock by carrying out a systematic approach using human tissue. As described in Cell Reports, the scientists isolated somites from early human embryos and studied their gene activity. By comparing somites that were just beginning to emerge with fully formed somites, the researchers pinpointed differences in gene activity patterns. With this data in hand, the team added factors to the cells that were known to affect the activity of those genes. Through some trial and error, they produced a recipe – different than those used in animal cells – that could convert 90 percent of the human stem cells into somites in only four days. Those somites could then readily transform into muscle or bone or cartilage.

This new method for making human muscle will be critical for the lab’s goal to develop therapies for Duchenne muscular dystrophy, an incurable muscle wasting disease that strikes young boys and is usually fatal by their 20’s.

The new protocol turned 90 percent of human pluripotent stem cells into somite cells in just four days; those somite cells then generated (left to right) cartilage, bone and muscle cells.  Image: April Pyle Lab/UCLA

The new protocol turned 90 percent of human pluripotent stem cells into somite cells in just four days; those somite cells then generated (left to right) cartilage, bone and muscle cells. Image: April Pyle Lab/UCLA

Curing the Incurable through Definitive Medicine

“Curing the Incurable”. That was the theme for the first annual Center for Definitive and Curative Medicine (CDCM) Symposium held last week at Stanford University, in Palo Alto, California.

The CDCM is a joint initiative amongst Stanford Healthcare, Stanford Children’s Health and the Stanford School of Medicine. Its mission is to foster an environment that accelerates the development and translation of cell and gene therapies into clinical trials.

The research symposium focused on “the exciting first-in-human cell and gene therapies currently under development at Stanford in bone marrow, skin, cardiac, neural, pancreatic and neoplastic diseases.” These talks were organized into four different sessions: cell therapies for neurological disorders, stem cell-derived tissue replacement therapies, genome-edited cell therapies and anti-cancer cell-based therapies.

A few of the symposium speakers are CIRM-funded grantees, and we’ll briefly touch on their talks below.

Targeting cancer

The keynote speaker was Irv Weissman, who talked about hematopoietic or blood-forming stem cells and their value as a cell therapy for patients with blood disorders and cancer. One of the projects he discussed is a molecule called CD47 that is found on the surface of cancer cells. He explained that CD47 appears on all types of cancer cells more abundantly than on normal cells and is a promising therapeutic target for cancer.

Irv Weissman

Irv Weissman

“CD47 is the first gene whose overexpression is common to all cancer. We know it’s molecular mechanism from which we can develop targeted therapies. This would be impossible without collaborations between clinicians and scientists.”

 

At the end of his talk, Weissman acknowledged the importance of CIRM’s funding for advancing an antibody therapeutic targeting CD47 into a clinical trial for solid cancer tumors. He said CIRM’s existence is essential because it “funds [stem cell-based] research through the [financial] valley of death.” He further explained that CIRM is the only funding entity that takes basic stem cell research all the way through the clinical pipeline into a therapy.

Improving bone marrow transplants

judith shizuru

Judith Shizuru

Next, we heard a talk from Judith Shizuru on ways to improve current bone-marrow transplantation techniques. She explained how this form of stem cell transplant is “the most powerful form of cell therapy out there, for cancers or deficiencies in blood formation.” Inducing immune system tolerance, improving organ transplant outcomes in patients, and treating autoimmune diseases are all applications of bone marrow transplants. But this technique also carries with it toxic and potentially deadly side effects, including weakening of the immune system and graft vs host disease.

Shizuru talked about her team’s goal of improving the engraftment, or survival and integration, of bone marrow stem cells after transplantation. They are using an antibody against a molecule called CD117 which sits on the surface of blood stem cells and acts as an elimination signal. By blocking CD117 with an antibody, they improved the engraftment of bone marrow stem cells in mice and also removed the need for chemotherapy treatment, which is used to kill off bone marrow stem cells in the host. Shizuru is now testing her antibody therapy in a CIRM-funded clinical trial in humans and mentioned that this therapy has the potential to treat a wide variety of diseases such as sickle cell anemia, leukemias, and multiple sclerosis.

Tackling stroke and heart disease

img_1327We also heard from two CIRM-funded professors working on cell-based therapies for stroke and heart disease. Gary Steinberg’s team is using human neural progenitor cells, which develop into cells of the brain and spinal cord, to treat patients who’ve suffered from stroke. A stroke cuts off the blood supply to the brain, causing the death of brain cells and consequently the loss of function of different parts of the body.  He showed emotional videos of stroke patients whose function and speech dramatically improved following the stem cell transplant. One of these patients was Sonia Olea, a young woman in her 30’s who lost the ability to use most of her right side following her stroke. You can read about her inspiring recover post stem cell transplant in our Stories of Hope.

Dr. Joe Wu. (Image Source: Sean Culligan/OZY)

Dr. Joe Wu. (Image Source: Sean Culligan/OZY)

Joe Wu followed with a talk on adult stem cell therapies for heart disease. His work, which is funded by a CIRM disease team grant, involves making heart cells called cardiomyocytes from human embryonic stem cells and transplanting these cells into patient with end stage heart failure to improve heart function. His team’s work has advanced to the point where Wu said they are planning to file for an investigational new drug (IND) application with the US Food and Drug Administration (FDA) in six months. This is the crucial next step before a treatment can be tested in clinical trials. Joe ended his talk by making an important statement about expectations on how long it will take before stem cell treatments are available to patients.

He said, “Time changes everything. It [stem cell research] takes time. There is a lot of promise for the future of stem cell therapy.”

California’s stem cell agency rounds up the year with two more big hits

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CIRM Board meeting with  Jake Javier, CIRM Chair Jonathan Thomas, Vice Chair Sen. Art Torres (Ret.) and President/CEO Randy Mills

It’s traditional to end the year with a look back at what you hoped to accomplish and an assessment of what you did. By that standard 2016 has been a pretty good year for us at CIRM.

Yesterday our governing Board approved funding for two new clinical trials, one to help kidney transplant patients, the second to help people battling a disease that destroys vision. By itself that is a no small achievement. Anytime you can support potentially transformative research you are helping advance the field. But getting these two clinical trials over the start line means that CIRM has also met one of its big goals for the year; funding ten new clinical trials.

If you had asked us back in the summer, when we had funded only two clinical trials in 2016, we would have said that the chances of us reaching ten trials by the end of the year were about as good as a real estate developer winning the White House. And yet……..

Helping kidney transplant recipients

The Board awarded $6.65 million to researchers at Stanford University who are using a deceptively simple approach to help people who get a kidney transplant. Currently people who get a transplant have to take anti-rejection medications for the rest of their life to prevent their body rejecting the new organ. These powerful immunosuppressive medications are essential but also come with a cost; they increase the risk of cancer, infection and heart disease.

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CIRM President/CEO Randy Mills addresses the CIRM Board

The Stanford team will see if it can help transplant patients bypass the need for those drugs by injecting blood stem cells and T cells (which play an important role in the immune system) from the kidney donor into the kidney recipient. The hope is by using cells from the donor, you can help the recipient’s body more readily adjust to the new organ and reduce the likelihood the body’s immune system will attack it.

This would be no small feat. Every year around 17,000 kidney transplants take place in the US, and many people who get a donor kidney experience fevers, infections and other side effects as a result of taking the anti-rejection medications. This clinical trial is a potentially transformative approach that could help protect the integrity of the transplanted organ, and improve the quality of life for the kidney recipient.

Fighting blindness

The second trial approved for funding is one we are already very familiar with; Dr. Henry Klassen and jCyte’s work in treating retinitis pigmentosa (RP). This is a devastating disease that typically strikes before age 30 and slowly destroys a person’s vision. We’ve blogged about it here and here.

Dr. Klassen, a researcher at UC Irvine, has developed a method of injecting what are called retinal progenitor cells into the back of the eye. The hope is that these cells will repair and replace the cells damaged by RP. In a CIRM-funded Phase 1 clinical trial the method proved safe with no serious side effects, and some of the patients also reported improvements in their vision. This raised hopes that a Phase 2 clinical trial using a larger number of cells in a larger number of patients could really see if this therapy is as promising as we hope. The Board approved almost $8.3 million to support that work.

Seeing is believing

How promising? Well, I recently talked to Rosie Barrero, who took part in the first phase clinical trial. She told me that she was surprised how quickly she started to notice improvements in her vision:

“There’s more definition, more colors. I am seeing colors I haven’t seen in years. We have different cups in our house but I couldn’t really make out the different colors. One morning I woke up and realized ‘Oh my gosh, one of them is purple and one blue’. I was by myself, in tears, and it felt amazing, unbelievable.”

Amazing was a phrase that came up a lot yesterday when we introduced four people to our Board. Each of the four had taken part in a stem cell clinical trial that changed their lives, even saved their lives. It was a very emotional scene as they got a chance to thank the group that made those trials, those treatments possible.

We’ll have more on that in a future blog.

 

 

 

 

A single protein can boost blood stem cell regeneration

Today, CIRM-funded scientists from the UCLA Broad Stem Cell Research Center reported  in Nature Medicine that hematopoietic stem cells (HSCs) – blood stem cells that generate the cell in your blood and immune system – get a helping hand after injury from cells in the bone marrow called bone progenitor cells. By secreting a protein called dickkopf-1 (Dkk1), bone progenitor cells improve the recovery and survival of blood stem cells in a culture dish and in mice whose immune systems are suppressed by irradiation.

These findings build upon a related study published by the same UCLA team last month showing that deleting a single gene in HSCs boosts blood stem cell regeneration. We covered this initial story previously on the Stem Cellar, and you can refer to it for background on the importance of stimulating the regenerative capacity of HSCs in patients that need bone marrow transplants or have undergone radiation therapy for cancer.

Dkk1 boost blood stem cell regeneration

Senior author on the study, UCLA Professor Dr. John Chute, wanted to understand how the different cell types in the bone marrow environment, or niche, interact with HSCs to enhance their ability to recover from injury and regenerate the immune system. As mentioned earlier, he and his team found that bone progenitor cells secrete Dkk1 protein in response to injury caused by exposing mice to full body irradiation. Dkk1 promoted blood stem cell regeneration in the mice and increased their survival rates.

I inquired with Dr. Chute about this seemingly beneficial relationship between HSCs and cells in the bone marrow niche.

Dr. John Chute, UCLA

Dr. John Chute, UCLA

“The precise functions of bone cells, stromal cells and endothelial cells in regulating blood stem cell fate are not completely understood,” said Dr. Chute. “Our prior studies demonstrated that endothelial cells are necessary for blood stem cell regeneration after irradiation.  The current study suggests that bone progenitor cells are also necessary for normal blood stem cell regeneration after irradiation, and that this activity is mediated by secretion of Dkk1 by the bone progenitor cells.”

He further commented in a UCLA press release:

“The cellular niche is like the soil that surrounds the stem cell ‘seed’ and helps it grow and proliferate. Our hypothesis was that the bone progenitor cell in the niche may promote hematopoietic stem cell regeneration after injury.”

Not only did Dkk1 improve HSC regeneration in irradiated mice, it also boosted the regeneration of HSCs that were irradiated in a culture dish. On the other hand, when Dkk1 was deleted from HSCs in irradiated mice, the HSCs did not recover and regenerate. Diving in deeper, the team found that Dkk1 promotes blood stem cell regeneration by direct action on the stem cells and by indirectly increasing the secretion of the stem cell growth factor EGF by bone marrow blood vessels. Taken together, the team concluded that Dkk1 is necessary for blood stem cell recovery following injury/irradiation.

After radiation, blood cells (purple) regenerated in bone marrow when mice were given DKK1 intravenously (left), but not in those that received saline solution (right). (UCLA/Nature Medicine)

After radiation, blood cells (purple) regenerated in bone marrow when mice were given DKK1 (left), but not in those that received saline solution (right). (UCLA/Nature Medicine)

Future applications for blood stem cell regeneration

When I asked Dr. Chute how his current study on Dkk1 and HSCs relates to his previous study on boosting HSC regeneration by deleting a gene called Grb10, he explained:

“In this paper we discovered the role of a niche cell-derived protein, Dkk1, and how it promotes blood stem cell regeneration after myelosuppression in mice.  In the Cell Reports paper, we described our discovery of an adaptor protein, Grb10, which is expressed by blood stem cells and the inhibition of which also promotes blood stem cell regeneration after myelosuppression. So, these are two novel molecular mechanisms that regulate blood stem cell regeneration that could be therapeutically targeted.”

Both studies offer new strategies for promoting blood stem cell regeneration in patients who need to replenish their blood and immune systems following radiation treatments or bone marrow transplants.

Dr. Chute concluded:

“We are very interested in translating our observations into the clinic for the purpose of accelerating hematologic recovery in patients receiving chemotherapy or undergoing hematopoietic stem cell transplantation.”


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Here’s a new gene editing strategy to treat genetic blood disorders

If you’re taking a road trip across the country, you have a starting point and an ending point. How you go from point A to point B could be one of a million different routes, but the ultimate outcome is the same: reaching your final destination.

Yesterday scientists from St. Jude Children’s Research Hospital published exciting findings in the journal Nature Medicine on a new gene editing strategy that could offer a different route for treating genetic blood disorders such as sickle cell disease (SCD) and b-thalassemia.

The scientists used a gene editing tool called CRISPR. Unless you’ve been living under a rock, you’ve heard about CRISPR in the general media as the next, hot technology that could possibly help bring cures for serious diseases.

In simple terms, CRISPR acts as molecular scissors that facilitate cutting and pasting of DNA sequences at specific locations in the genome. For blood diseases like SCD and b-thalassemia, in which blood cells have abnormal hemoglobin, CRISPR gene editing offers ways to turn on and off genes that cause the clinical symptoms of these diseases.

Fetal vs. Adult hemoglobin

Before I get into the meat of this story, let’s take a moment to discuss hemoglobin. What is it? It’s a protein found in red blood cells that transports oxygen from the lungs to the rest of the body. Hemoglobin is made up of different subunits and the composition of these hemoglobin subunits change as newborns develop into adults.

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Healthy red blood cell (left), sickle cell (right).

Fetal hemoglobin (HbF) is comprised of a and g subunits while adult hemoglobin (HbA) is typically comprised of a and b subunits. Patients with SCD and b-thalassemia typically have mutations in the b globin gene. In SCD, this causes blood cells to take on an unhealthy, sickle cell shape that can clog vessels and eventually cause premature death. In b-thalassemia, the b-globin gene isn’t synthesized into protein at the proper levels and patients suffer from anemia (low red blood cell count).

One way that scientists are attempting to combat the negative side effects of mutant HbF is to tip the scales towards maintaining expression of the fetal g-globin gene. The idea spawned from individuals with hereditary persistence of fetal hemoglobin (HPFH), a condition where the hemoglobin composition fails to transition from HbF to HbA, leaving high levels of HbF in adult blood. Individuals who have HPFH and are predisposed to SCD or b-thalassemia amazingly don’t have clinical symptoms, suggesting that HbF plays either a protective or therapeutic role.

The current study is taking advantage of this knowledge in their attempt to treat blood disorders. Mitchell Weiss, senior author on the study and chair of the St. Jude Department of Hematology, explained the thought process behind their study:

“It has been known for some time that individuals with genetic mutations that persistently elevate fetal hemoglobin are resistant to the symptoms of sickle cell disease and beta-thalassemia, genetic forms of severe anemia that are common in many regions of the world. We have found a way to use CRISPR gene editing to produce similar benefits.”

CRISPRing blood stem cells for therapeutic purposes

Weiss and colleagues engineered red blood cells to have elevated levels of HbF in hopes of preventing symptoms of SCD. They used CRISPR to create a small deletion in a sequence of DNA, called a promoter, that controls expression of the hemoglobin g subunit 1 (HBG1) gene. The deletion elevates the levels of HbF in blood cells and closely mimics genetic mutations found in HPFH patients.

Weiss further explained the genome editing process in a news release:

Mitchell Weiss

Mitchell Weiss

“Our work has identified a potential DNA target for genome editing-mediated therapy and offers proof-of-principle for a possible approach to treat sickle cell and beta-thalassemia. We have been able to snip that DNA target using CRISPR, remove a short segment in a “control section” of DNA that stimulates gamma-to-beta switching, and join the ends back up to produce sustained elevation of fetal hemoglobin levels in adult red blood cells.”

The scientists genetically modified hematopoietic stem cells and blood progenitor cells from healthy individuals to make sure that their CRISPR gene editing technique was successful. After modifying the stem cells, they matured them into red blood cells in the lab and observed that the levels of HbF increased from 5% to 20%.

Encouraged by these results, they tested the therapeutic potential of their CRISPR strategy on hematopoietic stem cells from three SCD patients. While 25% of unmodified SCD blood stem cells developed red blood cells with a sickle cell shape under low-oxygen conditions (to induce stress), CRISPR edited SCD stem cells generated way fewer sickle cells (~4%) and had a higher level of HbF expression.

Many routes, one destination

The authors concluded that their genome editing technique is successful at switching hemoglobin expression from the adult form back to the fetal form. With further studies and safety testing, this strategy could be one day be developed into a treatment for patients with SCD and b-thalassemia

But the authors were also humble in their findings and admitted that there are many different genome editing strategies or routes for developing therapies for inherited blood diseases.

“Our results represent an additional approach to these existing innovative strategies and compare favorably in terms of the levels of fetal hemoglobin that are produced by our experimental system.”

My personal opinion is the more strategies thrown into the pipeline the better. As things go in science, many of these strategies won’t be successful in reaching the final destination of curing one of these diseases, but with more shots on goal, our chances of developing a treatment that works there are a lot higher.


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HIV/AIDS: Progress and Promise of Stem Cell Research

Our friends at Americans for Cures and Youreka Science have done it again. They’ve produced another whiteboard video about the progress and promise of stem cell research that’s so inspiring that it would probably make Darth Vader consider coming back to the light side. This time they tackled HIV.

If you haven’t watched one of these videos already, let me bring you up to speed. Americans for Cures is a non-profit organization, the legacy of the passing of Proposition 71, that supports patient advocates in the fight for stem cell research and cures. They’ve partnered with Youreka Science to produce eye-catching and informative videos to teach patients and the general public about the current state of stem cell research and the quest for cures for major diseases.

Stem cell cure for HIV?

Their latest video is on HIV, a well-known and deadly virus that attacks and disables the human immune system. Currently, 37 million people globally are living with HIV and only a few have been cured.

The video begins with the story of Timothy Brown, also known as the Berlin patient. In 2008 at the age of 40, he was dying of a blood cancer called acute myeloid leukemia and needed a bone marrow stem cell transplant to survive. Timothy was also HIV positive, so his doctor decided to use a bone marrow donor who happened to be naturally resistant to HIV infection. The transplanted donor stem cells were not only successful in curing Timothy of his cancer, but they also “rebooted his immune system” and cured his HIV.

Screen Shot 2015-12-23 at 2.21.18 PMSo why haven’t all HIV patients received this treatment? The video goes on to explain that bone marrow transplants are dangerous and only used in cancer patients who’ve run out of options. Additionally, only a small percentage of the world’s population is resistant to HIV and the chances that one of these individuals is a bone marrow donor match to a patient is very low.

This is where science comes to the rescue. Three research groups in California, all currently supported by CIRM funding, have proposed alternative solutions: they are attempting to make a patient’s own immune system resistant to HIV instead of relying on donor stem cells. Using gene therapy, they are modifying blood stem cells from HIV patients to be HIV resistant, and then transplanting the modified stem cells back into the same patient to rebuild a new immune system that can block HIV infection.

Screen Shot 2015-12-23 at 4.47.17 PM

All three groups have proven their stem cell technology works in animals; two of them are now testing their approach in early phase clinical trials in humans, and one is getting ready to do so. If these trials are successful, there is good reason to hope for an HIV cure and maybe even cures for other immune diseases.

My thoughts…

What I liked most about this video was the very end. It concludes by saying that these accomplishments were made possible not just by funding promising scientific research, but also by the hard work of HIV patients and patient advocate communities, who’ve brought awareness to the disease and influenced policy changes. Ultimately, a cure for HIV will depend on researchers and patient advocates working together to push the pace and to tackle any obstacles that will likely appear with testing stem cell therapies in human clinical trials.

I couldn’t say it any better than the final line of the video:

“We must remember that human trials will celebrate successes, but barriers will surface along with complications and challenges. So patience and understanding of the scientific process are essential.”