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.”


Related Links:

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.


Related links:

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.

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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.”

Helping patient’s fight back against deadliest form of skin cancer

Caladrius Biosciences has been funded by CIRM to conduct a Phase 3 clinical trial to treat the most severe form of skin cancer: metastatic melanoma. Metastatic melanoma is a disease with no effective treatment, only around 15 percent of people with it survive five years, and every year it claims an estimated 10,000 lives in the U.S.

The CIRM/Caladrius Clinical Advisory Panel meets to chart future of clinical trial

The CIRM/Caladrius Clinical Advisory Panel meets to chart future of clinical trial

The Caladrius team has developed an innovative cancer treatment that is designed to target the cells responsible for tumor growth and spread. These are called cancer stem cells or tumor-initiating cells. Cancer stem cells can spread in the body because they have the ability to evade the body’s immune defense and survive standard anti-cancer treatments such as chemotherapy. The aim of the Caladrius treatment is to train the body’s immune system to recognize the cancer stem cells and attack them.

Attacking the cancer

The treatment process involves taking a sample of a patient’s own tumor and, in a laboratory, isolating specific cells responsible for tumor growth . Cells from the patient’s blood, called “peripheral blood monocytes,” are also collected. The mononucleocytes are responsible for helping the body’s immune system fight disease. The tumor and blood cells (after maturation into dendritic cells) are then combined and incubated so that the patient’s immune cells become trained to recognize the cancer cells.

After the incubation period, the patient’s immune cells are injected back into their body where they generate an immune response to the cancer cells. The treatment is like a vaccine because it trains the body’s immune system to recognize and rapidly attack the source of disease.

Recruiting the patients

Caladrius has already dosed the first patient in the trial (which is double blinded so no one knows if the patient got the therapy or a placebo) and hopes to recruit 250 patients altogether.

This is the first Phase 3 trial that CIRM has funded so we’re obviously excited about its potential to help people battling this deadly disease.  In a recent news release David J. Mazzo, the CEO of Caladrius echoed this excitement, with a sense of cautious optimism:

“The dosing of the first patient in this Phase 3 trial is an important milestone for our Company and the timing underscores our focus on this program and our commitment to impeccable trial execution. We are delighted by the enthusiasm and productivity of the team at Jefferson University (where the patient was dosed) and other trial sites around the country and look forward to translating that into optimized patient enrollment and a rapid completion of the Phase 3 trial.”

And that’s the key now. They have the science. They have the funding. Now they need the patients. That’s why we are all working together to help Caladrius recruit patients as quickly as possible. Because their work perfectly reflects our mission of accelerating the development of stem cell therapies for patients with unmet medical needs.

You can learn more about what the study involves and who is eligible by clicking here.

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.”

Goodnight, Stem Cells: How Well Rested Cells Keep Us Healthy

Plenty of studies show that a lack of sleep is nothing but bad news and can contribute to a whole host of health problems like heart disease, poor memory, high blood pressure and obesity.

HSCs_Sleeping_graphic100x100

Even stem cells need rest to stay healthy

In a sense, the same holds true for the stem cells in our body. In response to injury, adult stem cells go to work by dividing and specializing into the cells needed to heal specific tissues and organs. But they also need to rest for long-lasting health. Each cell division carries a risk of introducing DNA mutations—and with it, a risk for cancer. Too much cell division can also deplete the stem cell supply, crippling the healing process. So it’s just as important for the stem cells to assume an inactive, or quiescent, state to maintain their ability to mend the body. Blood stem cells for instance are mostly quiescent and only divide about every two months to renew their reserves.

Even though the importance of this balance is well documented, exactly how it’s achieved is not well understood; that is, until now. Earlier this week, a CIRM-funded research team from The Scripps Research Institute (TSRI) reported on the identification of an enzyme that’s key in controlling the work-rest balance in blood stem cells, also called hematopoietic stem cells (HSCs). Their study, published in the journal Blood, could point the way to drugs that treat anemias, blood cancers, and other blood disorders.

Previous studies in other cell types suggested that this key enzyme, called ItpkB, might play a role in promoting a rested state in HSCs. Senior author Karsten Sauer explained their reasoning for focusing on the enzyme in a press release:

“What made ItpkB an attractive protein to study is that it can dampen activating signaling in other cells. We hypothesized that ItpkB might do the same in HSCs to keep them at rest. Moreover, ItpkB is an enzyme whose function can be controlled by small molecules. This might facilitate drug development if our hypothesis were true.”

Senior author Karsten Sauer is an associate professor at The Scripps Research Institute.

Senior author Karsten Sauer is an associate professor at The Scripps Research Institute.

To test their hypothesis, the team studied HSCs in mice that completely lacked ItpkB. Sure enough, without ItpkB the HSCs got stuck in the “on” position and continually multiplied until the supply of HSCs stores in the bone marrow were exhausted. Without these stem cells, the mice could no longer produce red blood cells, which deliver oxygen to the body or white blood cells, which fight off infection. As a result the animals died due to severe anemia and bone marrow failure. Sauer used a great analogy to describe the result:

“It’s like a car—you need to hit the gas pedal to get some activity, but if you hit it too hard, you can crash into a wall. ItpkB is that spring that prevents you from pushing the pedal all the way through.”

With this new understanding of how balancing stem cell activation and deactivation works, Sauer and his team have their sights set on human therapies:

“If we can show that ItpkB also keeps human HSCs healthy, this could open avenues to target ItpkB to improve HSC function in bone marrow failure syndromes and immunodeficiencies or to increase the success rates of HSC transplantation therapies for leukemias and lymphomas.”

The search for a cure: how stem cells could eradicate the AIDS virus

It’s hard to overstate just how devastating the AIDS crisis was at its peak in the U.S. – and still is today in many parts of the world. In 1995 almost 51,000 Americans died from the disease, the numbers of new cases were at almost record highs, and there were few effective therapies against the virus.

HIV/AIDS medications

HIV/AIDS medications

Today that picture is very different. New medications and combination therapies have helped reduce the death rate, in some cases turning HIV into a chronic rather than fatal condition. But even now there is no cure.

That’s why the news that the Food and Drug Administration (FDA) has approved a clinical trial, that we are funding, aimed at eradicating HIV in the body, was so welcome. This could be an important step towards the Holy Grail of AIDS therapies, curing the disease.

The project is headed by Dr. John Zaia at City of Hope near Los Angeles. The team, with researchers from Keck Medicine of the University of Southern California (USC) and Sangamo BioSciences, plans on using an individual’s own stem cells to beat the virus.  They will remove some blood stem cells from HIV-infected individuals, then treat them with zinc finger nucleases (ZFNs), a kind of molecular scissors, snipping off a protein the AIDS virus needs to infect those cells.

It’s hoped the re-engineered stem cells, when returned to the body, will help create a new blood and immune system that is resistant to the virus. And if the virus can’t infect any new immune cells it could, theoretically, die off. Check out the video we produced a few years back about the project:

Studies in the lab show this approach holds a lot of promise. In a news release announcing the start of the clinical trial, Dr. Zaia said now it’s time to see if it will work in people:

“While we have a number of drugs that are effective in holding HIV at bay, we have nothing that cures it. In addition, for many patients, these medications come with significant long-term problems so there is a real need for a therapy that can help eradicate the virus from a patient completely. That is where our work is focused.”

Like all Phase 1 trials this one is focused on making sure this approach is safe for people, and identifying what, if any, side-effects there are from the treatment. The first group of patients to be treated consists of people with HIV/AIDS who have not responded well to the existing medications.

This is the second trial that CIRM is funding focused on curing HIV/AIDS. Our first, involving the company Calimmune, began its human clinical trial in July 2013. You can read more about that work here.

We know that the road to a cure will not be simple or straightforward. There have been too many false claims of cures or miracle therapies over the years for any of us to want to fall victim to hope and hype. It may even be that the most realistic goal for these approaches is what is called a “functional cure”, one that doesn’t eliminate the virus completely but does eliminate the need to take antiretroviral pills every day.

But when compared to the dark days of 1995, a functional cure is a world away from certain death.