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.”

Stem Cell Profiles in Courage: Karl’s Fight with Cancer

Karl Trede

Karl Trede

When I think of a pioneer I have an image in my head of people heading west across the Americans plains in the 18th century, riding in a covered wagon pulled by weary oxen.

Karl Trede doesn’t fit that image at all. He is a trim, elegant man who has a ready smile and a fondness for Hawaiian shirts. But he is no less a pioneer for all that. That’s why we profiled him in our 2016 Annual Report.

In 2006 Karl was diagnosed with cancer of the throat. He underwent surgery to remove his vocal chords and thought he had beaten the cancer. A few years later, it came back. That was when Karl became the first person ever treated in a CIRM-funded clinical trial testing a new anti-tumor therapy targeting cancer stem cells that so far has helped hold the disease at bay.

Here is Karl’s story, in his own words:

“I had some follow-up tests and those showed spots in my lungs. Over the course of several years, they saw those spots grow, and we knew the cancer had spread to my lungs. I went to Stanford and was told there was no effective treatment for it, fortunately it was slow growing.

Then one day they said we have a new clinical trial we’re going to start would you be interested in being part of it.

I don’t believe I knew at the time that I was going to be the first one in the trial [now that’s what I call a pioneer] but I thought I’d give it a whirl and I said ‘Sure’. I wasn’t real concerned about being the first in a trial never tested in people before. I figured I was going to have to go someday so I guess if I was the first person and something really went wrong then they’d definitely learn something; so, to me, that was kind of worth my time.

Fortunately, I lasted 13 months, 72 treatments with absolutely no side effects. I consider myself really lucky to have been a part of it.

It was an experience for me, it was eye opening. I got an IV infusion, and the whole process was 4 hours once a week.

Dr. Sikic (the Stanford doctor who oversees the clinical trial) made it a practice of staying in the room with me when I was getting my treatments because they’d never tried it in people, they’d tested it in mice, but hadn’t tested it in people and wanted to make sure they were safe and nothing bad happened.

The main goals of the trial were to define what the side effects were and what the right dose is and they got both of those. So I feel privileged to have been a part of this.

My wife and I (Vita) have four boys. They’re spread out now – two in the San Francisco Bay Area, one in Oregon and one in Nevada. But we like to get together a few times a year. They’re all good cooks, so when we have a family get together there’s a lot of cooking involved.

The Saturday after Thanksgiving, in 2015, the boys decided they wanted to have a rib cook-off for up to around 30 people and I can proudly say that I kicked their ass on the rib cook-off. I have an electric cooker and I just cook ‘em slow and long. I do a cranberry sauce, just some home made bbq sauces

I’m a beef guy, I love a good steak, a good ribeye or prime rib, I make a pretty mean Oso bucco, I make a good spaghetti sauce, baked chicken with an asparagus mousse that is pretty good.

I just consider myself a lucky guy.”

Karl Trede with CIRM President Randy Mills at the 2016 December Board meeting.

Karl Trede with CIRM President Randy Mills at the 2016 December Board meeting.


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Stem cell stories that caught our eye: designer socks for cancer patients, stem-cell derived stomachs and fighting off bone infections

Inspiring cancer patients with designer socks. (Karen Ring)
Here’s a motivating story we found in the news this week about a cancer survivor who’s bringing inspiration to other cancer patients with designer socks. Yes, you read that correctly, socks.

Jake Teitelbaum is a student at Wake Forest University and suffers from a rare form of blood cancer called Refractory Hodgkin’s lymphoma. Since his diagnosis, Jake has been admitted to hospitals multiple times. Each time he received a welcome package of a gown and a pair of beige, “lifeless” socks. After his fifth welcome package, this time to receive a life-saving stem cell treatment, Jake had had enough of the socks.

He explained in a story by USA Today College,

“[Those socks] represented chemotherapy and being in isolation. They were the embodiment of that experience.”

Jake ditched the hospital socks and started bringing his own to prove that his cancer didn’t define him. Even though his cancer kept coming back, Jake wanted to prove he was just as resilient.

Jake Teitelbaum

Jake Teitelbaum

Feeling liberated and in control, Jake decided to share his socks with other patients by starting the Resilience Project. Patients can go to the Resilience website and design their own socks that represent their experiences with cancer. The Resilience project also raises money for cancer patients and their families.

“We provide tangible benefits and create fun socks, but what we’re doing comes back to the essence of resilience,” said Jake. “These terrible circumstances where we’re at our most vulnerable also give us the unique opportunity to grow.”

Jake was declared cancer free in October of 2016. You can learn more about the Resilience project on their website and by watching Jake’s video below.

 

Feeding disease knowledge with stem cell-derived stomach cells.
Using educated guess work and plenty of trial and error in the lab, researchers around the world have successfully generated many human tissues from stem cells, including heart muscle cells, insulin-producing cells and nerve cells to name just a few. Reporting this week in Nature, stem cell scientists at Cincinnati’s Children Hospital have a new cell type under their belt. Or maybe I should say above their belt, because they have devised a method for coaxing stem cells to become stomach mini organs that can be studied in a petri dish.

Confocal microscopic image shows tissue-engineered human stomach tissues from the corpus/fundus region, which produce acid and digestive enzymes. Image: Cincinnati Children’s Hospital Medical Center

Confocal microscopic image shows tissue-engineered human stomach tissues from the corpus/fundus region, which produce acid and digestive enzymes. Image: Cincinnati Children’s Hospital Medical Center

With this method in hand, the team is poised to make new discoveries about how the stomach forms during human development and to better understand stomach diseases. In a press release, team lead Jim Wells pointed out the need to find new therapies for stomach disease:

“Diseases of the stomach impact millions of people in the United States and gastric [stomach] cancer is the third leading cause of cancer-related deaths worldwide.”

The cells they generated are those found in the corpus/fundus area of the stomach which releases enzymes and hydrochloric acid to help us break down and digest the food we eat. The team is particularly interested to use the mini organs to study the impact of H. pylori infection, a type of bacteria that causes ulcers and has been linked to stomach cancers.

In an earlier study, Wells’ group devised stem cell recipes for making cells from an area of the stomach, called the antrum, that produces hormones that affect digestion and appetite. Wells thinks having both tissue types recreated in a petri dish may help provide a complete picture of stomach function:

James Wells

James Wells

“Now that we can grow both antral- and corpus/fundic-type human gastric mini-organs, it’s possible to study how these human gastric tissues interact physiologically, respond differently to infection, injury and react to pharmacologic treatments.”

 

 

A silver bullet for antibiotic-resistant bone infections?
Alexander Fleming’s discover of penicillin in the 1920’s marked the dawn of antibiotics – drugs which kill off bacteria and help stop infections. Rough estimates suggest that over 200 million lives have been saved by these wonder drugs. But over time there’s been a frightening rise in bacteria that are resistant to almost all available antibiotics.

These super resistant “bugs” are particularly scary for people with chronic bone infections because the intense, long term antibiotic medication required to keep the infection in check isn’t effective. But based on research published this week in Tissue Engineering, the use of stem cells and silver may provide a new treatment option.

Scanning Electron micrograph of methicillin-resistant Staphylococcus aureus (MRSA, brown spheres) surrounded by cellular debris. MRSA, the bacteria examined in this study, is resistant by many antibiotics

Scanning Electron micrograph of methicillin-resistant Staphylococcus aureus (MRSA, brown spheres) surrounded by cellular debris. MRSA, the bacteria examined in this study, is resistant by many antibiotics. (Wikimedia)

It’s been known for many years that silver in liquid form can kill bacteria and scientists have examined ways to deliver a controlled release of silver nanoparticles at the site of the bone infection. But there has been a lot of concern, including by the Food and Drug Administration (FDA), about the toxicity of silver nanoparticles to human cells.

In this study, a team led by Elizabeth Loboa from the University of Missouri instead looked at the use of silver ions which are safer than the nanoparticles. The team developed a three-dimensional cell culture system that resembles bone by growing human bone-forming stem cells on a tissue engineered scaffold, which also slowly releases silver ions.

The researchers stimulated the stem cells within the scaffold to specialize into bone cells and included a strain of bacteria that’s resistant to multiple antibiotics. They found that the silver ions effectively killed the bacteria and at the same time did not block the bone-forming stem cells. If this work holds up, doctors may one day use this silver ion-releasing, biodegradable scaffold to directly treat the area of bone infection. And to help prevent infection after joint replacement procedures, surgeons may rely on implants that are coated with these scaffolds.

How stem cells are helping change the face of medicine, one pioneering patient at a time

One of the many great pleasures of my job is that I get to meet so many amazing people. I get to know the researchers who are changing the face of medicine, but even more extraordinary are the people who are helping them do it, the patients.

Attacking Cancer

Karl

Karl Trede

It’s humbling to meet people like Karl Trede from San Jose, California. Karl is a quiet, witty, unassuming man who when the need arose didn’t hesitate to put himself forward as a medical pioneer.

Diagnosed with throat cancer in 2006, Karl underwent surgery to remove the tumor. Several years later, his doctors told him it had returned, only this time it had spread to his lungs. They told him there was no effective treatment. But there was something else.

“One day the doctor said we have a new trial we’re going to start, would you be interested? I said “sure”. I don’t believe I knew at the time that I was going to be the first one, but I thought I’d give it a whirl.”

Karl was Patient #1 in a clinical trial at Stanford University that was using a novel approach to attack cancer stem cells, which have the ability to evade standard anti-cancer treatments and cause the tumors to regrow. The team identified a protein, called CD47, that sits on the surface of cancer stem cells and helps them evade being gobbled up and destroyed by the patient’s own immune system. They dubbed CD47 the “don’t eat me” signal and created an antibody therapy they hoped would block the signal, leaving the cancer and the cancer stem cells open to attack by the immune system.

The team did pre-clinical testing of the therapy, using mice to see if it was safe. Everything looked hopeful. Even so, this was still the first time it was being tested in a human. Karl said that didn’t bother him.

“It was an experience for me, it was eye opening. I wasn’t real concerned about being the first in a trial never tested in people before. I said we know that there’s no effective treatment for this cancer, it’s not likely but it’s possible that this could be the one and if nothing else, if it doesn’t do anything for me hopefully it does something so they learn for others.”

It’s that kind of selflessness that is typical of so many people who volunteer for clinical trials, particularly Phase 1 trials, where a treatment is often being tried in people for the first time ever. In these trials, the goal is to make sure the approach is safe, so patients are given a relatively small dose of the therapy (cells or drugs) and told ahead of time it may not do any good. They’re also told that there could be some side effects, potentially serious, even life-threatening ones. Still, they don’t hesitate.

Improving vision

Rosie Barrero certainly didn’t hesitate when she got a chance to be part of a clinical trial testing the use of stem cells to help people with retinitis pigmentosa, a rare progressive disease that destroys a person’s vision and ultimately leaves them blind.

Rosalinda Barrero

Rosie Barrero

“I was extremely excited about the clinical trial. I didn’t have any fear or trepidation about it, I would have been happy being #1, and I was #6 and that was fine with me.”

 

Rosie had what are called retinal progenitor cells injected into her eye, part of a treatment developed by Dr. Henry Klassen at the University of California, Irvine. The hope was that those cells would help repair and perhaps even replace the light-sensing cells damaged by the disease.

Following the stem cell treatment, gradually Rosie noticed a difference. It was small things at first, like being able to make out the colors of cups in her kitchen cupboard, or how many trash cans were outside their house.

“I didn’t expect to see so much, I thought it would be minor, and it is minor on paper but it is hard to describe the improvement. It’s visible, it’s visible improvement.”

These are the moments that researchers like Henry Klassen live for, and have worked so tirelessly for. These are the moments that everyone at CIRM dreams of, when the work we have championed, supported and funded shows it is working, shows it is changing people’s lives.

One year ago this month our governing Board approved a new Strategic Plan, a detailed roadmap of where we want to go in the coming years. The plan laid out some pretty ambitious goals, such as funding 50 new clinical trials in the next 5 years, and at our Board meeting next week we’ll report on how well we are doing in terms of hitting those targets.

People like Karl and Rosie help motivate us to keep trying, to keep working as hard as we can, to achieve those goals. And if ever we have a tough day, we just have to remind ourselves of what Rosie said when she realized she could once again see her children.

“Seeing their faces. It’s pretty incredible. I always saw them with my heart so I just adore them, but now I can see them with my eye.”


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Buildup of random mutations in adult stem cells doesn’t explain varying frequency of cancers

To divide or not to divide?

 It’s a question every cell in your body must constantly ask itself. Cells in your small intestine, for instance, replace themselves about every three days so the cells in that tissue must divide frequently to replenish the tissue. Liver cell are less active and turn over about once a year. And on the other extreme, the cells in the lens of the eye are kept over a life time.

The cell cycle, an exquisitely controlled process.

The cell cycle, an exquisitely controlled process. (Source wikipedia)

It’s no wonder that the process of cell division, also called the cell cycle, is exquisitely controlled by many different proteins and signaling molecules. It also makes sense that mutations in genes that produce the cell cycle proteins, could cause the regulation of cell division to go awry.

Mutations pave a path to cancer

Accumulation of enough mutations over a lifetime can lead to uncontrolled cell growth and eventually cancer. Adult stem cells are thought to be especially vulnerable to cell cycle mutations since these cells already have the capacity to self-renew and can pass mutations to their daughter cells.

Now, gene mutations can be inherited from one’s parents or caused by environmental factors like UV rays from the sun or acquired by random mistakes that occur as DNA replicates itself during cells division. Studying how the accumulation of these different mutation types impact cell division is important for understanding the formation of cancers. Results from a study in early 2015 indicated that mutations caused by random mistakes in DNA replication had a bigger impact on many cancers than mutations arising from lifestyle and environmental factors.

“Bad luck” mutations may not be the most harmful

But a new research publication in Nature suggests that, while these “bad luck” mutations can drive the development of cancer, they probably are not the main contributors. To reach this conclusion, the research team – which hails from the University Medical Center Utrecht in the Netherlands – directly measured mutation rates in human adult stem cells collected from donors as young as three years and as old as 87. In particular, stem cells from the liver, small intestine and colon were obtained. Individual stem cells were grown in the lab into mini-organs, or organoids, that resemble the structures of the source tissue. After studying these organoids, they determined that the frequency of cancer is very different in these organs, with the incidence cancer in the colon being much higher than in the other two organs.

Mutation rate the same, despite age, despite organ type

Through a various genetic analyses, the team found that an interesting pattern: the mutation rate was the same – about 40 mutations per year – for all organ types and all ages despite the higher incidence of colon cancer and older age-related cancers. Dr. Ruben van Boxtel, the team leader, expressed his reaction to these results in an interview with Medical News Today:

“We were surprised to find roughly the same mutation rate in stem cells from organs with different cancer incidence. This suggests that simply the gradual accumulation of more and more ‘bad luck’ DNA errors over time cannot explain the difference we see in cancer incidence – at least for some cancers.”

Still, the team did observe that different types of random mutations were specific to one organ over the other. These differences may help explain why the colon, for example, has a higher cancer incidence than the liver or small intestine. Van Boxtel and his team are interested in examining this result further:

“It seems ‘bad luck’ is definitely part of the story but we need much more evidence to find out how, and to what extent. This is what we want to focus on next.”

T cell fate and future immunotherapies rely on a tag team of genetic switches

Imagine if scientists could build microscopic smart missiles that specifically seek out and destroy deadly, hard-to-treat cancer cells in a patient’s body? Well, you don’t have to imagine it actually. With techniques such as chimeric antigen receptor (CAR) T therapy, a patient’s own T cells – immune system cells that fight off viruses and cancer cells – can be genetically modified to produce customized cell surface proteins to recognize and kill the specific cancer cells eluding the patient’s natural defenses. It is one of the most exciting and promising techniques currently in development for the treatment of cancer.

Human T Cell (Wikipedia)

Human T Cell (Wikipedia)

Although there have been several clinical trial success stories, it’s still early days for engineered T cell immunotherapies and much more work is needed to fine tune the approach as well as overcome potential dangerous side effects. Taking a step back and gaining a deeper understanding of how stem cells specialize into T cells in the first place could go a long way into increasing the efficiency and precision of this therapeutic strategy.

Enter the CIRM-funded work of Hao Yuan Kueh and others in Ellen Rothenberg’s lab at CalTech. Reporting yesterday in Nature Immunology, the Rothenberg team uncovered a time dependent array of genetic switches – some with an ON/OFF function, others with “volume” control – that together control the commitment of stem cells to become T cells.

Previous studies have shown that the protein encoded by the Bcl11b gene is the key master switch that when activated sets a “no going back” path toward a T cell fate. A group of other genes, including Runx1, TCF-1 and GATA-3 are known to play a role in activating Bcl11b. The dominant school of thought is that these proteins gradually accumulate at the Bcl11b gene and once a threshold level is achieved, the proteins combine to enable the Bcl11b activation switch to flip on. However, other studies suggest that some of these proteins may act as “pioneer” factors that loosen up the DNA structure and allow the other proteins to readily access and turn on the Bcl11b gene. Figuring out which mechanism is at play is critical to precisely manipulating T cell development through genetic engineering.

To tease out the answer, the CalTech team engineered mice such that cells with activated Bcl11b would glow which allows visualizing the fate of single cells. We reached out to Dr. Kueh on the rationale for this experimental approach:

Hao Yuan Kueh, CalTech

Hao Yuan Kueh, CalTech

“To fully understand how genes are controlled, we need to watch them turn on and off in single, living cells over time.  As cells in our body are unique and different from one another, standard measurement methods, which average over millions of cells, often do not tell us the entire picture.”

The team examined the impact of inhibiting the T cell specific proteins GATA-3 and TCF-1 at different stages in T cell development in single cells. When the production of these two proteins were blocked in very early T cell progenitor (ETPs) cells, activation of Bcl11b was dramatically reduced. But that’s not what they observed when the experiment was repeated in a later stage of T cell development. In this case, blocking GATA-3 and TCF-1 had a much weaker impact on Bcl11b. So GATA-3 and TCF-1 are important for turning on Bcl11b early in T cell development but are not necessary for maintaining Bcl11b activation at later stages.

Inhibition of Runx1, on the other hand, did lead to a reduction in Bcl11b in these later T cell development stages. Making Runx1 levels artificially high conversely led to elevated Bcl11b in these cells.

Together, these results point to GATA-3 and TCF-1 as the key factors for turning on Bcl11b to commit cells to a T cell fate and then they hand off their duties to Runx1 to keep Bcl11b on and maintaining the T cell identity. Dr. Kuhn sums up the results and their implications this way:

“Our work shows that control of gene expression is very much a team effort, where some proteins flip the gene’s master ON-OFF switch, and others set its expression levels after it turns on…These results will help us generate customized T-cells to fight cancer and other diseases.  As T-cells are specialized to recognize and fight foreign agents in our body, this therapy strategy holds much promise for diseases that are difficult to treat with standard drug-based methods.  Also, these intricate gene regulation mechanisms are likely to be in play in other cell types in our body, not just T-cells, and so we believe our results will be widely relevant.”

Multi-Talented Stem Cells: The Many Ways to Use Them in the Clinic

CIRM kicked off the 2016 International Society for Stem Cell Research (ISSCR) Conference in San Francisco with a public stem cell event yesterday that brought scientists, patients, patient advocates and members of the general public together to discuss the many ways stem cells are being used in the clinic to develop treatments for patients with unmet medical needs.

Bruce Conklin, Gladstone Institutes & UCSF

Bruce Conklin, Gladstone Institutes & UCSF

Bruce Conklin, an Investigator at the Gladstone Institutes and UCSF Professor, moderated the panel of four scientists and three patient advocates. He immediately captured the audience’s attention by showing a stunning video of human heart cells, beating in synchrony in a petri dish. Conklin explained that scientists now have the skills and technology to generate human stem cell models of cardiomyopathy (heart disease) and many other diseases in a dish.

Conklin went on to highlight four main ways that stem cells are contributing to human therapy. First is using stem cells to model diseases whose causes are still largely unknown (like with Parkinson’s disease). Second, genome editing of stem cells is a new technology that has the potential to offer cures to patients with genetic disorders like sickle cell anemia. Third, stem cells are known to secrete healing factors, and transplanting them into humans could be beneficial. Lastly, stem cells can be engineered to attack cancer cells and overcome cancer’s normal way of evading the immune system.

Before introducing the other panelists, Conklin made the final point that stem cell models are powerful because scientists can use them to screen and develop new drugs for diseases that have no treatments or cures. His lab is already working on identifying new drugs for heart disease using human induced pluripotent stem cells derived from patients with cardiomyopathy.

Scientists and Patient Advocates Speak Out

Malin Parmar, Lund University

Malin Parmar, Lund University

The first scientist to speak was Malin Parmar, a Professor at Lund University. She discussed the history of stem cell development for clinical trials in Parkinson’s disease (PD). Her team is launching the first in-human trial for Parkinson’s using cells derived from human pluripotent stem cells in 2016. After Parmar’s talk, John Lipp, a PD patient advocate. He explained that while he might look normal standing in front of the crowd, his PD symptoms vary wildly throughout the day and make it hard for him to live a normal life. He believes in the work that scientists like Parmar are doing and confidently said, “In my lifetime, we will find a stem cell cure for Parkinson’s disease.”

Adrienne Shapiro, Patient Advocate

Adrienne Shapiro, Patient Advocate

The next scientist to speak was UCLA Professor Donald Kohn. He discussed his lab’s latest efforts to develop stem cell treatments for different blood disorder diseases. His team is using gene therapy to modify blood stem cells in bone marrow to treat and cure babies with SCID, also known as “bubble-boy disease”. Kohn also mentioned their work in sickle cell disease (SCD) and in chronic granulomatous disease, both of which are now in CIRM-funded clinical trials. He was followed by Adrienne Shapiro, a patient advocate and mother of a child with SCD. Adrienne gave a passionate and moving speech about her family history of SCD and her battle to help find a cure for her daughter. She said “nobody plans to be a patient advocate. It is a calling born of necessity and pain. I just wanted my daughter to outlive me.”

Henry Klassen (UC Irvine)

Henry Klassen, UC Irvine

Henry Klassen, a professor at UC Irvine, next spoke about blinding eye diseases, specifically retinitis pigmentosa (RP). This disease damages the photo receptors in the back of the eye and eventually causes blindness. There is no cure for RP, but Klassen and his team are testing the safety of transplanting human retinal progenitor cells in to the eyes of RP patients in a CIRM-funded Phase 1/2 clinical trial.

Kristen MacDonald, RP patient

Kristen MacDonald, RP patient

RP patient, Kristen MacDonald, was the trial’s first patient to be treated. She bravely spoke about her experience with losing her vision. She didn’t realize she was going blind until she had a series of accidents that left her with two broken arms. She had to reinvent herself both physically and emotionally, but now has hope that she might see again after participating in this clinical trial. She said that after the transplant she can now finally see light in her bad eye and her hope is that in her lifetime she can say, “One day, people used to go blind.”

Lastly, Catriona Jamieson, a professor and Alpha Stem Cell Clinic director at UCSD, discussed how she is trying to develop new treatments for blood cancers by eradicating cancer stem cells. Her team is conducting a Phase 1 CIRM-funded clinical trial that’s testing the safety of an antibody drug called Cirmtuzumab in patients with chronic lymphocytic leukemia (CLL).

Scientists and Patients need to work together

Don Kohn, Catriona Jamieson, Malin Parmar

Don Kohn, Catriona Jamieson, Malin Parmar

At the end of the night, the scientists and patient advocates took the stage to answer questions from the audience. A patient advocate in the audience asked, “How can we help scientists develop treatments for patients more quickly?”

The scientists responded that stem cell research needs more funding and that agencies like CIRM are making this possible. However, we need to keep the momentum going and to do that both the physicians, scientists and patient advocates need to work together to advocate for more support. The patient advocates in the panel couldn’t have agreed more and voiced their enthusiasm for working together with scientists and clinicians to make their hopes for cures a reality.

The CIRM public event was a huge success and brought in more than 150 people, many of whom stayed after the event to ask the panelists more questions. It was a great kick off for the ISSCR conference, which starts today. For coverage, you can follow the Stem Cellar Blog for updates on interesting stem cell stories that catch our eye.

CIRM Public Stem Cell Event

CIRM Public Stem Cell Event

Stem cell stories that caught our eye: fashionable stem cells, eliminating HIV, cellular Trojan horse fights cancer

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.

Stem cell fashion for a cause. Science and art are not mutually exclusive subjects. I know plenty of scientists who are talented painters or designers. But you don’t often see science being displayed in an artistic way or art being used to help explain complex scientific topics. I think that in the future, this will change as both subjects have a lot to offer one another.

Stem cell ties are in fashion!

Stem cell ties are in fashion!

Take this story from the University of Michigan for instance. Designer Dominic Pangborn has joined forces with the Heinz C. Prechter Bipolar Research Fund at the University of Michigan (UOM) to design fashionable scarves and ties featuring beautiful pictures of stem cells. The goal of the Prechter Fund scarf and tie project is to raise awareness for mental health research.

The scarves and ties feature pictures of brain stem cells taken by UOM scientists who are studying them to understand the mechanisms behind bipolar disorder. These stem cells were generated from induced pluripotent stem cells or iPS cells that were derived from donated skin biopsies of patients with bipolar disease. Studying these diseased brain cells in a dish revealed that the nerve cells from bipolar patients were misbehaving, sending out electrical signals more frequently compared to healthy nerve cells.

Dr. Melvin McInnis, the Prechter Fund research director, explained:

“By understanding the causes of bipolar disorder, we will be able to develop new treatments for the illness and most importantly, we’ll be able to prevent destructive mood episodes. Our ultimate goal is to allow people to live happy, normal lives.”

Pangborn is passionate about using art to reflect an important cause.

“I decided to add butterflies to the design because they signify metamorphosis. Our society is finally at a point where mental illness is openly talked about and research is taking a turn for the better.”

He plans to release his collection in time for National Mental Health Awareness month in May. All proceeds will go to the Prechter bipolar research projects at UOM.

Dr. Melvin McInnis, left, and Dominic Pangborn in the Pangborn Design Store in Ann Arbor. (UOM)

Dr. Melvin McInnis, left, and Dominic Pangborn in the Pangborn Design Store in Ann Arbor. (UOM)

New stem cell therapy could eliminate HIV for good

The stem cells therapies being developed to cure HIV are looking more promising every day. A few are already being tested in clinical trials, and CIRM is funding two of them (you can read more about them here). News came out this week about a new trial conducted at the City of Hope’s CIRM Alpha Stem Cell Clinic. They reported in a news release that they’ve treated their first patient. His name is Aaron Kim, and he’s had HIV since he was born. In 1983, he and his twin sister were born prematurely and due to a complication, Aaron had to get a blood transfusion that unfortunately gave him HIV.

Aaron Kim with nurse. (City of Hope)

Aaron Kim with nurse. (City of Hope)

Aaron thought he would live with this disease the rest of his life, but now he has a chance at being cured. In March, Aaron received a transplant of his own bone marrow stem cells that were genetically engineered to have a modified version of the CCR5 gene that makes his cells resistant to HIV infection. CCR5 is a is a protein receptor on the surface of blood cells that acts as a gateway for HIV entry. The hope is that his reengineered stem cells will populate his immune system with HIV-resistant cells that can eliminate the virus completely.

Dr. John Zaia who is the director the the City of Hope Alpha Clinic explained,

“The stem cell therapy Aaron received is one of more than 20 cure strategies for HIV. It may not cure him, but our goal is to reduce or even halt Aaron’s reliance on HIV drugs, potentially eliminating the virus completely.”

My favorite part of this story was that it acknowledged how importance it is for patients to participate in clinical trials testing promising new stem cell therapies where the outcomes aren’t always known. Brave patients such as Aaron make it possible for scientists to make progress and develop better and safer treatments for patients in the future.

Dr. Zaia commented, “It’s a wonderful and generous humanitarian gesture on Aaron’s part to participate in this trial.”

Stem cell Trojan horse fights cancer

Chemotherapy is great at killing cancer cells, but unfortunately, it’s also great at killing healthy cells too. To combat this issue, scientists are developing new delivery methods that can bring high doses of chemotherapy drugs to the cancer tumors and minimize exposure of healthy tissues.

Mesenchymal stem cells loaded with drug-containing microparticles. Credit: Jeff Karp and Oren Levy, Brigham and Women's Hospital

Mesenchymal stem cells loaded with drug-containing microparticles.
Credit: Jeff Karp and Oren Levy, Brigham and Women’s Hospital

A study published this week in Biomaterials, describes a new drug delivery method that has the potential to be an effective treatment for prostate cancer. Researchers from the Brigham and Women’s Hospital and Johns Hopkins University developed a drug delivery platform using mesenchymal stem cells. They packaged a non-active, prodrug version of a potent prostate cancer chemotherapy drug into microparticles that they loaded into MSCs. When the MSCs and prostate cancer cells were cultured together in a dish, the MSCs released their prodrug cargo, which was then internalized by the prostate cancer cells. The prodrug was then metabolized into its active, cancer-killing form and was very effective at killing the cancer cells.

In a news release picked up by Science Daily, one of the lead scientists on the study, Dr. Oren Levy, further explained the stem cell Trojan horse concept:

“Mesenchymal stem cells represent a potential vehicle that can be engineered to seek out tumors. Loading those cells with a potent chemotherapeutic drug is a promising cell-based Trojan horse approach to deliver drugs to sites of cancer.”

If all goes well, the teams plan to develop different versions of their stem cell-based drug delivery method that target different cancers and other diseases.

Scientists tackle aging by stabilizing defective blood stem cells in mice

Aging is an inevitable process that effects every cell, tissue, and organ in your body. You can live longer by maintaining a healthy, active lifestyle, but there is no magic pill that can prevent your body’s natural processes from slowly breaking down and becoming less efficient. As author Chinua Achebe would say, “Things Fall Apart”.

Adult stem cells are an unfortunate victim of the aging process. They have the important job of replenishing the cells in your body throughout your lifetime. However, as you grow older, adult stem cells lose their regenerative ability and fail to maintain the integrity and function of their tissues and organs. This can happen for a number of reasons, but no matter the cause, dysfunctional stem cells can accelerate aging and contribute to a shortened lifespan.

So to put it simply, aging adult stem cells = decline in stem cell function = shortened lifespan.

Dysfunctional blood stem cells make an unhappy immune system

Human blood (red) and immune cells (green) are made from hematopoietic/blood stem cells. Photo credit: ZEISS Microscopy.

Human blood (red) and immune cells (green) are made from hematopoietic/blood stem cells. Photo credit: ZEISS Microscopy.

A good example of this process is hematopoietic stem cells (HSCs), which are adult stem cells found in bone marrow that make all the cells in our blood and immune system. When HSCs get old, they lose their edge and fail to generate some of the important blood cell types that are crucial for a healthy immune system. This can be life-threatening for elderly people who are at higher risk for infections and disease.

So how can we improve the function of aging HSCs to boost the immune system in older people and potentially extend their healthy years of life? A team of researchers from Germany might have an answer. They’ve identified a genetic switch that revitalizes aged, defective HSCs in mice and prolongs their lifespan. They published their findings this week in Nature Cell Biology.

Identifying the Per-petrator for aging HSCs

The perpetrator in this story is a gene called Per2. The team identified Per2 through a genetic screen of hundreds of potential tumor suppressor genes that could potentially impair the regenerative abilities of HSCs in response to DNA damage caused by aging.

It turns out that the Per2 gene is turned on in a subset of HSCs, called lymphoid-HSCs, that preferentially generate blood cells in the lymphatic system. These include B and T cells, both important parts of our immune system. When Per2 is turned on in lymphoid-HSCs, it activates the DNA damage response pathway. While responding to DNA damage may sound like a good thing, it also slows down the cell division process and prevents lymphoid-HSCs from producing their normal amount of lymphoid cells. Adding insult to injury, Per2 also activates the p53-dependent apoptosis pathway, which causes programmed cell death and further reduces the number of HSCs in reserve.

To address these problems, the team decided to delete the Per2 gene in mice and study the function of their HSCs as they aged. They found that removing Per2 stabilized lymphoid-HSCs and rescued their ability to generate the appropriate number of lymphoid cells. Per2 deletion also boosted their immune system, making the mice less susceptible to infection, and extended their lifespan by as much as 15 percent.

A key finding was that deleting Per2 did not increase the incidence of tumors in the aging mice – a logical concern as Per2 mutations in humans are link to increased cancer risk.

Per2 might not be a Per-fect solution for healthy aging

In summary, getting rid of Per2 in the HSCs of older mice improves their function and the function of their immune system while also extending their lifespan.

Senior author on the study, Karl Lenhard Rudolph, commented about their findings in a news release:

Karl Lenhard Rudolph. Photo: Anne Günther/FSU

Karl Lenhard Rudolph.

“All in all, these results are very promising, but equally surprising. We did not expect such a strong connection between switching off a single gene and improving the immune system so clearly.”

 

 

So Per2 may be a good healthy aging target in mice, but the real question is whether these results will translate to humans. Per2 is a circadian rhythm gene and is important for regulating the sleep-wake cycle. Deleting this gene in humans could cause sleep disorders and other unwanted side effects.

Rudolph acknowledges that his team needs to move their focus from mouse to humans.

“It is not yet clear whether this mutation in humans would have a benefit such as improved immune functions in aging — it is of great interest for us to further investigate this question.”

Rare disease underdogs come out on top at CIRM Board meeting

 

It seems like an oxymoron but one in ten Americans has a rare disease. With more than 7,000 known rare diseases it’s easy to see how each one could affect thousands of individuals and still be considered a rare or orphan condition.

Only 5% of rare diseases have FDA approved therapies

rare disease

(Source: Sermo)

People with rare diseases, and their families, consider themselves the underdogs of the medical world because they often have difficulty getting a proper diagnosis (most physicians have never come across many of these diseases and so don’t know how to identify them), and even when they do get a diagnosis they have limited treatment options, and those options they do have are often very expensive.  It’s no wonder these patients and their families feel isolated and alone.

Rare diseases affect more people than HIV and Cancer combined

Hopefully some will feel less isolated after yesterday’s CIRM Board meeting when several rare diseases were among the big winners, getting funding to tackle conditions such as ALS or Lou Gehrig’s disease, Severe Combined Immunodeficiency or SCID, Canavan disease, Tay-Sachs and Sandhoff disease. These all won awards under our Translation Research Program except for the SCID program which is a pre-clinical stage project.

As CIRM Board Chair Jonathan Thomas said in our news release, these awards have one purpose:

“The goal of our Translation program is to support the most promising stem cell-based projects and to help them accelerate that research out of the lab and into the real world, such as a clinical trial where they can be tested in people. The projects that our Board approved today are a great example of work that takes innovative approaches to developing new therapies for a wide variety of diseases.”

These awards are all for early-stage research projects, ones we hope will be successful and eventually move into clinical trials. One project approved yesterday is already in a clinical trial. Capricor Therapeutics was awarded $3.4 million to complete a combined Phase 1/2 clinical trial treating heart failure associated with Duchenne muscular dystrophy with its cardiosphere stem cell technology.  This same Capricor technology is being used in an ongoing CIRM-funded trial which aims to heal the scarring that occurs after a heart attack.

Duchenne muscular dystrophy (DMD) is a genetic disorder that is marked by progressive muscle degeneration and weakness. The symptoms usually start in early childhood, between ages 3 and 5, and the vast majority of cases are in boys. As the disease progresses it leads to heart failure, which typically leads to death before age 40.

The Capricor clinical trial hopes to treat that aspect of DMD, one that currently has no effective treatment.

As our President and CEO Randy Mills said in our news release:

Randy Mills, Stem Cell Agency President & CEO

Randy Mills, Stem Cell Agency President & CEO

“There can be nothing worse than for a parent to watch their child slowly lose a fight against a deadly disease. Many of the programs we are funding today are focused on helping find treatments for diseases that affect children, often in infancy. Because many of these diseases are rare there are limited treatment options for them, which makes it all the more important for CIRM to focus on targeting these unmet medical needs.”

Speaking on Rare Disease Day (you can read our blog about that here) Massachusetts Senator Karen Spilka said that “Rare diseases impact over 30 Million patients and caregivers in the United States alone.”

Hopefully the steps that the CIRM Board took yesterday will ultimately help ease the struggles of some of those families.