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

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

Stomach bacteria crank up stem cell renewal, may be link to gastric cancer (Todd Dubnicoff)

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

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

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

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

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Vitamin C may have anti-blood cancer properties

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

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

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

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

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

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

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

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

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

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

In an interview with the Richmond Times Dispatch he said:

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

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

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

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

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

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Stories that caught our eye: smelling weight gain, colon cancer & diet and diabetes & broken bones

How smelling your food could cause weight gain (Karen Ring).
Here’s the headline that caught my eye this week: “Smelling your food first can make you fat…”

It’s a bizarre statement, but the claim is backed by scientific research coming from a new study in Cell Metabolism by researchers at the University of California Berkeley. The team found that obese mice who smelled their food before eating it were more likely to gain weight compared to obese mice that couldn’t smell their food.

Their experiments revealed a connection between the olfactory system, which is responsible for our sense of smell, and how the mice metabolize food into energy. Obese mice that lost their ability to smell actually lost weight on a high-fat diet, burned more fat, and became more sensitive to the hormone insulin. Insulin regulates how much glucose, or sugar, is in the blood by facilitating the absorption of glucose by fat, liver and muscle cells. In obese individuals, insulin resistance can occur where their cells are no longer sensitive to the hormone and therefore can’t regulate how much glucose is in the blood.

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Both mice in this picture were fed the same high-fat diet. The only difference: the lower mouse’s sense of smell was temporarily blocked. Image: UC Berkeley

For obese mice that could smell their food, the same high fat diet given to the “no-smellers” resulted in massive weight gain in the “smellers” because their metabolism was impaired. Even more interesting is the fact that other types of smells unrelated to food, such as the scent of other mice, influenced weight gain in the “smellers”.

The authors concluded that the centers in our brain that are responsible for smell (the olfactory system) and metabolism (the hypothalamus) are connected and that manipulating smell could be a future strategy to influence how the brain controls the balance of energy during food consumption.

In an interview with Tech Times, senior author on the study, Dr. Andrew Dillin, explained how their research could potentially lead to a new strategy to promote weight loss,

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Andrew Dillin. Image: HHMI

“Sensory systems play a role in metabolism. Weight gain isn’t purely a measure of the calories taken in; it’s also related to how those calories are perceived. If we can validate this in humans, perhaps we can actually make a drug that doesn’t interfere with smell but still blocks that metabolic circuitry. That would be amazing.”

A link between colorectal cancer and a Western diet identified
Weight gain isn’t the only concern of a eating a high-fat diet. It’s thought that 80% of colorectal cases are associated with a high-fat, Western diet. The basis for this connection hasn’t been well understood. But this week, researchers at the Cleveland Clinic report in Stem Cell Reports that they’ve pinpointed a protein signaling network within cancer stem cells as a possible source of the link.

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Cancer stem cells have properties that resemble embryonic stem cells and are thought to be the source of a cancer’s unlimited growth and spread. A cancer stem cell maintains its properties by exploiting various cell signaling processes that when functioning abnormally can lead to inappropriate cell division and tumor growth. In this study, the team focused on one cell signaling process carried out by a protein called STAT3, known to promote tumor growth in a mouse model of colon cancer. When the team blocked STAT3 activity, high fat diet-induced cancer stem cell growth subsided.

In a press release, Dr. Matthew Kalady, a colorectal surgeon at the Cleveland Clinic and an author on this study, explained how this new insight can open new therapeutic avenues:

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Matthew Kalady. Image: Cleveland Clinic

“We have known the influence of diet on colorectal cancer. However, these new findings are the first to show the connection between high-fat intake and colon cancer via a specific molecular pathway. We can now build upon this knowledge to develop new treatments aimed at blocking this pathway and reducing the negative impact of a high-fat diet on colon cancer risk.”

 

 

Scientists connect dots between diabetes and broken bones.
Type 2 diabetes carries a whole host of long-term complications including heart disease, nerve damage, kidney dysfunction and even an increased risk for bone fractures. The connection between diabetes and fragile bones has not been well understood. But this week, researchers at New York University of Dentistry, Stanford University and China’s Dalian Medical University published a report, funded in part by CIRM, in this week’s Nature Communications showing a biochemical basis for this connection. The new insight may lead to treatment options to prevent fractures.

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Chemical structure of succinate.
Image: Wikimedia Commons.

Fundamentally, diabetes is a disease that causes hyperglycemia, or abnormally high levels of blood sugar. The team ran a systematic analysis of hyperglycemia’s effects on bone metabolism using bone marrow samples from diabetic and healthy mice. They found that the levels of succinate, a key molecule involved in energy production, are over 20 times higher in the diabetic mice. In turns out that succinate also acts as a stimulator of bone breakdown. Now, bone is continually in a process of turnover and, in a healthy state, the breakdown of old bone is balanced with the formation of new bone. So, it appears that the huge increase of succinate is tipping the balance of bone turnover. In fact, the team found that the porous, yet strong inner region of bone, called trabecular bone, was significantly reduced in the diabetic mice, making them more susceptible to fractures.

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The density of spongy bone, or trabecular bone, is reduced in type 2 diabetes.
Image: Wikimedia commons

Dr. Xin Li, the study’s lead scientist, explained the importance of these new insights for people living with type 2 diabetes in a press release:

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Xin Li.
Image: NYU Dentistry

“The results are important because diabetics have a significantly higher fracture risk and their healing process is always delayed. In our study, the hyperglycemic mice had increased bone resorption [the breakdown and absorption of old bone], which outpaced the formation of new bone. This has implications for bone protection, as well as for the treatment of diabetes-associated collateral bone damage.”

 

Baseball’s loss is CIRM’s gain as Stanford’s Linda Boxer is appointed to Stem Cell Agency Board

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Dr. Linda Boxer: Photo courtesy Stanford University

One of the things that fascinates me is finding out how people end up in the job they have, the job they love. It is rare that the direction they started out on is the one they end on. Usually, people take several different paths, some intended, some unintended, to get to where they want to be.

A case in point is Dr. Linda Boxer, a renowned and respected researcher and physician at the Stanford School of Medicine, and now the newest member of the CIRM Board (you can read all about that in our news release).

In Dr. Boxer’s case, her original career path was a million miles from working with California’s stem cell agency:

“The first career choice that I recall as a young child was professional baseball—growing up in Minnesota, I was a huge Twins fan—I did learn fairly quickly that this was not likely to be a career that was available for a girl, and it wasn’t clear what one did after that career ended at a relatively young age.”

Fortunately for us she became interested in science.

“I have always been curious about how things work—science classes in grade school were fascinating to me. I was given a chemistry kit as a birthday gift, and I was amazed at what happened when different chemicals were mixed together: color changes, precipitates forming, gas bubbles, explosions (small ones, of course).

Then when we studied biology in middle school, I was fascinated by what one could observe with a microscope and became very interested in trying to understand how living organisms work.

It was an easy decision to plan a career in science.  The tougher decision came in college when I had planned to apply to graduate school and earn a PhD, but I was also interested in human health and disease and thought that perhaps going to medical school made more sense.  Fortunately, one of my faculty advisors told me about combined MD/PhD programs, and that choice seemed perfect for me.”

Along the way she says she got a lot of help and support from her colleagues. Now she wants to do the same for others:

“Mentors are incredibly important at every career stage.  I have been fortunate to have been mentored by some dedicated scientists and physicians.  Interestingly, they have all been men.  There were really very few women available as mentors at the time—of course, that has changed for the better now.  It never occurred to me then that gender made a difference, and I just looked for mentors who had successful careers as scientists and physicians and who could provide advice to someone more junior.

One of the aspects of my role now that I enjoy the most is mentoring junior faculty and trainees.  I don’t think one can have too many mentors—different mentors can help with different aspects of one’s life and career.  I think it is very important for established scientists to give back and to help develop the next generation of physicians and scientists.”

Dr. Boxer is already well known to everyone at CIRM, having served as the “alternate” on the Board for Stanford’s Dr. Lloyd Minor. But her appointment by State Controller Betty Yee makes her the “official” Board member for Stanford. She brings a valuable perspective as both a scientist and a physician.

The Minnesota Twins lost out when she decided to pursue a career in science. We’re glad she did.

 

Three people left blind by Florida clinic’s unproven stem cell therapy

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Unproven stem cell treatments endanger patients: Photo courtesy Healthline

The report makes for chilling reading. Three women, all suffering from macular degeneration – the leading cause of vision loss in the US – went to a Florida clinic hoping that a stem cell therapy would save their eyesight. Instead, it caused all three to go blind.

The study, in the latest issue of the New England Journal of Medicine, is a warning to all patients about the dangers of getting unproven, unapproved stem cell therapies.

In this case, the clinic took fat and blood from the patient, put the samples through a centrifuge to concentrate the stem cells, mixed them together and then injected them into the back of the woman’s eyes. In each case they injected this mixture into both eyes.

Irreparable harm

Within days the women, who ranged in age from 72 to 88, began to experience severe side effects including bleeding in the eye, detached retinas, and vision loss. The women got expert treatment at specialist eye centers to try and undo the damage done by the clinic, but it was too late. They are now blind with little hope for regaining their eyesight.

In a news release Thomas Alibini, one of the lead authors of the study, says clinics like this prey on vulnerable people:

“There’s a lot of hope for stem cells, and these types of clinics appeal to patients desperate for care who hope that stem cells are going to be the answer, but in this case these women participated in a clinical enterprise that was off-the-charts dangerous.”

Warning signs

So what went wrong? The researchers say this clinic’s approach raised a number of “red flags”:

  • First there is almost no evidence that the fat/blood stem cell combination the clinic used could help repair the photoreceptor cells in the eye that are attacked in macular degeneration.
  • The clinic charged the women $5,000 for the procedure. Usually in FDA-approved trials the clinical trial sponsor will cover the cost of the therapy being tested.
  • Both eyes were injected at the same time. Most clinical trials would only treat one eye at a time and allow up to 30 days between patients to ensure the approach was safe.
  • Even though the treatment was listed on the clinicaltrials.gov website there is no evidence that this was part of a clinical trial, and certainly not one approved by the Food and Drug Administration (FDA) which regulates stem cell therapies.

As CIRM’s Abla Creasey told the San Francisco Chronicle’s Erin Allday, there is little evidence these fat stem cells are effective, or even safe, for eye conditions.

“There’s no doubt there are some stem cells in fat. As to whether they are the right cells to be put into the eye, that’s a different question. The misuse of stem cells in the wrong locations, using the wrong stem cells, is going to lead to bad outcomes.”

The study points out that not all projects listed on the Clinicaltrials.gov site are checked to make sure they are scientifically sound and have done the preclinical testing needed to reduce the likelihood they may endanger patients.

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Jeffrey Goldberg

Jeffrey Goldberg, a professor of Ophthalmology at Stanford and the co-author of the study, says this is a warning to all patients considering unproven stem cell therapies:

“There is a lot of very well-founded evidence for the positive potential of stem therapy for many human diseases, but there’s no excuse for not designing a trial properly and basing it on preclinical research.”

There are a number of resources available to people considering being part of a clinical trial including CIRM’s “So You Want to Participate in a Clinical Trial”  and the  website A Closer Look at Stem Cells , which is sponsored by the International Society for Stem Cell Research (ISSCR).

CIRM is currently funding two clinical trials aimed at helping people with vision loss. One is Dr. Mark Humayun’s research on macular degeneration – the same disease these women had – and the other is Dr. Henry Klassen’s research into retinitis pigmentosa. Both these projects have been approved by the FDA showing they have done all the testing required to try and ensure they are safe in people.

In the past this blog has been a vocal critic of the FDA and the lengthy and cumbersome approval process for stem cell clinical trials. We have, and still do, advocate for a more efficient process. But this study is a powerful reminder that we need safeguards to protect patients, that any therapy being tested in people needs to have undergone rigorous testing to reduce the likelihood it may endanger them.

These three women paid $5,000 for their treatment. But the final cost was far greater. We never want to see that happen to anyone ever again.

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

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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.

 

 

 

 

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

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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.

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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.”


Related Links:

Stem cell agency funds clinical trials in three life-threatening conditions

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A year ago the CIRM Board unanimously approved a new Strategic Plan for the stem cell agency. In the plan are some rather ambitious goals, including funding ten new clinical trials in 2016. For much of the last year that has looked very ambitious indeed. But today the Board took a big step towards reaching that goal, approving three clinical trials focused on some deadly or life-threatening conditions.

The first is Forty Seven Inc.’s work targeting colorectal cancer, using a monoclonal antibody that can strip away the cancer cells ability to evade  the immune system. The immune system can then attack the cancer. But just in case that’s not enough they’re going to hit the tumor from another side with an anti-cancer drug called cetuximab. It’s hoped this one-two punch combination will get rid of the cancer.

Finding something to help the estimated 49,000 people who die of colorectal cancer in the U.S. every year would be no small achievement. The CIRM Board thought this looked so promising they awarded Forty Seven Inc. $10.2 million to carry out a clinical trial to test if this approach is safe. We funded a similar approach by researchers at Stanford targeting solid tumors in the lung and that is showing encouraging results.

Our Board also awarded $7.35 million to a team at Cedars-Sinai in Los Angeles that is using stem cells to treat pulmonary hypertension, a form of high blood pressure in the lungs. This can have a devastating, life-changing impact on a person leaving them constantly short of breath, dizzy and feeling exhausted. Ultimately it can lead to heart failure.

The team at Cedars-Sinai will use cells called cardiospheres, derived from heart stem cells, to reduce inflammation in the arteries and reduce blood pressure. CIRM is funding another project by this team using a similar  approach to treat people who have suffered a heart attack. This work showed such promise in its Phase 1 trial it’s now in a larger Phase 2 clinical trial.

The largest award, worth $20 million, went to target one of the rarest diseases. A team from UCLA, led by Don Kohn, is focusing on Adenosine Deaminase Severe Combined Immune Deficiency (ADA-SCID), which is a rare form of a rare disease. Children born with this have no functioning immune system. It is often fatal in the first few years of life.

The UCLA team will take the patient’s own blood stem cells, genetically modify them to fix the mutation that is causing the problem, then return them to the patient to create a new healthy blood and immune system. The team have successfully used this approach in curing 23 SCID children in the last few years – we blogged about it here – and now they have FDA approval to move this modified approach into a Phase 2 clinical trial.

So why is CIRM putting money into projects that it has either already funded in earlier clinical trials or that have already shown to be effective? There are a number of reasons. First, our mission is to accelerate stem cell treatments to patients with unmet medical needs. Each of the diseases funded today represent an unmet medical need. Secondly, if something appears to be working for one problem why not try it on another similar one – provided the scientific rationale and evidence shows it is appropriate of course.

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

“Our Board’s support for these programs highlights how every member of the CIRM team shares that commitment to moving the most promising research out of the lab and into patients as quickly as we can. These are very different projects, but they all share the same goal, accelerating treatments to patients with unmet medical needs.”

We are trying to create a pipeline of projects that are all moving towards the same goal, clinical trials in people. Pipelines can be horizontal as well as vertical. So we don’t really care if the pipeline moves projects up or sideways as long as they succeed in moving treatments to patients. And I’m guessing that patients who get treatments that change their lives don’t particularly

Stem cell stories that caught our eye: How Zika may impact adult brains; Move over CRISPR there’s a new kid in town; How our bodies store fat

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.

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Zika mosquito

Zika virus could impact adult brains

It’s not just a baby’s developing brain that is vulnerable to the Zika virus, adult brains may be too. A new study shows that some stem cells that help repair damage in the adult brain can be impacted by Zika. This is the first time we’ve had any indication this could be a problem in a fully developed brain.

The study, in the journal Cell Stem Cell, looked at neural progenitors, a  stem cell that plays an important role in helping replace or repair damaged neurons, or nerve cells, in the brain. The researchers exposed the cells to the Zika virus and found that it infected the cells, causing some of the cells to die, and also limited the ability of the cells to proliferate.

In an interview in Healthday, Sujan Shresta, a researcher at the La Jolla Institute for Allergy and Immunology and one of the lead authors of the study, says although their work was done in adult mice, it may have implications for people:

“Zika can clearly enter the brains of adults and can wreak havoc. But it’s a complex disease, it’s catastrophic for early brain development, yet the majority of adults who are infected with Zika rarely show detectable symptoms. Its effect on the adult brain may be more subtle and now we know what to look for.”

Move over CRISPR, there’s a new gene-editing tool in town

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Jennifer Lopez: Photo courtesy MTV

For much of the last year the hottest topic in stem cell and gene editing research has been CRISPR and the ease with which it can be used to edit genes. It’s so hot that apparently it’s the title of an upcoming TV show starring Jeniffer Lopez.

But hold on J-Lo, a new study in Nature Communications says by the time the show is on the air it may be old hat. Researchers at Carnegie Mellon and Yale University have developed a new gene-editing system, one they claim is easier to use and more accurate than CRISPR. And to prove it, they say they have successfully cured a genetic blood disorder in mice, using a simple IV approach.

Tools like CRISPR use enzymes to cut open sections of DNA to edit a specific gene. It’s like using a pair of scissors to cut a piece of string that has a big knot in the middle; you cut out the knot then join the ends of the string together. The problem with CRISPR is that the enzymes it uses are quite large and hard to use in a living animal – let alone a human – so they have to remove the target cells from the body and do the editing in the lab. Another problem is that CRISPR sometimes cuts sections of DNA that the researchers don’t want cut and could lead to dangerous side effects.

Greater precision

The Carnegie Mellon/Yale team say their new method avoids both problems. They use nanoparticles that contain molecules made from peptide nucleic acid (PNA), a kind of artificial form of DNA. This PNA is engineered to be able to cut open DNA and bind to a specific target without cutting anything else.

The team used this approach to target the mutated gene in beta thalassemia, a blood disorder that can be fatal if left untreated. The therapy binds to the malfunctioning gene, enabling the body’s own DNA repair system to correct the problem.

In a news story in Science Daily Danith Ly, one of the lead authors on the study, says even though the technique was successful in editing the target genes just 7 percent of the time, that is way more than the 0.1 percent rate most other gene editing tools achieve.

“The effect may only be 7 percent, but that’s curative. In the case of this particular disease model, you don’t need a lot of correction. You don’t need 100 percent to see the phenotype return to normal.”

Hormone that controls if and when fat cells mature

Obesity is one of the fastest growing public health problems in the US and globally. Understanding the mechanisms behind how that happens could be key to finding ways to address it. Now researchers at Stanford University think they may have uncovered an important part of the answer.

Their findings, reported in Science Signaling, show that mature fat cells produce a hormone called Adamts1 which acts like a switch for surrounding stem cells, determining if they change into fat-storing cells.   People who eat a high-fat diet experience a change in their Adamst1 production, and that triggers the nearby stem cells to specialize and start storing fat.

There are still a lot of questions to be answered about Adamst1, including whether it acts alone or in conjunction with other as yet unknown hormones. But in an article in Health Canal, Brian Feldman, the senior author of the study, says they can now start looking at potential use of Adamst1 to fight obesity.

“That won’t be a simple answer. If you block fat formation, extra calories have to go somewhere in the body, and sending them somewhere else outside fat cells could be more detrimental to metabolism. We know from other researchers’ work that liver and muscle are both bad places to store fat, for example. We do think there are going to be opportunities for new treatments based on our discoveries, but not by simply blocking fat formation alone.”

 

New approach could help turn back the clock and reverse damage for stroke patients

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Stroke: courtesy WebMD

Stroke is the leading cause of serious, long-term disability in the US. Every year almost 800,000 people suffer from a stroke. The impact on their lives, and the lives of those around them can be devastating.

Right now the only treatment approved by the US Food and Drug Administration (FDA) is tissue plasminogen activator or tPA. This helps dissolve the blood clot causing most strokes and restores blood flow to the brain. However, to be fully effective this has to be administered within about 3-4 hours after the stroke. Many people are unable to get to the hospital in time and as a result suffer long-term damage, damage that for most people has been permanent.

But now a new study in Nature Medicine shows that might not be the case, and that this damage could even be reversible.

The research, done by a team at the University of Southern California (USC) uses a one-two punch combination of stem cells and a protein that helps those cells turn into neurons, the cells in the brain damaged by a stroke.

First, the researchers induced a stroke in mice and then transplanted human neural stem cells alongside the damaged brain tissue. They then added in a dose of the protein 3K3A-APC or a placebo.

hey found that mice treated with 3K3A-APC had 16 times more human stem-cell derived neurons than the mice treated with the placebo. Those neurons weren’t just sitting around doing nothing. USC’s Berislav Zlokovic, senior author of the paper, says they were actively repairing the stroke-induced damage.

“We showed that 3K3A-APC helps the grafted stem cells convert into neurons and make structural and functional connections with the host’s nervous system. No one in the stroke field has ever shown this, so I believe this is going to be the gold standard for future studies. Functional deficits after five weeks of stroke were minimized, and the mice were almost back to normal in terms of motor and sensorimotor functions. Synapses formed between transplanted cells and host cells, so there is functional activation and cooperation of transplanted cells in the host circuitry.”

The researchers wanted to make sure the transplanted cell-3K3A-ACP combination was really the cause of the improvement in the mice so they then used what’s called an “assassin toxin” to kill the neurons they had created. That reversed the improvements in the treated mice, leaving them comparable to the untreated mice. All this suggests the neurons had become an integral part of the mouse’s brain.

So how might this benefit people? You may remember that earlier this summer Stanford researchers produced a paper showing they had helped some 18 stroke patients, by injecting stem cells from donor bone marrow into their brain. The improvements were significant, including in at least one case regaining the ability to walk. We blogged about that work here

In that study, however, the cells did not become neurons nor did they seem to remain in the brain for an extended period. It’s hoped this new work can build on that by giving researchers an additional tool, the 3K3A-ACP protein, to help the transplanted cells convert to neurons and become integrated into the brain.

One of the other advantages of using this protein is that it has already been approved by the FDA for use in people who have experienced an ischemic stroke, which accounts for about 87 percent of all strokes.

The USC team now hope to get approval from the FDA to see if they can replicate their experiences in mice in people, through a Phase 2 clinical trial.