Stem cell stories that caught our eye: spinal cord injury trial update, blood stem cells in lungs, and using parsley for stem cell therapies

More good news on a CIRM-funded trial for spinal cord injury. The results are now in for Asterias Biotherapeutics’ Phase 1/2a clinical trial testing a stem cell-based therapy for patients with spinal cord injury. They reported earlier this week that six out of six patients treated with 10 million AST-OPC1 cells, which are a type of brain cell called oligodendrocyte progenitor cells, showed improvements in their motor function. Previously, they had announced that five of the six patients had shown improvement with the jury still out on the sixth because that patient was treated later in the trial.

 In a news release, Dr. Edward Wirth, the Chief Medical officer at Asterias, highlighted these new and exciting results:

 “We are excited to see the sixth and final patient in the AIS-A 10 million cell cohort show upper extremity motor function improvement at 3 months and further improvement at 6 months, especially because this particular patient’s hand and arm function had actually been deteriorating prior to receiving treatment with AST-OPC1. We are very encouraged by the meaningful improvements in the use of arms and hands seen in the SciStar study to date since such gains can increase a patient’s ability to function independently following complete cervical spinal cord injuries.”

Overall, the trial suggests that AST-OPC1 treatment has the potential to improve motor function in patients with severe spinal cord injury. So far, the therapy has proven to be safe and likely effective in improving some motor function in patients although control studies will be needed to confirm that the cells are responsible for this improvement. Asterias plans to test a higher dose of 20 million cells in AIS-A patients later this year and test the 10 million cell dose in AIS-B patients that a less severe form of spinal cord injury.

 Steve Cartt, CEO of Asterias commented on their future plans:

 “These results are quite encouraging, and suggest that there are meaningful improvements in the recovery of functional ability in patients treated with the 10 million cell dose of AST-OPC1 versus spontaneous recovery rates observed in a closely matched untreated patient population. We look forward to reporting additional efficacy and safety data for this cohort, as well as for the currently-enrolling AIS-A 20 million cell and AIS-B 10 million cell cohorts, later this year.”

Lungs aren’t just for respiration. Biology textbooks may be in need of some serious rewrites based on a UCSF study published this week in Nature. The research suggests that the lungs are a major source of blood stem cells and platelet production. The long prevailing view has been that the bone marrow was primarily responsible for those functions.

The new discovery was made possible by using special microscopy that allowed the scientists to view the activity of individual cells within the blood vessels of a living mouse lung (watch the fascinating UCSF video below). The mice used in the experiments were genetically engineered so that their platelet-producing cells glowed green under the microscope. Platelets – cell fragments that clump up and stop bleeding – were known to be produced to some extent by the lungs but the UCSF team was shocked by their observations: the lungs accounted for half of all platelet production in these mice.

Follow up experiments examined the movement of blood cells between the lung and bone marrow. In one experiment, the researchers transplanted healthy lungs from the green-glowing mice into a mouse strain that lacked adequate blood stem cell production in the bone marrow. After the transplant, microscopy showed that the green fluorescent cells from the donor lung traveled to the host’s bone marrow and gave rise to platelets and several other cells of the immune system. Senior author Mark Looney talked about the novelty of these results in a university press release:

Mark Looney, MD

“To our knowledge this is the first description of blood progenitors resident in the lung, and it raises a lot of questions with clinical relevance for the millions of people who suffer from thrombocytopenia [low platelet count].”

If this newfound role of the lung is shown to exist in humans, it may provide new therapeutic approaches to restoring platelet and blood stem cell production seen in various diseases. And it will give lung transplants surgeons pause to consider what effects immune cells inside the donor lung might have on organ rejection.

Add a little vanilla to this stem cell therapy. Typically, the only connection between plants and stem cell clinical trials are the flowers that are given to the patient by friends and family. But research published this week in the Advanced Healthcare Materials journal aims to use plant husks as part of the cell therapy itself.

Though we tend to focus on the poking and prodding of stem cells when discussing the development of new therapies, an equally important consideration is the use of three-dimensional scaffolds. Stem cells tend to grow better and stay healthier when grown on these structures compared to the flat two-dimensional surface of a petri dish. Various methods of building scaffolds are under development such as 3D printing and designing molds using materials that aren’t harmful to human tissue.

Human fibroblast cells growing on decellularized parsley.
Image: Gianluca Fontana/UW-Madison

But in the current study, scientists at the University of Wisconsin-Madison took a creative approach to building scaffolds: they used the husks of parsley, vanilla and orchid plants. The researchers figured that millions of years of evolution almost always leads to form and function that is much more stable and efficient than anything humans can create. Lead author Gianluca Fontana explained in a university press release how the characteristics of plants lend themselves well to this type of bioengineering:

Gianluca Fontana, PhD

“Nature provides us with a tremendous reservoir of structures in plants. You can pick the structure you want.”

The technique relies on removing all the cells of the plant, leaving behind its outer layer which is mostly made of cellulose, long chains of sugars that make up plant cell walls. The resulting hollow, tubular husks have similar shapes to those found in human intestines, lungs and the bladder.

The researchers showed that human stem cells not only attach and grow onto the plant scaffolds but also organize themselves in alignment with the structures’ patterns. The function of human tissues rely on an organized arrangement of cells so it’s possible these plant scaffolds could be part of a tissue replacement cell product. Senior author William Murphy also points out that the scaffolds are easily altered:

William Murphy, PhD

“They are quite pliable. They can be easily cut, fashioned, rolled or stacked to form a range of different sizes and shapes.”

And the fact these scaffolds are natural products that are cheap to manufacture makes this a project well worth watching.

Newest member of CIRM Board is a fan of horses, Star Trek and Harry Potter – oh, and she just happens to be a brilliant cancer researcher too.

malkas-linda

An addition to the family is always a cause for celebration, whether it be a new baby, a puppy, or, in our case, a new Board member. That’s why we are delighted to welcome City of Hope’s Linda Malkas, Ph.D., as the newest member of the CIRM Board.

Dr. Malkas has a number of titles including Professor of Molecular and Cellular Biology at Beckman Research Institute; Deputy Director of Basic Research, Comprehensive Cancer Center, City of Hope; and joint head of the Molecular Oncology Program at the Cancer Center.

Her research focus is cancer and she has a pretty impressive track record in the areas of human cell DNA replication/repair, cancer cell biomarker and therapeutic target discovery. As evidence of that, she discovered a molecule that can inhibit certain activities in cancerous cells and hopes to move that into clinical trials in the near future.

California Treasure John Chiang made the appointment saying Dr. Malkas is “extraordinarily well qualified” for the role. It’s hard to disagree. She has a pretty impressive resume:

  • She served for five years on a National Cancer Institute (NCI) subcommittee reviewing cancer center designations.
  • She has served as chair on several NCI study panels and recently took on an advisory role on drug approval policy with the Food and Drug Administration.
  • She has published more than 75 peer-reviewed articles
  • She sits on the editorial boards of several high profile medical journals.

In a news release Dr. Malkas says she’s honored to be chosen to be on the Board:

“The research and technologies developed through this agency has benefited the health of not only Californians but the nation and world itself. I am excited to see what the future holds for the work of this agency.”

With all this in her work life it’s hard to imagine she has time for a life outside of the lab, and yet she does. She has four horses that she loves to ride – not all at the same time we hope – a family, friends, dogs and cats she likes spending time with. And as if that wasn’t enough to make you want to get to know her, she’s a huge fan of Star Trek, vintage sci-fi movies and Harry Potter.

Now that’s what I call a well-rounded individual. We are delighted to have her join the CIRM Team and look forward to getting her views on who are the greater villains, Klingons or Death Eaters.

 

Don’t Be Afraid: High school stem cell researcher on inspiring girls to pursue STEM careers

As part of our CIRM scholar blog series, we’re featuring the research and career accomplishments of CIRM funded students.

Shannon Larsuel

Shannon Larsuel is a high school senior at Mayfield Senior School in Pasadena California. Last summer, she participated in Stanford’s CIRM SPARK high school internship program and did stem cell research in a lab that studies leukemia, a type of blood cancer. Shannon is passionate about helping people through research and medicine and wants to become a pediatric oncologist. She is also dedicated to inspiring young girls to pursue STEM (Science, Technology, Engineering, and Mathematics) careers through a group called the Stem Sisterhood.

I spoke with Shannon to learn more about her involvement in the Stem Sisterhood and her experience in the CIRM SPARK program. Her interview is below.


Q: What is the Stem Sisterhood and how did you get involved?

SL: The Stem Sisterhood is a blog. But for me, it’s more than a blog. It’s a collective of women and scientists that are working to inspire other young scientists who are girls to get involved in the STEM field. I think it’s a wonderful idea because girls are underrepresented in STEM fields, and I think that this needs to change.

I got involved in the Stem Sisterhood because my friend Bridget Garrity is the founder. This past summer when I was at Stanford, I saw that she was doing research at Caltech. I reconnected with her and we started talking about our summer experiences working in labs. Then she asked me if I wanted to be involved in the Stem Sisterhood and be one of the faces on her website. She took an archival photo of Albert Einstein with a group of other scientists that’s on display at Caltech and recreated it with a bunch of young women who were involved in the STEM field. So I said yes to being in the photo, and I’m also in the midst of writing a blog post about my experience at Stanford in the SPARK program.

Members of The Stem Sisterhood

Q: What does the Stem Sisterhood do?

SL: Members of the team go to elementary schools and girl scout troop events and speak about science and STEM to the young girls. The goal is to inspire them to become interested in science and to teach them about different aspects of science that maybe are not that well known.

The Stem Sisterhood is based in Los Angeles. The founder Bridget wants to expand the group, but so far, she has only done local events because she is a senior in high school. The Stem Sisterhood has an Instagram account in addition to their blog. The blog is really interesting and features interviews with women who are in science and STEM careers.

Q: How has the Stem Sisterhood impacted your life?

SL: It has inspired me to reach out to younger girls more about science. It’s something that I am passionate about, and I’d like to pursue a career in the medical field. This group has given me an outlet to share that passion with others and to hopefully change the face of the STEM world.

Q: How did you find out about the CIRM SPARK program?

SL: I knew I wanted to do a science program over the summer, but I wasn’t sure what type. I didn’t know if I wanted to do research or be in a hospital. I googled science programs for high school seniors, and I saw the one at Stanford University. It looked interesting and Stanford is obviously a great institution. Coming from LA, I was nervous that I wouldn’t be able to get in because the program had said it was mostly directed towards students living in the Bay Area. But I got in and I was thrilled. So that’s basically how I heard about it, because I googled and found it.

Q: What was your SPARK experience like?

SL: My program was incredible. I was a little bit nervous and scared going into it because I was the only high school student in my lab. As a high school junior going into senior year, I was worried about being the youngest, and I knew the least about the material that everyone in the lab was researching. But my fears were quickly put aside when I got to the lab. Everyone was kind and helpful, and they were always willing to answer my questions. Overall it was really amazing to have my first lab experience be at Stanford doing research that’s going to potentially change the world.

Shannon working in the lab at Stanford.

I was in a lab that was using stem cells to characterize a type of leukemia. The lab is hoping to study leukemia in vitro and in vivo and potentially create different treatments and cures from this research. It was so cool knowing that I was doing research that was potentially helping to save lives. I also learned how to work with stem cells which was really exciting. Stem cells are a new advancement in the science world, so being able to work with them was incredible to me. So many students will never have that opportunity, and being only 17 at the time, it was amazing that I was working with actual stem cells.

I also liked that the Stanford SPARK program allowed me to see other aspects of the medical world. We did outreach programs in the Stanford community and helped out at the blood drive where we recruited people for the bone marrow registry. I never really knew anything about the registry, but after learning about it, it really interested me. I actually signed up for it when I turned 18. We also met with patients and their families and heard their stories about how stem cell transplants changed their lives. That was so inspiring to me.

Going into the program, I was pretty sure I wanted to be a pediatric oncologist, but after the program, I knew for sure that’s what I wanted to do. I never thought about the research side of pediatric oncology, I only thought about the treatment of patients. So the SPARK program showed me what laboratory research is like, and now that’s something I want to incorporate into my career as a pediatric oncologist.

I learned so much in such a short time period. Through SPARK, I was also able to connect with so many incredible, inspired young people. The students in my program and I still have a group chat, and we text each other about college and what’s new with our lives. It’s nice knowing that there are so many great people out there who share my interests and who are going to change the world.

Stanford SPARK students.

Q: What was your favorite part of the SPARK program?

SL: Being in the lab every day was really incredible to me. It was my first research experience and I was in charge of a semi-independent project where I would do bacterial transformations on my own and run the gels. It was cool that I could do these experiments on my own. I also really loved the end of the summer poster session where all the students from the different SPARK programs came together to present their research. Being in the Stanford program, I only knew the Stanford students, but there were so many other awesome projects that the other SPARK students were doing. I really enjoyed being able to connect with those students as well and learn about their projects.

Q: Why do you want to pursue pediatric oncology?

SL: I’ve always been interested in the medical field but I’ve had a couple of experiences that really inspired me to become a doctor. My friend has a charity that raises money for Children’s Hospital Los Angeles. Every year, we deliver toys to the hospital. The first year I participated, we went to the hospital’s oncology unit and something about it stuck with me. There was one little boy who was getting his chemotherapy treatment. He was probably two years old and he really inspired to create more effective treatments for him and other children.

I also participated in the STEAM Inquiry program at my high school, where I spent two years reading tons of peer reviewed research on immunotherapy for pediatric cancer. Immunotherapy is something that really interests me. It makes sense that since cancer is usually caused by your body’s own mutations, we should be able to use the body’s immune system that normally regulates this to try and cure cancer. This program really inspired me to go into this field to learn more about how we can really tailor the immune system to fight cancer.

Q: What advice do you have for young girls interested in STEM.

SL: My advice is don’t be afraid. I think that sometimes girls are expected to be interested in less intellectual careers. This perception can strike fear into girls and make them think “I won’t be good enough. I’m not smart enough for this.” This kind of thinking is not good at all. So I would say don’t be afraid and be willing to put yourself out there. I know for me, sometimes it’s scary to try something and know you could fail. But that’s the best way to learn. Girls need to know that they are capable of doing anything and if they just try, they will be surprised with what they can do.

A stem cell clinical trial for blindness: watch Rosie’s story

Everything we do at CIRM is laser-focused on our mission: to accelerate stem cell treatments for patients with unmet medical needs. So, you might imagine what a thrill it is to meet the people who could be helped by the stem cell research we fund. People like Rosie Barrero who suffers from Retinitis Pigmentosa (RP), an inherited, incurable form of blindness, which she describes as “an impressionist painting in a foggy room”.

The CIRM team first met Rosie Barrero back in 2012 at one of our governing Board meetings. She and her husband, German, attended the meeting to advocate for a research grant application submitted by UC Irvine’s Henry Klassen. The research project aimed to bring a stem cell-based therapy for RP to clinical trials. The Board approved the project giving a glimmer of hope to Rosie and many others stricken with RP.

Now, that hope has become a reality in the form of a Food and Drug Administration (FDA)-approved clinical trial which Rosie participated in last year. Sponsored by jCyte, a company Klassen founded, the CIRM-funded trial is testing the safety and effectiveness of a non-surgical treatment for RP that involves injecting stem cells into the eye to help save or even restore the light-sensing cells in the back of the eye. The small trial has shown no negative side effects and a larger, follow-up trial, also funded by CIRM, is now recruiting patients.

Almost five years after her first visit, Rosie returned to the governing Board in February and sprinkled in some of her witty humor to describe her preliminary yet encouraging results.

“It has made a difference. I’m still afraid of public speaking but early on [before the clinical trial] it was much easier because I couldn’t see any of you. But, hello everybody! I can see you guys. I can see this room. I can see a lot of things.”

After the meeting, she sat down for an interview with the Stem Cellar team to talk about her RP story and her experience as a clinical trial participant. The three-minute video above is based on that interview. Watch it and be inspired!

Stem cells reveal developmental defects in Huntington’s disease

Three letters, C-A-G, can make the difference between being healthy and having a genetic brain disorder called Huntington’s disease (HD). HD is a progressive neurodegenerative disease that affects movement, cognition and personality. Currently more than 30,000 Americans have HD and there is no cure or treatment to stop the disease from progressing.

A genetic mutation in the huntingtin gene. caused by an expanded repeat of CAG nucleotides, the building blocks of DNA that make our genes, is responsible for causing HD. Normal people have less than 26 CAG repeats while those with 40 or more repeats will get HD. The reasons are still unknown why this trinucleotide expansion causes the disease, but scientists hypothesize that the extra CAG copies in the huntingtin gene produce a mutant version of the Huntingtin protein, one that doesn’t function the way the normal protein should.

The HD mutation causes neurodegeneration.

As with many diseases, things start to go wrong in the body long before symptoms of the disease reveal themselves. This is the case for HD, where symptoms typically manifest in patients between the ages of 30 and 50 but problems at the molecular and cellular level occur decades before. Because of this, scientists are generating new models of HD to unravel the mechanisms that cause this disease early on in development.

Induced pluripotent stem cells (iPSCs) derived from HD patients with expanded CAG repeats are an example of a cell-based model that scientists are using to understand how HD affects brain development. In a CIRM-funded study published today in the journal Nature Neuroscience, scientists from the HD iPSC Consortium used HD iPSCs to study how the HD mutation causes problems with neurodevelopment.

They analyzed neural cells made from HD patient iPSCs and looked at what genes displayed abnormal activity compared to healthy neural cells. Using a technique called RNA-seq analysis, they found that many of these “altered” genes in HD cells played important roles in the development and maturation of neurons, the nerve cells in the brain. They also observed differences in the structure of HD neurons compared to healthy neurons when grown in a lab. These findings suggest that HD patients likely have problems with neurodevelopment and adult neurogenesis, the process where the adult stem cells in your brain generate new neurons and other brain cells.

After pinpointing the gene networks that were altered in HD neurons, they identified a small molecule drug called isoxazole-9 (Isx-9) that specifically targets these networks and rescues some of the HD-related symptoms they observed in these neurons. They also tested Isx-9 in a mouse model of HD and found that the drug improved their cognition and other symptoms related to impaired neurogenesis.

The authors conclude from their findings that the HD mutation disrupts gene networks that affect neurodevelopment and neurogenesis. These networks can be targeted by Isx-9, which rescues HD symptoms and improves the mental capacity of HD mice, suggesting that future treatments for HD should focus on targeting these early stage events.

I reached out to the leading authors of this study to gain more insights into their work. Below is a short interview with Dr. Leslie Thompson from UC Irvine, Dr. Clive Svendsen from Cedars-Sinai, and Dr. Steven Finkbeiner from the Gladstone Institutes. The responses were mutually contributed.

Leslie Thompson

Steven Finkbeiner

Clive Svendsen

 

 

 

 

 

 Q: What is the mission of the HD iPSC Consortium?

To create a resource for the HD community of HD derived stem cell lines as well as tackling problems that would be difficult to do by any lab on its own.  Through the diverse expertise represented by the consortium members, we have been able to carry out deep and broad analyses of HD-associated phenotypes [observable characteristics derived from your genome].  The authorship of the paper  – the HD iPSC consortium (and of the previous consortium paper in 2012) – reflects this goal of enabling a consortium and giving recognition to the individuals who are part of it.

Q: What is the significance of the findings in your study and what novel insights does it bring to the HD field?

 Our data revealed a surprising neurodevelopmental effect of highly expanded repeats on the HD neural cells.  A third of the changes reflected changes in networks that regulate development and maturation of neurons and when compared to neurodevelopment pathways in mice, showed that maturation appeared to be impacted.  We think that the significance is that there may be very early changes in HD brain that may contribute to later vulnerability of the brain due to the HD mutation.  This is compounded by the inability to mount normal adult neurogenesis or formation of new neurons which could compensate for the effects of mutant HTT.  The genetic mutation is present from birth and with differentiated iPSCs, we are picking up signals earlier than we expected that may reflect alterations that create increased susceptibility or limited homeostatic reserves, so with the passage of time, symptoms do result.

What we find encouraging is that using a small molecule that targets the pathways that came out of the analysis, we protected against the impact of the HD mutation, even after differentiation of the cells or in an adult mouse that had had the mutation present throughout its development.

Q: There’s a lot of evidence suggesting defects in neurodevelopment and neurogenesis cause HD. How does your study add to this idea?

Agree completely that there are a number of cell, mouse and human studies that suggest that there are problems with neurodevelopment and neurogenesis in HD.  Our study adds to this by defining some of the specific networks that may be regulating these effects so that drugs can be developed around them.  Isx9, which was used to target these pathways specifically, shows that even with these early changes, one can potentially alleviate the effects. In many of the assays, the cells were already through the early neurodevelopmental stages and therefore would have the deficits present.  But they could still be rescued.

Q: Has Isx-9 been used previously in cell or animal models of HD or other neurodegenerative diseases? Could it help HD patients who already are symptomatic?

The compound has not been used that we know of in animal models to treat neurodegeneration, although was shown to affect neurogenesis and memory in mice. Isx9 was used in a study by Stuart Lipton in Parkinson’s iPSC-derived neurons in one study and it had a protective effect on apoptosis [cell death] in a study by Ryan SD et al., 2013, Cell.

We think this type of compound could help patients who are symptomatic.  Isx-9 itself is a fairly pleiotropic drug [having multiple effects] and more research would be needed [to test its safety and efficacy].

Q: Have you treated HD mice with Isx-9 during early development to see whether the molecule improves HD symptoms?

Not yet, but we would like to.

Q: What are your next steps following this study and do you have plans to translate this research into humans?

We are following up on the research in more mature HD neurons and to determine at what stages one can rescue the HD phenotypes in mice.  Also, we would need to do pharmacodynamics and other types of assays in preclinical models to assess efficacy and then could envision going into human trials with a better characterized drug.  Our goal is to ultimately translate this to human treatments in general and specifically by targeting these altered pathways.

Stem Cell Stories that Caught our Eye: stem cell insights into anorexia, Zika infection and bubble baby disease

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 model identifies new culprit for anorexia.

Eating disorders like anorexia nervosa are often thought to be caused by psychological disturbances or societal pressure. However, research into the genes of anorexia patients suggests that what’s written in your DNA can be associated with an increased vulnerability to having this disorder. But identifying individual genes at fault for a disease this complex has remained mostly out of scientists’ reach, until now.

A CIRM-funded team from the UC San Diego (UCSD) School of Medicine reported this week that they’ve developed a stem cell-based model of anorexia and used it to identify a gene called TACR1, which they believe is associated with an increased likelihood of getting anorexia.

They took skin samples from female patients with anorexia and reprogrammed them into induced pluripotent stem cells (iPSCs). These stem cells contained the genetic information potentially responsible for causing their anorexia. The team matured these iPSCs into brain cells, called neurons, in a dish, and then studied what genes got activated. When they looked at the genes activated by anorexia neurons, they found that TACR1, a gene associated with psychiatric disorders, was switched on higher in anorexia neurons than in healthy neurons. These findings suggest that the TACR1 gene could be an identifier for this disease and a potential target for developing new treatments.

In a UCSD press release, Professor and author on the study, Alysson Muotri, said that they will follow up on their findings by studying stem cell lines derived from a larger group of patients.

Alysson Muotri UC San Diego

“But more to the point, this work helps make that possible. It’s a novel technological advance in the field of eating disorders, which impacts millions of people. These findings transform our ability to study how genetic variations alter brain molecular pathways and cellular networks to change risk of anorexia nervosa — and perhaps our ability to create new therapies.”

Anorexia is a disease that affects 1% of the global population and although therapy can be an effective treatment for some, many do not make a full recovery. Stem cell-based models could prove to be a new method for unlocking new clues into what causes anorexia and what can cure it.

Nature versus Zika, who will win?

Zika virus is no longer dominating the news headlines these days compared to 2015 when large outbreaks of the virus in the Southern hemisphere came to a head. However, the threat of Zika-induced birth defects, like microcephaly to pregnant women and their unborn children is no less real or serious two years later. There are still no effective vaccines or antiviral drugs that prevent Zika infection but scientists are working fast to meet this unmet need.

Speaking of which, scientists at UCLA think they might have a new weapon in the war against Zika. Back in 2013, they reported that a natural compound in the body called 25HC was effective at attacking viruses and prevented human cells from being infected by viruses like HIV, Ebola and Hepatitis C.

When the Zika outbreak hit, they thought that this compound could potentially be effective at preventing Zika infection as well. In their new study published in the journal Immunity, they tested a synthetic version of 25HC in animal and primate models, they found that it protected against infection. They also tested the compound on human brain organoids, or mini brains in a dish made from pluripotent stem cells. Brain organoids are typically susceptible to Zika infection, which causes substantial cell damage, but this was prevented by treatment with 25HC.

Left to right: (1) Zika virus (green) infects and destroys the formation of neurons (pink) in human stem cell-derived brain organoids.  (2) 25HC blocks Zika infection and preserves neuron formation in the organoids. (3) Reduced brain size and structure in a Zika-infected mouse brain. (4) 25HC preserves mouse brain size and structure. Image courtesy of UCLA Stem Cell.

A UCLA news release summarized the impact that this research could have on the prevention of Zika infection,

“The new research highlights the potential use of 25HC to combat Zika virus infection and prevent its devastating outcomes, such as microcephaly. The research team will further study whether 25HC can be modified to be even more effective against Zika and other mosquito-borne viruses.”

Harnessing a naturally made weapon already found in the human body to fight Zika could be an alternative strategy to preventing Zika infection.

Gene therapy in stem cells gives hope to bubble-babies.

Last week, an inspiring and touching story was reported by Erin Allday in the San Francisco Chronicle. She featured Ja’Ceon Golden, a young baby not even 6 months old, who was born into a life of isolation because he lacked a properly functioning immune system. Ja’Ceon had a rare disease called severe combined immunodeficiency (SCID), also known as bubble-baby disease.

 

Ja’Ceon Golden is treated by patient care assistant Grace Deng (center) and pediatric oncology nurse Kat Wienskowski. Photo: Santiago Mejia, The Chronicle.

Babies with SCID lack the body’s immune defenses against infectious diseases and are forced to live in a sterile environment. Without early treatment, SCID babies often die within one year due to recurring infections. Bone marrow transplantation is the most common treatment for SCID, but it’s only effective if the patient has a donor that is a perfect genetic match, which is only possible for about one out of five babies with this disease.

Advances in gene therapy are giving SCID babies like Ja’Ceon hope for safer, more effective cures. The SF Chronicle piece highlights two CIRM-funded clinical trials for SCID run by UCLA in collaboration with UCSF and St. Jude Children’s Research Hospital. In these trials, scientists isolate the bone marrow stem cells from SCID babies, correct the genetic mutation causing SCID in their stem cells, and then transplant them back into the patient to give them a healthy new immune system.

The initial results from these clinical trials are promising and support other findings that gene therapy could be an effective treatment for certain genetic diseases. CIRM’s Senior Science Officer, Sohel Talib, was quoted in the Chronicle piece saying,

“Gene therapy has been shown to work, the efficacy has been shown. And it’s safe. The confidence has come. Now we have to follow it up.”

Ja’Ceon was the first baby treated at the UCSF Benioff Children’s Hospital and so far, he is responding well to the treatment. His great aunt Dannie Hawkins said that it was initially hard for her to enroll Ja’Ceon in this trial because she was a partial genetic match and had the option of donating her own bone-marrow to help save his life. In the end, she decided that his involvement in the trial would “open the door for other kids” to receive this treatment if it worked.

Ja’Ceon Golden plays with patient care assistant Grace Deng in a sterile play area at UCSF Benioff Children’s Hospital.Photo: Santiago Mejia, The Chronicle

It’s brave patients and family members like Ja’Ceon and Dannie that make it possible for research to advance from clinical trials into effective treatments for future patients. We at CIRM are eternally grateful for their strength and the sacrifices they make to participate in these trials.

Mixed Matches: How Your Heritage Can Save a Life

Today we bring you a guest blog from Athena Mari Asklipiadis. She’s the founder of Mixed Marrow, which is an organization dedicated to finding bone marrow and blood cell donors to patients of multiethnic descent. Athena helped produce a 2016 documentary film called Mixed Match that encourages mixed race and minority donors to register as adult donors.

Athena Asklipiadis

Due to the lack of diversity on the national and world bone marrow donor registries, Mixed Marrow was started in 2009 to increase the numbers of mixed race donors.

Prior to Mixed Marrow starting, other ethnic recruiters like Asians for Miracle Marrow Matches (A3M), based in Los Angeles, CA and Asian American Donor Program (AADP), based in Alameda, CA had been raising awareness in the Asian and minority communities for decades.  Closing the racial gap on the registry was something I was very much interested in helping them with so I began my outreach on the most familiar medium I knew—social media.

Because matching relies heavily on similar inherited genetic markers, I was particularly astonished seeing the less than 3% (back in 2009) sliver of the ethnic pie that mixed race donors made up.  Caucasians made up for about 70% at the time, with all minorities making up for the difference.  The ethnic breakdown made sense when comparing against actual population numbers, but a larger pool of minority donors was definitely something needed especially when multiracial people were being reported as the fastest growing demographic in the US.  Odds were just not in the favor of non-white searching patients.

Current Be The Match ethnic breakdown as of 2016.

After getting to know a local mixed race searching patient, Krissy Kobata, and hearing of her struggles finding a match, I knew I had to do my best to reach out to fellow multiracial people, most of which were young and likely online.  At the time, I was engaged with fellow hapas (half in Hawaiian Pidgin, referring mixed heritage) and mixed people via multiracial community Facebook groups and other internet forums.  One common thing I noticed, unlike topics like identity, food and culture– health was definitely not widely talked about. So with that lack of awareness, Mixed Marrow began as a facebook page and later as a website.  With the help of organizations like A3M supplying Be The Match testing kits, Mixed Marrow was able to also exist outside of the virtual world by hosting donor recruitment drives at different cultural and college events.

Athena Asklipiadis, Krissy Kobata and Mixed Match director, Jeff Chiba Stearns

After about a year of advocacy, in 2010, I connected with filmmaker Jeff Chiba Stearns to pitch an idea for a documentary on the patients I worked with.  Telling their stories in words and on flyers was not effective enough for me, I felt that more people would be inclined to register as a donor if they got to know the patients as well as I did.  Thus, the film Mixed Match was born.

Still from Mixed Match, Imani (center) and parents, Darrick and Tammy.

Still from Mixed Match, Imani mother, Tammy.

Over the course of the next 6 years, Jeff and I went on a journey across the US to gather not only patient stories, but input from pioneers in stem cell transplantation like Dr. Paul Terasaki and Dr. John E. Wagner.  It was so important to share these transplant tales while being as accurate and informed as possible.

Still from Mixed Match – Dr. Paul Teriyaki.

Our goal was to educate audiences and present a call-to-action where everyone can learn how they can save a life. Mixed Match not only highlights bone marrow and peripheral blood stem cell (PBSC) donation, but it also shares the possibilities of umbilical cord stem cells.

Mixed Match director, Jeff Chiba Stearns decided a great way to explain stem cell science and matching was through animation.  Stearns, with the help of animator, Kaho Yoshida, was able to reach across to non-medical expert audiences and create digestible and engaging imagery to teach what is usually very complex science.

Animation Still from Mixed Match.

At every screening we also make sure to host a bone marrow registry drive so audiences have the opportunity to sign up.  We have partnered with both the US national registry, Be The Match and Canadian Blood Services’ One Match registry.

Bone marrow drive at a Mixed Match screening in Toronto.

Nearly 8 years and about 40 cities later, Mixed Marrow has managed to spread advocacy for the need for more mixed race donors all over the US and even other countries like Canada, Japan, Korea and Austria all the while being completely volunteer-run.  It is our hope that through social media and film, Mixed Match, we can help share these important stories and save lives.

Further Information

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

Unproven treatment

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.

goldberg-jeffrey

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.

A horse, stem cells and an inspiring comeback story that may revolutionize tendon repair

Everyone loves a good comeback story. Probably because it leaves us feeling inspired and full of hope. But the comeback story about a horse named Dream Alliance may do more than that: his experience promises to help people with Achilles tendon injuries get fully healed and back on their feet more quickly.

Dream Alliance

Dream Alliance was bred and raised in a very poor Welsh town in the United Kingdom. One of the villagers had the dream of owning a thoroughbred racehorse. She convinced a group of her fellow townsfolk to pitch in $15 dollars a week to cover the costs of training the horse. Despite his lowly origins, Dream Alliance won his fourth race ever and his future looked bright. But during a race in 2008, one of his back hoofs cut a tendon in his front leg. The seemingly career-ending injury was so severe that the horse was nearly euthanized.

It works in horses, how about humans?
Instead, he received a novel stem cell procedure which healed the tendon and, incredibly, the thoroughbred went on to win the Welsh Grand National race 15 months later – one of the biggest races in the UK that is almost 4 miles long and involves jumping 22 fences. Researchers at the Royal Veterinary College in Liverpool developed the method and data gathered from the treatment of 1500 horses with this stem cell therapy show a 50% decrease in re-injury of the tendon.

It’s been so successful in horses that researchers at the University College of London and the Royal National Orthopaedic Hospital are currently running a clinical trial to test the procedure in humans.  Over the weekend, the Daily Mail ran a news story about the clinical trial. In it, team lead Andrew Goldberg explained how they got the human trial off the ground:

“Tendon injuries in horses are identical to those in humans, and using this evidence [from the 1500 treated horses] we were able to persuade the regulators to allow us to launch a small safety study in humans.”

Tendon repair: there’s got to be another way

Achilles tendon connects the calf muscle to the heel bone

The Achilles tendon is the largest tendon in the body and connects the calf muscle to the heel bone. It takes on a lot of strain during running and jumping so it’s a well-known injury to professional and recreational athletes but injuries also occur in those with a sedentary lifestyle. Altogether Achilles tendon injury occurs in about 5-10 people per 100,000. And about 25%-45% of those injuries require surgery which involves many months of crutches and it doesn’t always work. That’s why this stem cell approach is sorely needed.

The procedure is pretty straight forward as far as stem cell therapies go. Bone marrow from the patient’s hip is collected and mesenchymal stem cells – making up a small fraction of the marrow – are isolated. The stem cells are transferred to petri dishes and allowed to divide until there are several million cells. Then they are injected directly into the injured tendon.

A reason to be cautiously optimistic
Early results from the clinical trial are encouraging with a couple of the patients experiencing improvements. The Daily Mail article featured the clinical trial’s first patient who went from a very active lifestyle to one of excruciating ankle pain due to a gradually deteriorating Achilles tendon. Though hesitant when she first learned about the trial, the 46-year-old ultimately figured that the benefits outweighed the risk. That turned out to be a good decision:

“I worried, because no one had ever had it before, except a horse. But I was more worried I’d end up in a wheelchair. The difference now is amazing. I can do five miles on the treadmill without pain, and take my dog Honey on long walks again.”

The researchers aren’t exactly sure how the therapy works but mesenchymal stem cells are known to release factors that promote regeneration and reduce inflammation. The first patient’s positive results are just anecdotal at this point. The clinical trial is still recruiting volunteers so definitive results are still on the horizon. And even if that small trial is successful, larger clinical trials will be required to confirm effectiveness and safety. It will take time but without the careful gathering of this data, doctors and patients will remain in the dark about their chances for success with this stem cell treatment.

Hopefully the treatment proves to be successful and ushers in a golden era of comeback stories. Not just for star athletes eager to get back on the field but also for the average person whose career, good health and quality of life depends on their mobility.

Stem Cell Stories That Caught Our Eye: Three new ways to target cancer stem cells

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.

Targeting cancer stem cells. This week, three studies came out with novel ways for targeting cancer stem cells in different types of cancers. Here’s a brief run-down of this trifecta of cancer stem cell-crushing stories:

Take your vitamins! Scientists in the UK were experimenting on cancer stem cells and comparing natural substances to on-the-market cancer drugs to determine whether any of the natural substances were effective at disrupting the metabolism (the chemical reactions that keep cells alive and functioning) of cancer stem cells. Interestingly, they found that ascorbic acid, which you’ll know as Vitamin C, was ten times better at curbing cancer stem cell growth compared to a cancer drug called 2-DG.

Vitamin C has popped up as an anti-cancer treatment in the past when Nobel Laureate Linus Pauling found that it dramatically reduced the death rate in breast cancer patients. However this current study is the first to show that Vitamin C has a direct effect on cancer stem cells.

In coverage by ScienceDaily, the UK team hinted at plans to test Vitamin C in clinical trials:

“Vitamin C is cheap, natural, non-toxic and readily available so to have it as a potential weapon in the fight against cancer would be a significant step. Our results indicate it is a promising agent for clinical trials, and a as an add-on to more conventional therapies, to prevent tumour recurrence, further disease progression and metastasis.”

 

A gene called ZEB1 determines how aggressive brain tumors are. A team from Cedars-Sinai Medical Center was interested to know how cancer stem cells in aggressive brain tumors called gliomas survive, reproduce and affect patient survival. In a study published in Scientific Reports, they studied the genetic information of over 4000 brain tumor samples and found ZEB1, a gene that regulates tumor growth and is associated with patient survival.

They found that patients with a healthy copy of the ZEB1 gene had a higher survival rate and less aggressive tumors compared to patients that didn’t have ZEB1 or had a mutated version of the gene.

In coverage by ScienceDaily, the senior author on the study explained how their study’s findings will allow for more personalized treatments for patients with glioma based on whether they have ZEB1 or not:

“Patients without the gene in their tumors have more aggressive cancers that act like stem cells by developing into an uncontrollable number of cell types. This new information could help us to measure the mutation in these patients so that we are able to provide a more accurate prognosis and treatment plan.”

 

Beating resistant tumors by squashing cancer stem cells. Our final cancer stem cell story today comes from the UCLA School of Dentistry. This team is studying another type of aggressive cancer called a squamous cell carcinoma that causes tumors in the head and neck. Often these tumors resist treatment and spread to a patient’s lymph nodes, which quickly reduces their survival rate.

The UCLA team thought that maybe pesky cancer stem cells were to blame for the aggressive and resistant nature of these head and neck tumors. In a study published in Cell Stem Cell, they developed a mouse model of head and neck carcinoma and isolated cancer stem cells from the tumors of these mice. When they studied these stem cells, they found that they expressed unique proteins compared to non-cancer cells. These included Bmi1, a well-known stem cell protein, and AP-1, a transcription factor protein that regulates other cancer genes.

At left, head and neck squamous cell carcinoma invasive growth, and at right, cancer stem cells (shown in red) in head and neck squamous cell carcinoma. (Image Demeng Chen and Cun-Yu Wang/UCLA)

After identifying the culprits, the team developed a new combination strategy that targeted the cancer stem cells while also killing off the tumors using chemotherapy drugs.

In a UCLA Newsroom press release, the lead scientist on the study Dr. Cun-Yu Wang explained the importance of their study for the future treatment of cancer and solid tumors:

“This study shows that for the first time, targeting the proliferating tumor mass and dormant cancer stem cells with combination therapy effectively inhibited tumor growth and prevented metastasis compared to monotherapy in mice. Our discovery could be applied to other solid tumors such as breast and colon cancer, which also frequently metastasizes to lymph nodes or distant organs.”