The Stem Cellar | The Official Blog of CIRM, California’s …

Lessons learned from babies with heart failure could now help adults

Inspiration can sometimes come from the most unexpected of places. For English researcher Stephen Westaby it came from seeing babies who had heart attacks bounce back and recover. It led Westaby to a new line of research that could offer hope to people who have had a heart attack.

Westaby, a researcher at the John Radcliffe hospital in Oxford, England, found that implanting a novel kind of stem cell in the hearts of people undergoing surgery following a heart attack had a surprisingly significant impact on their recovery.

Westaby got his inspiration from studies showing babies who had a heart attack and experienced scarring on their heart, were able to bounce back and, by the time they reached adolescence, had no scarring. He wondered if it was because the babies own heart stem cells were able to repair the damage.

Scarring is a common side effect of a heart attack and affects the ability of the heart to be able to pump blood efficiently around the body. As a result of that diminished pumping ability people have less energy, and are at increased risk of further heart problems. For years it was believed this scarring was irreversible. This study, published in the Journal of Cardiovascular Translational Research, suggests it may not be.

Westaby and his team implanted what they describe as a novel mesenchymal precursor (iMP) type of stem cell in the hearts of patients who were undergoing heart bypass surgery following a heart attack. The cells were placed in parts of the heart that showed sizeable scarring and poor blood flow.

Two years later the patients showed a 30 percent improvement in heart function, a 40 percent reduction in scar size, and a 70 percent improvement in quality of life.

In an interview with the UK Guardian newspaper, Westaby admitted he was not expecting such a clear cut benefit:

Quite frankly it was a big surprise to find the area of scar in the damaged heart got smaller,

Of course it has to be noted that the trial was small, only involving 11 patients. Nonetheless the findings are important and impressive. Westaby and his team now hope to do a much larger study.

CIRM is funding a clinical trial with Capricor that is taking a similar approach, using stem cells to rejuvenate the hearts of patients who have had heart attacks.

Fred Lesikar, one of the patients in the first phase of that trial, experienced a similar benefit to those in the English trial and told us about it in our Stories of Hope.

Like Loading...

A healthy T cell

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.

Directing the creation of T cells. To paraphrase the GOP Presidential nominee, any sane person LOVES, LOVES LOVES their T cells, in a HUGE way, so HUGE. They scamper around the body getting rid of viruses and the tiny cancers we all have in us all the time. A CIRM-funded team at CalTech has worked out the steps our genetic machinery must take to make more of them, a first step in letting physicians turn up the action of our immune systems.

We have known for some time the identity of the genetic switch that is the last, critical step in turning blood stem cells into T cells, but nothing in our body is as simple as a single on-off event. The Caltech team isolated four genetic factors in the path leading to that main switch and, somewhat unsuspected, they found out those four steps had to be activated sequentially, not all at the same time. They discovered the path by engineering mouse cells so that the main T cell switch, Bcl11b, glows under a microscope when it is turned on.

We identify the contributions of four regulators of Bcl11b, which are all needed for its activation but carry out surprisingly different functions in enabling the gene to be turned on, said Ellen Rothenberg, the senior author in a university press release picked up by Innovations Report. Its interestingthe gene still needs the full quorum of transcription factors, but we now find that it also needs them to work in the right order.

Video primer on stem cells in the brain. In conjunction with an article in its August issue, Scientific American posted a video from the Brain Forum in Switzerland of Elena Cattaneo of the University of Milan explaining the basics of adult versus pluripotent stem cells, and in particular how we are thinking about using them to repair diseases in the brain.

The 20-minute talk gives a brief review of pioneers who stood alone in unmarked territory. She asks how can stem cells be so powerful; and answers by saying they have lots of secrets and those secrets are what stem cell scientist like her are working to unravel. She notes stem cells have never seen a brain, but if you show them a few factors they can become specialized nerves. After discussing collaborations in Europe to grow replacement dopamine neurons for Parkinsons disease, she went on to describe her own effort to do the same thing in Huntingtons disease, but in this case create the striatal nerves lost in that disease.

The video closes with a discussion of how basic stem cell research can answer evolutionary questions, in particular how genetic changes allowed higher organisms to develop more complex nervous systems.

CIRM Science Officers Kelly Shepard and Kent Fitzgerald

A stem cell review that hits close to home. IEEE Pulse, a publication for scientists who mix engineering and medicine and biology, had one of their reporters interview two of our colleagues on CIRMs science team. They asked senior science officers Kelly Shepard and Kent Fitzgerald to reflect on how the stem cell field has progressed based on their experience working to attract top researchers to apply for our grants and watching our panel of outside reviewers select the top 20 to 30 percent of each set of applicants.

One of the biggest changes has been a move from animal stem cell models to work with human stem cells, and because of CIRMs dedicated and sustained funding through the voter initiative Proposition 71, California scientists have led the way in this change. Kelly described examples of how mouse and human systems are different and having data on human cells has been critical to moving toward therapies.

Kelly and Kent address several technology trends. They note how quickly stem cell scientists have wrapped their arms around the new trendy gene editing technology CRISPR and discuss ways it is being used in the field. They also discuss the important role of our recently developed ability to perform single cell analysis and other technologies like using vessels called exosomes that carry some of the same factors as stem cells without having to go through all the issues around transplanting whole cells.

Were really looking to move things from discovery to the clinic. CIRM has laid the foundation by establishing a good understanding of mechanistic biology and how stem cells work and is now taking the knowledge and applying it for the benefit of patients, Kent said toward the end of the interview.

Jake Javier and his family

Jakes story: one young mans journey to and through a stem cell transplant; As a former TV writer and producer I tend to be quite critical about the way TV news typically covers medical stories. But a recent story on KTVU, the Fox News affiliate here in the San Francisco Bay Area, showed how these stories can be done in a way that balances hope, and accuracy.

Reporter Julie Haener followed the story of Jake Javier we have blogged about Jake before a young man who broke his spine and was then given a stem cell transplant as part of the Asterias Biotherapeutics clinical trial that CIRM is funding.

Its a touching story that highlights the difficulty treating these injuries, but also the hope that stem cell therapies holds out for people like Jake, and of course for his family too.

If you want to see how a TV story can be done well, this is a great example.

Like Loading...

A recent study estimated there may be more than 500 million people worldwide who have diabetes. Thats an astounding figure and makes diabetes one of the largest chronic disease epidemics in human history.

One of the most serious consequences of untreated or uncontrolled diabetes is kidney damage. That can lead to fatigue, weakness, confusion, kidney failure and even death. So two decisions taken by the CIRM Board today were good news for anyone already suffering from either diabetes or kidney disease. Or both.

The Board awarded almost $10 million to Humacyte to run a Phase 3 clinical trial of an artificial vein needed by people undergoing hemodialysis thats the most common form of dialysis for people with kidney damage. Hemodialysis helps clean out impurities and toxins from the blood. Without it waste will build up in the kidneys with devastating consequences.

The artificial vein is a kind of bioengineered blood vessel. It is implanted in the individuals arm and, during dialysis, is connected to a machine to move the blood out of the body, through a filter, and then back into the body. The current synthetic version of the vein is effective but is prone to clotting and infections, and has to be removed regularly. All this puts the patient at risk.

Humacytes version called a human acellular vessel or HAV uses human cells from donated aortas that are then seeded onto a biodegradable scaffold and grown in the lab to form the artificial vein. When fully developed the structure is then washed to remove all the cellular tissue, leaving just a collagen tube. That is then implanted in the patient, and their own stem cells grow onto it, essentially turning it into their own tissue.

In earlier studies Humacytes HAV was shown to be safer and last longer than current versions. As our President and CEO, Randy Mills, said in a news release, thats clearly good news for patients:

This approach has the potential to dramatically improve our ability to care for people with kidney disease. Being able to reduce infections and clotting, and increase the quality of care the hemodialysis patients get could have a significant impact on not just the quality of their life but also the length of it.

There are currently almost half a million Americans with kidney disease who are on dialysis. Having something that makes life easier, and hopefully safer, for them is a big plus.

The Humacyte trial is looking to enroll around 350 patients at three sites in California; Sacramento, Long Beach and Irvine.

While not all people with diabetes are on dialysis, they all need help maintaining healthy blood sugar levels, particularly people with type 1 diabetes. Thats where the $3.9 million awarded to ViaCyte comes in.

Were already funding a clinical trial with ViaCyte using an implantable delivery system containing stem cell-derived cells that is designed to measure blood flow, detect when blood sugar is low, then secrete insulin to restore it to a healthy level.

This new program uses a similar device, called a PEC-Direct. Unlike the current clinical trial version, the PEC-Direct allows the patients blood vessels to directly connect, or vasularize, with the cells inside it. ViaCyte believes this will allow for a more robust engraftment of the stem cell-derived cells inside it and that those cells will be better able to produce the insulin the body needs.

Because it allows direct vascularization it means that people who get the delivery system will also need to get chronic immune suppression to stop their bodys immune system attacking it. For that reason it will be used to treat patients with type 1 diabetes that are at high risk for acute complications such as severe hypoglycemic (low blood sugar) events associated with hypoglycemia unawareness syndrome.

In a news release Paul Laikind, Ph.D., President and CEO of ViaCyte, said this approach could help patients most at risk.

This high-risk patient population is the same population that would be eligible for cadaver islet transplants, a procedure that can be highly effective but suffers from a severe lack of donor material. We believe PEC-Direct could overcome the limitations of islet transplant by providing an unlimited supply of cells, manufactured under cGMP conditions, and a safer, more optimal route of administration.

The Board also approved more than $13.6 million in awards under our Discovery program. You can see the winners here.

Like Loading...

Now that Asterias Biotherapeutics CIRM-funded, stem cell-based clinical trial for spinal cord injury (SCI) has safely treated its first group of patients and begun recruiting the second, should other SCI researchers close up shop? Of course not. Since its a first-in-human trial, there certainly will be room for improvement even if the therapy proves successful. And it may not work for every SCI victim. So the development of other therapeutic approaches is critical to ensure effective treatments for all patients with this unmet medical need.

Enter the lab of Michael Fehlings at the University of Toronto. Their recent Stem Cells Translational Medicine study describes a potential, minimally invasive therapeutic strategy which involvesa type of brain cell not previously studied in the context of SCI.

In the case of the Asterias trial, embryonic stem cell-derived cells called oligodendrocytes are being transplanted directly into the injured spinal cord to help restore the disrupted nerve signals that cause a whole range of debilitating symptoms, including painful tingling and loss of movement in arms and legs, loss of bladder control and difficulty breathing.

Instead of trying to directly repair the disconnected nerve signals, Fehlings team looked at reducing the damaging effects of inflammation that occur at the site of injury in the days and weeks following the spinal cord trauma. This sounds like a perfect job for mesenchymal stem cells (MSCs) whose anti-inflammatory effects are well established. But previous animal studies using MSCs for spinal cord injury have had mixed results. Different sources of MSCs are known to have different anti-inflammatory actions so perhaps this is the culprit behind the variability. On top of that, the exact mechanism of action isnt well understood which presents a barrier to getting FDA approval for clinical trials.

So the current study performed a careful comparative analysis of the healing effects of human cord blood MSCs and human brain vascular pericytes (HBVPs) MSC-like cells found near blood vessels in the brain in a rat model of spinal cord injury. Shortly after the SCI injury, the cells were delivered into the rats through the blood. The blood levels of various cytokines proteins that modulate the inflammation response were measured for several days. The only cytokine that increased in the days after the cell delivery of either cell type was IL-10 which is known for its anti-inflammatory effects.

Examining the spinal cord one to seven days after injury, the researchers found that both MSCs and HBVPs were better than controls at reducing hemorrhaging, with the HBVPs showing better improvement. In terms of long-term effects on functional behaviors, the researchers showed that after three weeks, grip strength, body coordination, and hind limb movement were most improved in the HBVPs.

In a university press release, Fehlings described these promising results:

Michael Fehlings

Our study demonstrates that these cells not only display a MSC phenotype in a dish, but also have similar immunomodulatory effects in animals after spinal cord injury that are more potent than those of non-central nervous system tissue-derived cells. Therefore, these cells are of interest for therapeutic use in acute spinal cord injury.

A lot more work will be needed to translate these findings into clinical trials but for the sake of those suffering from spinal cord injury its encouraging that alternative approaches to treating this devastating, life-changing condition are in development.

Like Loading...

Where will stem cell research be in 10 years?

What would you say to patients who wanted stem cell therapies now?

What are the most promising applications for stem cell research?

Why is it important for the government to fund regenerative medicine?

These challenging and thought-provoking questions were posed to a vibrant group of undergraduate and masters-level students at this years CIRM Bridges to Stem Cell Research and Therapy conference.

Educating the next generation of stem cell scientists

The Bridges program is one of CIRMs educational programs that offers students the opportunity to take coursework at California state schools and community colleges and conduct stem cell research at top universities and industry labs. Its goal is to train the next generation of stem cell scientists by giving them access to the training and skills necessary to succeed in this career path.

The Bridges conference is the highlight of the program and the culmination of the students achievements. Its a chance for students to showcase the research projects theyve been working on for the past year, and also for them to network with other students and scientists.

Bridges students participated in a networking pitch event about stem cell research.

CIRM kicked off the conference with a quick and dirty Stem Cell Pitch networking event. Students were divided into groups, given one of the four questions above and tasked with developing a thirty second pitch that answered their question. They were only given ten minutes to introduce themselves, discuss the question, and pick a spokesperson, yet when each teams speaker took the stage, it seemed like they were practiced veterans. Every team had a unique, thoughtful answer that was inspiring to both the students and to the other scientists in the crowd.

Getting to the clinic and into patients

The bulk of the Bridges conference featured student poster presentations and scientific talks by leading academic and industry scientists. The theme of the talks was getting stem cell research into the clinic and into patients with unmet medical needs.

Here are a few highlights and photos from the talks:

On the clinical track for Huntingtons disease

Leslie Thompson, Professor at UC Irvine, spoke about her latest research in Huntingtons disease (HD). She described her work as a race against time. HD is a progressive neurodegenerative disorder thats associated with multiple social and physical problems and currently has no cure. Leslie described how her lab is heading towards the clinic with human embryonic stem cell-derived neural (brain) stem cells that they are transplanting into mouse models of HD. So far, theyve observed positive effects in HD mice that received human neural stem cell transplants including an improvement in the behavioral and motor defects and a reduction in the accumulation of toxic mutant Huntington protein in their nerve cells.

Leslie Thompson

Leslie noted that because thetransplanted stem cells are GMP-grade (meaning their quality is suitable for use in humans), they have a clear path forward to testing their potential disease modifying activity in human clinical trials. But before her team gets to humans, they must take the proper regulatory steps with the US Food and Drug Administration and conduct further experiments to test the safety and proper dosage of their stem cells in other mouse models as well as test other potential GMP-grade stem cell lines.

Gene therapy for SCID babies

Morton Cowan, a pediatric immunologist from UC San Francisco, followed Leslie with a talk about his efforts to get gene therapy for SCID (severe combined immunodeficiency disease) off the bench into the clinic. SCID is also known as bubble-baby disease and put simply, is caused by a lack of a functioning immune system. SCID babies dont have normal T and B immune cell function and as a result, they generally die of infection or other conditions within their first year of life.

Morton Cowan, UCSF

Morton described how the gold standard treatment for SCID, which is hematopoietic or blood stem cell transplantation, is only safe and effective when the patient has an HLA matched sibling donor. Unfortunately, many patients dont have this option and face life-threatening challenges of transplant rejection (graft-versus host disease). To combat this issue, Morton and his team are using gene therapy to genetically correct the blood stem cells of SCID patients and transplant those cells back into these patients so that they can generate healthy immune cells.

They are currently developing a gene therapy for a particularly hard-to-treat form of SCID that involves deficiency in a protein called Artemis, which is essential for the development of the immune system and for repairing DNA damage in cells. Currently his group is conducting the necessary preclinical work to start a gene therapy clinical trial for children with Artemis-SCID.

Treating spinal cord injury in the clinic

Casey Case, Asterias Biotherapeutics

Casey Case,Senior VP of Research and Nonclinical Development at Asterias Biotherapeutics, gave an update on the CIRM-funded clinical trial for cervical (neck) spinal cord injury (SCI). They are currently testing the safety of transplanting different doses of their oligodendrocyte progenitor cells (AST-OPC1) in a group of SCI patients. The endpoint for this trial is an improvement in movement greater than two motor levels, which would offer a significant improvement in a patients ability to do some things on their own and reduce the cost of their healthcare. You can read more about these results and the ongoing study in our recent blogs (here, here).

Opinion: Scientists should be patient advocates

David Higgins gave the most moving speech of the day. He is a Parkinsons patient and the Patient Advocate on the CIRM board and he spoke about what patient advocates are and how to become one. David explained how, these days, drug development and patient advocacy is more patient oriented and patients are involved at the center of every decision whether it be questions related to how a drug is developed, what side effects should be tolerated, or what risks are worth taking. He also encouraged the Bridges students to become patient advocates and understand what their needs are by asking them.

David Higgins

As a scientist or clinician, you need to be an ambassador. You have a job of translating science, which is a foreign language to most people, and you can all effectively communicate to a lay audience without being condescending. Its important to understand what patients needs are, and youll only know that if you ask them. Patients have amazing insights into what needs to be done to develop new treatments.

Bridging the gap between research and patients

The Bridges conference is still ongoing with more poster presentations, a career panel, and scientific talks on discovery and translational stem cell research and commercializing stem cell therapies to all patients in need. It truly is a once in a lifetime opportunity for the Bridges students, many of whom are considering careers in science and regenerative medicine and are taking advantage of the opportunity to talk and network with prominent scientists.

If youre interested in hearing more about the Bridges conference, follow us on twitter (@CIRMnews, @DrKarenRing, #CIRMBridges2016) and on Instagram (@CIRM_Stemcells).

Like Loading...

Read more:

The Stem Cellar | The Official Blog of CIRM, California's ...