How many stem cell trials will it take to get a cure?

When I think about how many clinical trials it will take before a stem cell therapy is available to patients, I’m reminded of the decades old Tootsie Pop commercial where a kid asks a series of talking animals, “How many licks does it take to get to the Tootsie Roll center of a Tootsie Pop?”

While Mr. Cow, Mr. Fox, and Mr. Turtle are all stumped, Mr. Owl tackles the question like a true scientist:

“A good question. Let’s find out. [Takes Tootsie pop and starts licking]. A One…A Two-hoo…A Three-hee. [Insert loud crunching sounds] A Three!”

The commercial ends with the narrator concluding that the world may never know how many licks it takes to get to the center (because Mr. Owl failed to complete his experiment…not a true scientist after all).

What do Tootsie Pops have to do with stem cell therapies?

I’m not saying that the Tootsie Pop question holds the same level of importance as the question of when scientists will develop a stem cell therapy that cures a disease, but I find it representative of the confusion and uncertainty that the general public has about when the “promise of stem cell research” will become a reality.

Let me explain…

Mr. Owl claims that it only takes three licks to get to the center of a Tootsie Pop, but three licks obviously aren’t enough to get through the hard candy exterior to the chewy tootsie center. According to the Tootsie “Scientific Endeavors” page, “at least three detailed scientific studies” determined that it takes between 144-411 licks to get to the center. My intuition is to go with the scientists, but depending on how the experiment was conducted or maybe the size of the tongue used, the final answer could vary.

Embryonic stem cells

Embryonic stem cells

For stem cell clinical trials, the situation is similar. The first clinical trial approved in the U.S. using human embryonic stem cells was in 2009. Since then, hundreds of clinical trials have been conducted globally using pluripotent – either embryonic or induced pluripotent stem cells (iPSCs) – or adult stem cells. But so far, none have made their way routinely to patients outside of a clinical trial setting in the U.S., (although a few stem cell-based products have been approved in other countries), and it’s unclear how many more trials it will take to get to this point.

Part of this murkiness is because we’re still in the early days of stem cell research: human embryonic stem cells were first isolated by James Thomson in 1998, and iPSCs weren’t discovered by Shinya Yamanaka until 2006. Scientists need more time to conduct preclinical research to understand how these stem cells can be best used to treat certain diseases and what stem cells will do when transplanted into patients.

Another other issue is that the U.S. Food and Drug Administration (FDA) has only approved one stem cell therapy – cord blood stem cell transplantation – for commercial use in 2011 and none since then. A big debate is currently ongoing about whether the regulatory landscape needs to change so that stem cell treatments that show promise in trials can get to patients who desperately need them.

Hopefully soon, the FDA will adopt a more efficient strategy for approving stem cell therapies that still keeps patient safety at the forefront. Otherwise it could take a lot longer for newer stem cell technologies like iPSCs to make their way to the clinic (although we’ve seen some encouraging preliminary results using iPSC-based therapy in clinical trials for blindness).

Trial, trial, trial again

So how many clinical trials will it take for a stem cell therapy to succeed sufficiently to gain approval and when will that happen?

Unfortunately, we don’t know the answers to these questions, but we do know that scientists need to continue to develop and test new stem cell treatments in human trials if we want to see any progress.

At CIRM, we are currently funding 16 clinical trials involving stem cell therapies for cancer, heart failure, diabetes, spinal cord injury and other diseases. But we need to fund more trials to increase the odds that some will make it through the gauntlet and prove both safe and effective at treating patients. Our goal now is to fund 50 clinical trials in the next five years. It’s an aggressive plan, but one we feel will hopefully take stem cell therapies from promise to reality.

We also know that CIRM is a soldier in a large army of funding agencies, universities, companies, and scientists around the world battling against time to develop stem cell therapies that could help patients in their lifetimes. And with this stem cell army, we believe we’re getting closer to the chewy center of the Tootsie pop, or in this case, an approved stem cell therapy for patients desperate for a cure.

This blog was written as part of the CCRM Signals iPSC anniversary blog carnival. Please click here to read what other bloggers have to say about the future of stem cells and regenerative medicine.

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

stroke

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.

 

 

 

 

 

 

 

Better, Faster Quality Control for Stem Cell-Based Therapies

“Based”.

It’s a pretty boring word but I make sure to include it when writing about the development of stem cell therapies, as in: “Asterias Biotherapeutics is testing an embryonic stem cell-based treatment for spinal cord injury”. It’s a key word here because no legitimate clinic would transplant embryonic stem cells (ESCs) or induced pluripotent stem cells (iPSCs) directly into a patient. The ability of these cells to make unlimited copies of themselves is great for growing them in the lab; but in the body, that same property presents a very real risk of tumor formation. Instead, ESCs and iPSCs are merely the base material from which specialized cells are matured from for the many promising therapies being developed for clinical trials.

To ensure safety to patients, minimizing the number of these potentially cancer-causing pluripotent stem cells still lingering in a cell therapy product is one of the main safety concerns of the Food and Drug Administration (FDA), the U.S. federal agency that approves therapies for clinical trials. So during therapy development, researchers run assays, or tests, to detect how many ESCs or iPSCs remain in their cell product and if they can form tumors.

In a paper published yesterday in Biomaterials, an Emory University research team reported on the development of a new technique that is several thousand-fold (!!!) higher in sensitivity than current assays and could be a game-changer for the quality control of stem cell-based therapies (also see an Emory U. blog about the study).

Surface-enhanced Raman Scattering Assay: it’s one in a million

SERS-schematic

Illustrated overview of the SERS assay workflow (Image: Biomaterials)

In the technique, called a surface-enhanced Raman scattering (SERS) assay, gold nanoparticles are attached to proteins, called antibodies, that specifically bind to the surface of stem cells. These antibody-nanoparticles are mixed with a preparation of the cell product. A laser is then directed at the cells and a device, called a spectrometer, measures the resulting light scatter which ultimately can be converted into the number of stem cells in the cell mix.

Incredibly, this assay can detect one stem cell out of one million specialized cells making it well suited for testing clinical grade cell therapy products. In comparison, the current flow cytometry technique which uses fluorescently tagged antibodies, can spot 1 stem cell in about 1000 cells.

Another current way to detect stem cells in a cell product is through the so-called teratoma assay. In this test, a mouse is injected with the cell therapy and observed for about three months to see if any teratomas, or tumors, form from residual stem cells. While this technique is a more direct safety test, it’s very costly, time-consuming, and impractical for testing very large doses of cell therapies. As the authors mention in the publication, the SERS technique could help overcome the limitations of both the teratoma and flow cytometry assays:

“Because of their remarkable sensitivity, these SERS assays may facilitate safety assessment of cell preparations for transplantations that require a large quantity of cells, which is unachievable using flow cytometry or the teratoma assay in mice. In addition, these assays are cost-effective, easy to use, and can be done within an hour, which is much faster than the traditional teratoma assay.”

“Faster”. Now that’s a pretty exciting word I always like to include when writing about the development of stem cell therapies.

 

A look back at the last year – but with our eyes firmly on the future

Randy

CIRM President & CEO Randy Mills doesn’t want “good”, he wants “better”

Better.

With that single word Randy Mills, our President and CEO, starts and ends his letter in our 2015 Annual Report and lays out the simple principle that guides the way we work at CIRM.

Better.

But better what?

“Better infrastructure to translate early stage ideas into groundbreaking clinical trials. Better regulatory practices to advance promising stem cell treatments more efficiently. Better treatments for patients in need.”

“Better” is also the standard everyone at CIRM holds themselves to. Getting better at what we do so we can fulfill our mission of accelerating stem cell treatments to patients with unmet medical needs.

The 2015 Annual Report highlights the achievements of the last year, detailing how we invested $135 million in 47 different projects at all levels of research. How our Board unanimously passed our new Strategic Plan, laying out an ambitious series of goals for the next five years from funding 50 new clinical trials, to creating a new regulatory process for stem cell therapies.

Snapshot of CIRM's 2015 Funding

The report offers a snapshot of where our money has gone this year, and how much we have left. It breaks down what percentage of our funding has gone to different diseases and how much we have spent on administration.

Jonathan Thomas, the Chair of our Board, takes a look back at where we started, 10 years ago, comparing what we did then (16 awards for a total of $12.5 million) to what we are doing today. His conclusion; we’re doing better.

But we still have a long way to go. And we are determined to get even better.

P.S. By the way we are changing the way we do our Annual Report. Our next one will come out on January 1, 2017. We figured it just made sense to take a look back at the last year as soon as the new year begins. It gives you a better (that word again) sense of what we did and where we  are heading. So look out for that, coming sooner than you think.

Fujifilm is Expanding Its Focus to Regenerative Medicine

Fujifilm began as a photography company, but today is a well-known multinational imaging and information technology corporation. More recently, it’s expanded its focus (pun intended) on developing innovative technologies in the healthcare and regenerative medicine space.

The news that Fujifilm was expanding into regenerative medicine was surprising to some given the company’s expertise in areas unrelated to stem cell research, but with the acquisition of Cellular Dynamics International, a company from Madison, Wisconsin that specializes in large-scale manufacturing of human cells, and the revamping of Fujifilm’s Japan Tissue Engineering subsidiary, which is developing regenerative treatments for damaged skin and cartilage, Fujifilm has solidified its position as a competitive company that’s accelerating the pace of regenerative medicine to develop treatments for patients with unmet medical needs.

Mr. Ban

Mr. Toshikazu Ban

So what progress has Fujifilm made in regenerative medicine and what advancements are they making towards the clinic? You’ll find the answers to these burning questions in my interview with Mr. Toshikazu Ban, Corporate Vice President, General Manager of Regenerative Medicine Business Division at Fujifilm Corporation. Enjoy!

Q: Why did Fujifilm decide to enter the regenerative medicine space?

TB: At first glance, Fujifilm may seem an unlikely candidate to become a leader in regenerative medicine, yet its engagement in the healthcare industry goes back many decades. Founded in 1934, Fujifilm started offering X-ray film just two years later. By 1983, Fujifilm became the first in the world to offer a digital X-ray diagnostic imaging system.

Today, Fujifilm has been able to expand the use of its core fundamental technologies in cosmetics and supplements and pharmaceuticals. Combined, these have allowed Fujifilm to transform into a major healthcare company committed to prevention, diagnosis and treatment.

Unfortunately, there are still many diseases for which there are no effective treatments, and millions wait in hope of their discovery. Regenerative medicine treatment has the potential to cure diseases that cannot be cured by drugs. Fujifilm feels a sense of responsibility to apply its technology in a way that helps make promising treatments a reality.

Q: What advantages do you think Fujifilm has over other healthcare companies in regenerative medicine?

TB: Fujifilm’s advanced engineering technology provides tremendous possibilities in the regenerative medicine space.

The chief component in photographic film is gelatin, which is derived from collagen. Fujifilm has developed a human-type recombinant peptide which can be scaffolds for growing cells and restoring tissue.  The human-type recombinant peptide is non-animal based, has high cellular adhesiveness, is flexible, safe, biocompatible, biodegradable and bioabsorbable. Cells survive better when they are combined with our recombinant peptide because it holds the cells better and allows space in between so that oxygen and other critical growth factors can reach the cells.

Fujifilm also has two subsidiaries that provide synergies and efficiencies to be more competitive in the regenerative medicine field, Cellular Dynamics International, Inc., (FCDI), and Japan Tissue Engineering Co., Ltd. (J-TEC).

In 2015, FCDI announced the launch of a stem cell bank with funding from CIRM to create induced pluripotent stem (iPS) cell lines for each of 3,000 healthy and diseased volunteer donors across 11 common diseases and disorders to be made available through the CIRM human pluripotent stem cell (hPSC) Repository.

The lines available from the CIRM stem cell bank directly complement FCDI’s ability to provide differentiated cells corresponding to each of the iPSC lines, which will allow researchers to model the diseases represented, better understand disease progression, perform more targeted drug discovery, and ultimately lead to better treatments.

A lot of pharmaceutical companies use these cells to test for the screening and toxicity of new drug candidates. If iPS cells can improve the productivity including efficacy and safety, the technology can greatly reduce time and cost as well as the drop-out rate in clinical development.

In 2014, J-TEC became a consolidated Fujifilm Group subsidiary. J-TEC launched the first two regenerative medicine products to receive approval from the Japanese government (one product is used to treat severe burns, while the other is used to replace damaged cartilage in knees).

J-TEC Lab (Image courtesy of Fujifilm)

J-TEC Lab (Image courtesy of Fujifilm)

Q: Can you describe some of the stem cell therapies you’re developing for the clinic for major diseases?

TB: FCDI plans to start iPS cell therapy clinical studies in the U.S. for age related macular degeneration in the year 2017, and clinical studies for retinitis pigmentosa, Parkinson’s and heart failure around 2019.

In March 2015, Fujifilm announced it had developed diabetes therapies in animal tests. CellSaic is a three-dimensional mosaic structure that combines cells with a recombinant peptide (RCP) scaffold made from micro-sized petaloid pieces of the protein. In a study involving type 1 diabetic mice, we created a CellSaic of human mesenchymal stem cells and cells from pancreatic islets and transplanted them in the mice. The purpose of the study was to verify whether using the recombinant peptide as a scaffold would increase the survival rate of the transplanted cells compared with just transplanting the cells alone. We also wanted to demonstrate a reduction in blood glucose levels of the diabetic mice since the recombinant peptide was able to sustain the viability of the pancreatic islet cells.

The study showed that seven days after the transplantation, CellSaic had a significantly more prominent introduction of blood vessels, which provide passageways for nutrients, oxygen and waste product to get to, and away from, the cells.  In addition, 28 days after transplantation, the test group of diabetic mice with the recombinant peptide-based CellSaic scaffold saw blood glucose levels lowered to the level equivalent to that of the healthy mice. In contrast, the diabetic mice who received pancreatic islets alone showed no change in blood glucose levels. 

Q: When you move into clinical trials, do you anticipate US trial sites in parallel with those in Japan?

TB: FCDI plans to start clinical trials of iPS cell treatments in the US. J-TEC conducts clinical trials for autologous cultured corneal epithelium and plans to start clinical trials for allogeneic cultured dermis in Japan. Currently we plan to conduct these clinical trials where these companies are located. We may expand the clinical trials of the products to other countries in the future.

Q: Can you speak to Japan’s regulatory system for stem cell therapies and how this could give Fujifilm a leg up on developing stem cell treatments more rapidly?

TB: The go-to market conditions for regenerative medicine in Japan have become more favorable since the November 2014 implementation of the Pharmaceutical and Medical Device Law, which has significantly cut the time it takes to gain marketing approval in Japan and created more interest in this sector.

Within regenerative medicine, academic institutions have shown remarkable progress. The mission of the industry is to apply findings from academia to patients and deliver high-quality treatments at a reasonable cost.

Note: Technologies that pertain to Japan Tissue Engineering Co., Ltd. (J-TEC) are not approved for use in the US.

You can learn more about Fujifilm’s latest efforts to “make regenerative medicine a reality” by visiting its Innovation website.

Stem cell stories that caught our eye: potential glaucoma therapy, Parkinson’s model, clinical trial list, cancer immune therapy

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 cells may be option in glaucoma.  A few (potentially) blind mice did not run fast enough in an Iowa lab. But lucky for them they did not run into a farmer’s wife wielding a knife. Instead they had their eye sight saved by a team at the University of Iowa that corrected the plumbing in the back of their eyes with stem cells. They had a rodent version of glaucoma, which allows fluid to build up in the eye causing pressure that eventually damages the optic nerve and leads to blindness.

human eye

The fluid buildup results from a breakdown of the trabecular meshwork, a patch of cells that drains fluid from the eye. The Iowa researchers repaired that highly valuable patch with cells grown from iPS type stem cells created by reprogramming adult cells into an embryonic-like state. The trick with any early stage stem cell is getting it to mature into the desired tissue. This team pulled that off by growing the cells in a culture dish that had previously housed trabecular meshwork cells, which must have left behind some chemical signals that directed the growth of the stem cells.

The cells restored proper drainage in the mice. Also notable, the cells not only acted to replace damaged tissue directly, but they also seem to have summoned the eye’s own healing powers to do more repair. The research team also worked at the university affiliated Veterans Affairs Hospital, and the VA system issued a press release on the work published in the Proceedings of the National Academy of sciences, which was posted by Science Codex.

 

A “mini-brain” from a key area.   The brain is far from a uniform organ. Its many distinct divisions have very different functions. A few research teams have succeeded in coaxing stem cells into forming multi-layered clumps of cells referred to as “brain organoids” that mimic some brain activity, but those have generally been parts of the brain near the surface responsible for speech, learning and memory. Now a team in Singapore has created an organoid that shows activity of the mid-brain, that deep central highway for signals key to vision, hearing and movement.

The midbrain houses the dopamine nerves damaged or lost in Parkinson’s disease, so the mini-brains in lab dishes become immediate candidates for studying potential therapies and they are likely to provide more accurate results than current animal models.

 “Considering one of the biggest challenges we face in PD research is the lack of accessibility to the human brains, we have achieved a significant step forward. The midbrain organoids display great potential in replacing animals’ brains which are currently used in research,” said Ng Huck Hui of A*Star’s Genome Institute of Singapore where the research was conducted in a press release posted by Nanowerk.

The website Mashable had a reporter at the press conference in Singapore when the institute announce the publication of the research in Cell Stem Cell. They have some nice photos of the organoids as well as a microscopic image showing the cells containing a black pigment typical of midbrain cells, one of the bits of proof the team needed to show they created what they wanted.

 

Stem cell clinical trials listings.  Not a day goes by that I, or one of my colleagues, do not refer a desperate patient or family member—often several per day—to the web site clinicaltrials.gov. We do it with a bit of unease and usually some caveats but it is the only resource out there providing any kind of searchable listing of clinical trials. Not everything listed at this site maintained by the National Institutes of Health (NIH) is a great clinical trial. NIH maintains the site, and sets certain baseline criteria to be listed, but the agency does not vet postings.

Over the past year a new controversy has cropped up at the site. A number of for profit clinics have registered trials that require patients to pay many thousands of dollars for the experimental stem cell procedure.  Generally, in clinical trials, participation is free for patients. Kaiser Health News, an independent news wire supported by the Kaiser Family Foundation distributed a story this week on the phenomenon that was picked up by a few outlets including the Washington Post. But the version with the best links to added information ran in Stat, an online health industry portal developed by The Boston Globe, which has become one of my favorite morning reads.

The story leads with an anecdote about Linda Smith who went to the trials site to look for stem cell therapies for her arthritic knees. She found a listing from StemGenex and called the listed contact only to find out she would first have to pay $14,000 for the experimental treatment. The company told the author that they are not charging for participation in the posted clinical trial because it only covers the observation phase after the therapy, not the procedure itself. The reporter found multiple critics who suggested the company was splitting hairs a bit too finely with that explanation.

But the NIH came in for just as much criticism for allowing those trials to be listed at all. The web site already requires organizations listing trials to disclose information about the committees that oversee the safety of the patients in the trial, and critics said they should also demand disclosure of payment requirements, or outright ban such trials from the site.

Paul-Knoepfler-2013 “The average patient and even people in health care … kind of let their guard down when they’re in that database. It’s like, ‘If a trial is listed here, it must be OK,’” said Paul Knoepfler, a CIRM grantee and fellow blogger at the University of California, Davis. “Most people don’t realize that creeping into that database are some trials whose main goal is to generate profit.”

The NIH representative quoted in the article made it sound like the agency was open to making some changes. But no promises were made.

Added note 7/30. While this post factually describes an article that appeared in the mainstream media, the role of this column, I should add that while I did not take a position on paid trials, I am thrilled Stemgenex is collecting data and look forward to them sharing that data in a timely, peer-reviewed fashion.

 

Off the shelf T cells.  We at CIRM got some good news this week. We always like it when we see an announcement that technology from a researcher we have supported gets licensed to a company. That commercialization moves it a giant step closer to helping patients.

This week, Kite Pharma licensed a system developed in the lab of Gay Crooks at the University of California, Los Angeles, that creates an artificial thymus “organoid” in a dish capable of mass producing the immune system’s T cells from pluripotent stem cells. Just growing stem cells in the lab yields tiny amounts of T cells. They naturally mature in our bodies in the thymus gland, and seem to need that nurturing to thrive.

T-cell based immune therapy is all the rage now in cancer therapy because early trials are producing some pretty amazing results, and Kite is a leader in the field. But up until now those therapies have all been autologous—they used the patient’s own cells and manipulate them individually in the lab. That makes for a very expensive therapy. Kite sees the Crooks technology as a way to turn the procedure into an allogeneic one—using donor cells that could be pre-made for an “off-the-shelf” therapy. Their press release also envisioned adding some genetic manipulation to make the cells less likely to cause immune complications.

FierceBiotech published a bit more analysis of the deal, but we are not going to go into more detail on the actual science now. Crooks is finalizing publication of the work in a scientific journal, and when she does you can get the details here. Stay tuned.

Out of the mouths, or in this case hearts, of babes comes a hopeful therapy for heart attack patients

Pediatric-Congenital-Heart-Disease-patient-300x200

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 patient’s 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.

Stem cell stories that caught our eye: turning on T cells; fixing our brains; progress and trends in stem cells; and one young man’s journey to recover from a devastating injury

Healthy_Human_T_Cell

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. “It’s interesting–the 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 Parkinson’s disease, she went on to describe her own effort to do the same thing in Huntington’s 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.

kelley and kent

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 CIRM’s 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 CIRM’s 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.

“We’re 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 and family

Jake Javier and his family

Jake’s story: one young man’s 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.

It’s 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.

CIRM Board targets diabetes and kidney disease with big stem cell research awards

diabetes2

A recent study  estimated there may be more than 500 million people worldwide who have diabetes. That’s 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 – that’s 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 individual’s 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.

Humacyte’s 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 Humacyte’s HAV was shown to be safer and last longer than current versions. As our President and CEO, Randy Mills, said in a news release, that’s 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. That’s where the $3.9 million awarded to ViaCyte comes in.

We’re 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 patient’s 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 body’s 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.

 

Advancing Stem Cell Research at the CIRM Bridges Conference

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 year’s CIRM Bridges to Stem Cell Research and Therapy conference.

Educating the next generation of stem cell scientists

The Bridges program is one of CIRM’s 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. It’s a chance for students to showcase the research projects they’ve 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.

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 team’s 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 Huntington’s disease

Leslie Thompson, Professor at UC Irvine, spoke about her latest research in Huntington’s disease (HD). She described her work as a “race against time.” HD is a progressive neurodegenerative disorder that’s 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, they’ve 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 Thompson

Leslie noted that because the transplanted 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 don’t 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

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 don’t 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, 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 patient’s 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 Parkinson’s 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, Parkinson's advocate and CIRM Board member

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. It’s important to understand what patients’ needs are, and you’ll 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 you’re interested in hearing more about the Bridges conference, follow us on twitter (@CIRMnews, @DrKarenRing, #CIRMBridges2016) and on Instagram (@CIRM_Stemcells).