A Win for Diabetes: Scientists Make Functional Pancreatic Cells From Skin

Today is an exciting day for diabetes research and patients. For the first time, scientists have succeeded in making functional pancreatic beta cells from human skin. This new method for making the insulin-producing cells of the pancreas could produce a new, more effective treatment for patients suffering from diabetes.

Researchers at the Gladstone Institutes and the University of California, San Francisco published these promising findings today in the journal Nature Communications.

Making pancreatic cells from skin

They used a technique called direct reprogramming to turn human skin cells directly into pancreatic beta cells without having to go all the way back to a pluripotent stem cell state. The skin cells were treated with factors used to generate induced pluripotent stem cells (iPSCs) and with pancreatic-specific molecules. This cocktail of factors and molecules shut off the skin genes and turned on genes of the pancreas.

The end product was endoderm progenitor cells, which are like stem cells but can only generate cell types specific to organs derived from the endoderm layer (for example: lungs, thyroid, pancreas). The scientists took these endoderm progenitors and further coaxed them into mature, pancreatic beta cells after treatment with another cocktail of molecules.

Functioning human pancreatic cells after they’ve been transplanted into a mouse. (Image: Saiyong Zhu, Gladstone)

Functioning human pancreatic cells after they’ve been transplanted into a mouse. (Image: Saiyong Zhu, Gladstone)

While the pancreatic cells they made looked and acted like the real thing in a dish (they were able to secrete insulin when exposed to glucose), the authors needed to confirm that they functioned properly in animals. They transplanted the mature beta cells into mice that were engineered to have diabetes, and observed that the human beta cells protected the mice from becoming diabetic by properly regulating their blood glucose levels.

Importantly, none of the mice receiving human cells got tumors, which is always a concern when transplanting reprogrammed cells or cells derived from pluripotent stem cells.

What does this mean?

This study is groundbreaking because it offers a new and more efficient method to make functioning human beta cells in mass quantities.

Dr. Sheng Ding, a CIRM funded senior investigator at the Gladstone and co-senior author, explained in a Gladstone news release:

Sheng Ding

Sheng Ding

“This new cellular reprogramming and expansion paradigm is more sustainable and scalable than previous methods. Using this approach, cell production can be massively increased while maintaining quality control at multiple steps. This development ensures much greater regulation in the manufacturing process of new cells. Now we can generate virtually unlimited numbers of patient-matched insulin-producing pancreatic cells.”

 

Matthias Hebrok, director of the Diabetes Center at UCSF and co-senior author on paper discussed the potential research and clinical applications of their findings:

Mattias Hebrok

Matthias Hebrok

“Our results demonstrate for the first time that human adult skin cells can be used to efficiently and rapidly generate functional pancreatic cells that behave similar to human beta cells. This finding opens up the opportunity for the analysis of patient-specific pancreatic beta cell properties and the optimization of cell therapy approaches.”

 

The study does mention the caveat that their direct reprogramming approach wasn’t able to generate all the cell types of the pancreas. Having these support cells would better recreate the pancreatic environment and likely improve the function of the transplanted beta cells.

Lastly, I find this study exciting because it kills two birds with one stone. Scientists can use this technique to make better cellular models of diabetes to understand why the disease happens, and they could also develop new cell replacement therapies in humans. Already, stem cell derived pancreatic beta cells are being tested in human clinical trials for type 1 diabetes (one of them is a CIRM-funded clinical trial by Viacyte) and it seems likely that beta cells derived from skin will follow suit.


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While You Were Away: Gene Editing Treats Mice with Duchenne Muscular Dystrophy

Welcome back everyone! I hope you enjoyed your holiday and are looking forward to an exciting new year. My favorite thing about coming back from vacation is to see what cool new science was published. Because as you know, science doesn’t take a vacation!

As I was reading over the news for this past week, one particular story stood out. On New Year’s Eve, Science magazine published three articles (here, here, here) simultaneously that successfully used CRISPR/Cas9 gene editing to treat mice that have Duchenne muscular dystrophy (DMD).

DMD is a rare, genetic disease that affects approximately 1 in 3,600 boys in the US. It’s caused by a mutation in the dystrophin gene, which generates a protein that is essential for normal muscle function. DMD causes the body’s muscles to weaken and degenerate, leaving patients deformed and unable to move. It’s a progressive disease, and the average life expectancy is around 25 years. Though there are treatments that help prolong or control the onset of symptoms, there is no cure for DMD.

Three studies use CRISPR to treat DMD in mice

For those suffering from this debilitating disease, there is hope for a new therapy – a gene therapy that is. Three groups from UT Southwestern, Harvard, and Duke, used the CRISPR gene editing method to remove and correct the mutation in the dystrophin gene in mice with DMD. All three used a safe viral delivery method to transport the CRISPR/Cas9 gene editing complex to the proper location on the dystrophin gene in the mouse genome. There, the complex was able to cut out the mutated section of DNA and paste together a version of the gene that could produce a functional dystrophin protein.

Dystrophin protein (green) in healthy heart muscle (left), absent in DMD mice (center), and partially restored in DMD mice treated with CRISPR/Cas9 (right). (Nelson et al., 2015)

Dystrophin protein (green) in healthy heart muscle (left), absent in DMD mice (center), and partially restored in DMD mice treated with CRISPR/Cas9 (right). (Nelson et al., 2015)

This technique was tested in newly born mice as well as in adult mice by injecting the virus into the mouse circulatory system (so that the gene editing could happen everywhere) or into specific areas like the leg muscle to target muscle cells and stem cells. After the gene editing treatment, all three studies found restored expression of the dystrophin protein in heart and skeletal muscle tissue, which are the main tissues affected in DMD. They were also able to measure improved muscle function and strength in the animals.

This is really exciting news for the DMD field, which has been waiting patiently for an approved therapy. Currently, two clinical trials are underway by BioMarin and Sarepta Therapeutics, but the future of these drugs is uncertain. A gene therapy that could offer a “one-time cure” would certainly be a more attractive option for these patients.

Charles Gersbach, Duke University

Charles Gersbach, Duke University

It’s important to note that none of these gene editing studies reported a complete cure. However, the results are still very promising. Charles Gersbach, senior author on the Duke study, commented, “There’s a ton of room for optimization of these approaches.”

Strong media coverage of DMD studies

The implications of these studies are potentially huge and suitably, these studies were covered by prominent news outlets like Science News, STAT News, The Scientist, and The New York Times.

What I like about the news coverage on the DMD studies is that the results and implications aren’t over hyped. All of the articles mention the promise of this research, but also mention that more work needs to be done in mice and larger animals before gene therapy can be applied to human DMD patients. The words “safe” or “safety” was used in each article, which signals to me that both the science and media worlds understand the importance of testing promising therapies rigorously before attempting in humans on a larger scale.

However, it does seem that CRISPR gene editing for DMD could reach clinical trials in the next few years. Charles Gersbach told STATnews that he could see human clinical trials using this technology in a few years after scientists properly test its safety. He also mentioned that they first will need to understand “how the human immune system will react to delivery of  the CRISPR complex within the body.” He went on, “The hope for gene editing is that if we do this right, we will only need to do one treatment. This method, if proven safe, could be applied to patients in the foreseeable future.”

Eric Olson, UT Southwestern

Eric Olson, UT Southwestern

Eric Olson, senior author on the UT Southwestern study, had a similar opinion, “To launch a clinical trial, we need to scale up, improve efficiency and assess safety. I think within a few years, those issues can be addressed.”

 


Related Links:

Four Challenges to Making the Best Stem Cell Models for Brain Diseases

Neurological diseases are complicated. A single genetic mutation causes some, while multiple genetic and environmental factors cause others. Also, within a single neurological disease, patients can experience varying symptoms and degrees of disease severity.

And you can’t just open up the brain and poke around to see what’s causing the problem in living patients. It’s also hard to predict when someone is going to get sick until it’s already too late.

To combat these obstacles, scientists are creating clinically relevant human stem cells in the lab to capture the development of brain diseases and the differences in their severity. However, how to generate the best and most useful stem cell “models” of disease is a pressing question facing the field.

Current state of stem cell models for brain diseases

Cold Spring Harbor Lab, Hillside Campus, Location: Cold Spring Harbor, New York, Architect: Centerbrook Architects

Cold Spring Harbor Lab, Hillside Campus, Location: Cold Spring Harbor, New York, Architect: Centerbrook Architects

A group of expert stem cell scientists met earlier this year at Cold Spring Harbor in New York to discuss the current state and challenges facing the development of stem cell-based models for neurological diseases. The meeting highlighted case studies of recent advances in using patient-specific human induced pluripotent stem cells (iPS cells) to model a breadth of neurological and psychiatric diseases causes and patient symptoms aren’t fully represented in existing human cell models and mouse models.

The point of the meeting was to identify what stem cell models have been developed thus far, how successful or lacking they are, and what needs to be improved to generate models that truly mimic human brain diseases. For a full summary of what was discussed, you can read a Meeting Report about the conference in Stem Cell Reports.

What needs to be done

After reading the report, it was clear that scientists need to address four major issues before the field of patient-specific stem cell modeling for brain disorders can advance to therapeutic and clinical applications.

1. Define the different states of brain cells: The authors of the report emphasized that there needs to be a consensus on defining different cell states in the brain. For instance, in this blog we frequently refer to pluripotent stem cells and neural (brain) stem cells as a single type of cell. But in reality, both pluripotent and brain stem cells have different states, which are reflected by their ability to turn into different types of cells and activate a different set of genes. The question the authors raised was what starting cell types should be used to model specific brain disorders and how do we make them from iPS cells in a reproducible and efficient fashion?

2. Make stem cell models more complex: The second point was that iPS cell-based models need to get with the times. Just like how most action-packed or animated movies come in 3D IMAX, stem cell models also need to go 3D. The brain is comprised of an integrated network of neurons and glial support cells, and this complex environment can’t be replicated on the flat surface of a petri dish.

Advances in generating organoids (which are mini organs made from iPS cells that develop similar structures and cell types to the actual organ) look promising for modeling brain disease, but the authors admit that it’s far from a perfect science. Currently, organoids are most useful for modeling brain development and diseases like microencephaly, which occurs in infants and is caused by abnormal brain development before or after birth. For more complex neurological diseases, organoid technology hasn’t progressed to the point of providing consistent or accurate modeling.

The authors concluded:

“A next step for human iPS cell-based models of brain disorders will be building neural complexity in vitro, incorporating cell types and 3D organization to achieve network- and circuit-level structures. As the level of cellular complexity increases, new dimensions of modeling will emerge, and modeling neurological diseases that have a more complex etiology will be accessible.”

3. Address current issues in stem cell modeling: The third issue mentioned was that of human mosaicism. If you think that all the cells in your body have the same genetic blue print, then you’re wrong. The authors pointed out that as many as 30% of your skin cells have differences in their DNA structure or DNA sequences. Remember that iPS cell lines are derived from a single patient skin or other cell, so the problem is that studies might need to develop multiple iPS cell lines to truly model the disease.

Additionally, some brain diseases are caused by epigenetic factors, which modify the structure of your DNA rather than the genetic sequence itself. These changes can turn genes on and off, and they are unfortunately hard to reproduce accurately when reprogramming iPS cells from patient adult cells.

4. Improve stem cell models for drug discovery: Lastly, the authors addressed the use of iPS cell-based modeling for drug discovery. Currently, different strategies are being employed by academia and industry, both with their pros and cons.

Industry is pursuing high throughput screening of large drug libraries against known disease targets using industry standard stem cell lines. In contrast, academics are pursuing candidate drug screening on a much smaller scale but using more relevant, patient specific stem cell models.

The authors point out that, “a major goal in the still nascent human stem cell field is to utilize improved cell-based assays in the service of small-molecule therapeutics discovery and virtual early-phase clinical trials.”

While in the past, the paths that academia and industry have taken to reach this goal were different, the authors predict a convergence between the paths:

“Now, research strategies are converging, and both types of researchers are moving toward human iPS cell-based screening platforms, drifting toward a hybrid model… New collaborations between academic and pharma researchers promise a future of parallel screening for both targets and phenotypes.”

Conclusions and Looking to the Future

This meeting successfully described the current landscape of iPS cell-based disease modeling for brain disorders and laid out a roadmap for advancing these stem cell models to a stage where they are more effective for understanding the mechanisms behind disease and for therapeutic screening.

I agree with the authors conclusion that:

“Moving forward, a critical application of human iPS cell-based studies will be in providing a platform for defining the cellular, molecular, and genetic mechanisms of disease risk, which will be an essential first step toward target discovery.”

My favorite points in the report were about the need for more collaboration between academia and industry and also the push for reproducibility of these iPS cell models. Ultimately, the goal is to understand what causes neurological disease, and what drugs or stem cell therapies can be used to cure them. While iPS cell models for brain diseases still have a way to go before being more clinically relevant, they will surely play a prominent role in attaining this goal.

Meeting Attendees

Meeting Attendees

A step forward for Parkinson’s disease?

Imagine how frustrating it would be to not know whether you could physically sit through a dinner with friends or to worry about getting stuck in the grocery isle, fighting against a body that refuses to move. These nightmare-like experiences are what many Parkinson’s disease (PD) patients deal with on a daily basis.

PD affects approximately one million people in the US, and there is no prevention or cure. While substantial funding efforts are being dedicated to PD research (CIRM, Michael J. Fox Foundation, Parkinson’s Disease Foundation, to name a few), a cure is still years or maybe even decades away.

However, a new stem cell therapy from Australia has the potential to make waves in what’s been a relatively flat sea of PD stem cell therapies that haven’t yet secured the funding or jumped the regulatory hurdles to make it into clinical trials. Biotech journalist Bradley Fikes broke the story yesterday in the San Diego Union Tribune. Fikes is one of my favorite science writers so instead of attempting to re-write an already eloquent piece, I’ll just mention a few highlights.

Stem cells down under

International Stem Cell Corporation (ISCO), a company based in Carlsbad, California, has developed a stem cell therapy that involves transplanting brain stem cells into the brains of PD patients. While stem cell therapy is viewed by some as the holy grail for PD – having the potential to replace lost dopamine-producing nerve cells in the brain – so far, no stem cell-derived therapy has been approved for testing in PD patients. (Previous clinical trials using fetal stem cells didn’t pan out.)

The Australian government approved the use of ISCO’s parthenogenic stem cell therapy in twelve PD patients in a clinical trial that is slated to start in the first quarter of 2016 (pending final approval from the Royal Melbourne Hospital review board). This therapy uses brain stem cells derived from pluripotent stem cells obtained from unfertilized human eggs, thus avoiding the ethical issues attached to use of embryonic stem cells. (For sciency details check out the ISCO website).

The goal of the trial will be to determine if ISCO’s stem cell therapy is safe and also effective at reducing PD symptoms like tremors and stunted movement. Fikes explained that ISCO chose Australia for it’s proposed clinical trial for regulatory reasons.

“The nation’s clinical trial system is more ‘interactive’, which allows for better collaboration with Australia’s Therapeutic Goods Administration on trial design.”

A comparison of primate brains to show an increase in the number of neurons after treatment with ISCO's stem cells. The left side is a control sample. The right side is from a treated brain. — International Stem Cell Corp.

A comparison of primate brains to show an increase in the number of neurons after treatment with ISCO’s stem cells. The left side is a control sample. The right side is from a treated brain. — International Stem Cell Corp.

Great minds think alike

ISCO’s is only one of a handful of groups proposing stem cell therapies for PD. Fikes mentioned other therapies currently being tested that are derived from embryonic stem cells, induced pluripotent stem cells (iPSCs), and adult stem cells like the mesenchymal and fat stem cells.

Jeanne Loring, Scripps Research Institute

Jeanne Loring, Scripps Research Institute

He also highlighted important ongoing research by CIRM grantee Dr. Jeanne Loring from the Scripps Research Institute. Loring founded the Summit for Stem Cell organization that’s generating iPSCs from PD patients with hopes of treating these patients with a dose of their own brain stem cells.

When asked about the ISCO study, she told Fikes that she sees ISCO as a “partner in fighting Parkinson’s.”

“The whole idea is to treat patients by whatever means possible.” – Loring


Related Links:

 

UCLA scientists find new targets for late-stage prostate cancer

Prostate cancer, which currently affects 3 million men in the United States, is no longer a death sentence if caught early. The five-year survival rate is very high (~98%) because of effective treatments like hormone therapy, chemotherapy, surgery, and radiation—and for many men with slow progressing tumors, the wait-and-watch approach offers an alternative to treatment.

However, for those patients who have more aggressive forms of prostate cancer, where the tumors spread to other organs and tissues, the five-year survival rate is much lower (~28%) and standard therapies only work temporarily until the tumors become resistant to them. Thus there is a need for finding new therapeutic targets that would lead to more effective and longer-lasting treatments.

Kinases are ABL to cause cancer

We recently wrote a blog about prostate cancer featuring the work of a pioneer in cancer research, Dr. Owen Witte from the UCLA Broad Stem Cell Research Center. Dr. Witte is well known for his work on understanding the biology of blood cancers (leukemias) and the role of cancer stem cells. One of his key discoveries was that the cancer-causing BCR-ABL gene produces an overactive protein kinase that causes chronic myelogenous leukemia (CML).

Protein kinases are enzymes that turn on important cell processes like growth, signaling, and metabolism, but they also can be involved in causing several different forms of cancer. This has made some kinases a prime target for developing cancer drugs that block their cancer-causing activity.

New targets for late-stage prostate cancer

Recently, Dr. Witte’s interests have turned to understanding and finding new treatments for aggressive prostate cancers. He has been on the hunt for new targets, and this week, Witte and his group published a CIRM-funded study in the journal PNAS showing that a specific set of kinases are involved in causing advanced stage prostate cancer that spreads to bones.

They selected a group of 125 kinases that are known to be active in aggressive forms of human cancers. From this pool, they found that 20 of these kinases caused metastasis, or the spreading of cancer cells from the starting tumor to different areas of the body, when activated in mouse prostate cancer cells that were injected into the tail veins of mice.

To narrow down the pool further, they activated each of the 20 kinases in human prostate cancer cells and injected these cells into the tails of mice. They found that five of the kinases caused the cancer cells to leave the tail and metastasize into the bones. When they compared the activity of these five kinases in the late-stage and early-stage prostate cancer cells as well as normal prostate cells, they only saw activity of these kinases in the late-stage cancer cells.

Microscopic view of a hip bone (left) and a magnified view of the bone showing the metastasized prostate cancer tumor (T), healthy bone marrow (M) and bone (B). Image courtesy of the UCLA Broad Stem Cell Research Center.

Microscopic view of a hip bone (left) and a magnified view of the bone showing the metastasized prostate cancer tumor (T), healthy bone marrow (M) and bone (B). Image courtesy of the UCLA Broad Stem Cell Research Center.

New treatment option?

Witte and his colleagues concluded that these five kinases can cause prostate tumor cells to spread and metastasize into bones, and that targeting kinase activity could be a new therapeutic strategy for late-stage prostate cancer patients that have exhausted normal treatment options.

In a UCLA press release, Claire Faltermeier, the study’s first author and a medical and doctoral student in Witte’s lab commented:

Our findings show that non-mutated protein kinases can drive prostate cancer bone metastasis. Now we can investigate if therapeutic targeting of these kinases can block or inhibit the growth of prostate cancer bone metastasis.

 

Dr. Witte followed up by mentioning the promise of targeting kinase activity for late-stage prostate cancer:

Cancer-causing kinase activity has been successfully targeted and inhibited before. As a result, chronic myelogenous leukemia is no longer fatal for many people. I believe we can accomplish this same result with advanced stages of prostate cancer with a fundamental understanding of the cellular nature of the disease.

UCLA scientists Owen Witte and

UCLA scientists Owen Witte and Claire Faltermeier


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Smoking out Leukemia Cells to Prevent Cancer Relapse

Ninety-five percent of all patients with chronic myeloid leukemia (CML), carry a Frankenstein-like gene, called BCR-ABL, created from an abnormal fusion of two genes normally found on two separate chromosomes. Like a water faucet without a shutoff valve, the resulting mutant protein is stuck in an “on” position and leads to uncontrolled cell division and eventually to CML as well as other blood cancers.

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An oversized bone marrow cell, typical of chronic myeloid leukemia. Credit:  Difu Wu

Gleevec, a revolutionary, targeted cancer drug that specifically blocks the BCR-ABL protein was approved by the FDA in 2001 and doubled 5-year survival rates for CML patients (31 to 59%) over that decade. Still, some patients who are responsive to the Gleevec class of drugs, become resistant to the treatment and suffer a relapse. Up until now, research studies pointed to an accumulation of additional DNA mutations as the driving force behind a rebound of the cancer cells.

But on Monday, a CIRM-funded UC San Diego team reported in PNAS that a reduction in just one protein, called MBNL3, in CML cancer cells activates a cascade of genes normally responsible for the unlimited self-renewing capacity of embryonic stem cells. Much like a researcher can reprogram a skin cell back into an embryonic like state via the induced pluripotent stem cell (iPSC) technique, this finding suggests that CML enhances its ability to spread by exploiting the same cellular reprogramming machinery.

CML is a slowly progressing cancer that initially begins with a chronic phase. At this stage, the cancerous cells, called blast cells, make up less than five percent of cells in the bone marrow. The phase usually lasts several years and is well controlled by drug treatment. A blast crisis phase follows when the blast cells make up 20 to 30% of the blood or bone marrow. At this stage, the patient’s condition deteriorates as symptoms like anemia and frequent infections worsen.

The UCSD team, led by Catriona Jamieson, director of Stem Cell Research at Moores Cancer Center, did a comparative analysis of CML patient samples and found that a reduction of MBNL3, a RNA binding protein, corresponded with CML progression from the chronic to blast phase. If you took intro biology in high school or college, you may recall that RNA acts as a messenger molecule critical to the translation of DNA’s genetic code into proteins. Some splicing and trimming of the RNA molecule occurs to prep it for this translation process. It turns out the decrease in MBNL3 in blast phase cells frees up stretches of RNA that leads to alternate splicing and, in turn, alternate forms of a given protein.

The study showed that in response to the decrease of MBNL3, an alternate form of the protein CD44, aptly named CD44 variant 3 (CD44v3), is increased in CML blast phase cells compared with chronic phase cells. Artificially over producing CD44v3 increased the activity of SOX2 and OCT4, two genes that are critical for maintaining the properties of embryonic stem cells. Genes involved with homing blood cells to the bone marrow were also upregulated.

Put together, these data suggest that this alternate RNA splicing not only helps CML blast phase cells preserve stem cell-like qualities, but it also helps sequester them in the bone marrow. Other studies have shown that the BCR-ABL protein inhibitor drugs are not effective in eradicating blast phase cells in the bone marrow, perhaps the reason behind relapse in some CML patients.

To try to smoke out these hiding blast phase cells in mouse CML studies, the team tested a combination treatment of a CD44 inhibitor along with the BCR-ABL inhibitor. While either treatment alone effectively removed the CML blast phase cells from the spleen and blood, only the combination significantly reduced survival of the cells in the bone marrow.

This tantalizing result has motivated the Jamieson team to pursue the clinical development of a CD44 blocking antibody with combination with the existing BCR-ABL inhibitors. As reported by Bradley Fikes in a San Diego Union Tribune story, the CD44 blocking antibody was not stable so more work is still needed to generate a new antibody.

But the goal remains the same as Jamieson mentions in a UCSD press release:

“If we target embryonic versions of proteins that are re-expressed by cancer, like CD44 variant 3, with specific antibodies together with tyrosine kinase [for example, BCR-ABL] inhibitors, we may be able to circumvent cancer relapse – a leading cause of cancer-related mortality.”

 

 

 

 

 

Eyeing Stem Cell Therapies for Vision Loss

Back by popular demand (well, at least a handful of you demanded it!) we’re pleased to present the third installment of our Stem Cells in Your Face video series. Episodes one and two set out to explain – in a light-hearted, engaging and clear way – the latest progress in CIRM-funded stem cell research related to Lou Gehrig’s disease (Amyotrophic Lateral Sclerosis, or ALS) and sickle cell disease.

With episode three, Eyeing Stem Cell Therapies for Vision Loss, we turn our focus (pun intended) to two CIRM-funded clinical trials that are testing stem cell-based therapies for two diseases that cause severe visual impairment, retinitis pigmentosa (RP) and age-related macular degeneration (AMD).

Two Clinical Trials in Five Minutes
Explaining both the RP and AMD trials in a five-minute video was challenging. But we had an ace up our sleeve in the form of descriptive eye anatomy animations graciously produced and donated by Ben Paylor and his award-winning team at InfoShots. Inserting these motion graphics in with our scientist and patient interviews, along with the fabulous on-camera narration by my colleague Kevin McCormack, helped us cover a lot of ground in a short time. For more details about CIRM’s vision loss clinical trial portfolio, visit this blog tomorrow for an essay by my colleague Don Gibbons.

Vision Loss: A Well-Suited Target for Stem Cell Therapies
Of the wide range of unmet medical needs that CIRM is tackling, the development of stem cell-based treatments for vision loss is one of the furthest along. There are a few good reasons for that.

The eye is considered to be immune privileged, meaning the immune system is less accessible to this organ. As a result, there is less concern about immune rejection when transplanting stem cell-based therapies that did not originally come from the patient’s own cells.

The many established, non-invasive tools that can peer directly into the eye also make it an attractive target for stem cell–based treatment. Being able to continuously monitor the structure and function of the eye post-treatment will be critical for confirming the safety and effectiveness of these pioneering therapies.

Rest assured that we’ll be following these trials carefully. We eagerly await the opportunity to write future blogs and videos about encouraging results that could help the estimated seven million people in the U.S. suffering from disabling vision loss.

Related Links:

Stem Cellar archive: retinitis pigmentosa
Stem Cellar archive: macular degeneration
Video: Spotlight on Retinitis Pigmentosa
Video: Progress and Promise in Macular Degeneration
CIRM Fact Sheet on Vision Loss

Have your cake and eat it too: Stem cells without the risk of tumors

journal.pmed.1000029.g001

An unregulated stem cell treatment in 2001 led to tumor growth in the (A) brain stem and (B) spinal cord of the patient four years later. (Fig 1. PLoS Med. 2009 Feb 17;6(2):e1000029)

A real stem cell tourism story
Back in 2001, an Israeli boy suffering from Ataxia Telangiectasia, a genetic brain disease that affects movement, traveled to Russia for an unregulated stem cell treatment. His brain and spinal cord were injected with fetal stem cells though the exact composition of those cells was not known. Four years later, the boy complained of headaches and his doctors back home found tumors in his brain and spinal cord.

 Stem cells: a double-edged sword
As the BBC  and many other news outlets reported in 2009, a Plos Medicine report eventually confirmed the tumor cells originated from the donor stem cells. And here lies a double-edged sword of stem cell-based therapies. On one side, stem cells hold great promise to repair diseased or damaged tissue because they can morph, or differentiate, into a wide range of cell types.

 But on the other side, they have the capacity to remain unspecialized and continually self-renew.This is great for producing enough cells to treat many people. Researchers try to make sure only more mature cells are transplanted, but if any of these propagating, undifferentiated cells get carried along with a stem cell-based treatment, there’s a risk of introducing uncontrolled cell growth and cancers instead of remedies. Human pluripotent stem cells (hPSCs), which can form almost any cell type found in our body, are believed to be especially susceptible to this dangerous potential side effect.

Reporting this week in the journal, eLife, CIRM-funded researchers at UCSD found a way to dodge the risk of tumor growth by identifying a unique, alternate stem cell type that could be applied to kidney disease. To find this cell type, the research team focused on cells that were a bit further along a differentiation path compared to unspecialized hPSCs.

Repeat after me: endoderm, ectoderm, mesoderm

In the earliest stages of embryo development, three germ layers form. (image: Internet Science Room)

In the earliest stages of embryo development, three germ layers form. (image: Internet Science Room)

To explain, let’s take a brief detour into developmental biology. In the very early stages of specialization, the cells of the embryo form the three germ layers: ectoderm, endoderm and mesoderm. Each layer gives rise to specific set of cells and tissues. Endoderm forms, to just name a few, the lungs, intestines and pancreas; ectoderm develops into skin, the brain and spinal cord; mesoderm forms blood, muscle, bone and kidneys. Within each germ layer lie progenitor stem cells, that maintain the capacity to self-renew and can also differentiate into the adult cells formed by that germ layer.

Finding a mesoderm progenitor
While methods for growing ectoderm and endoderm progenitor stem cells from hPSCs had been previously developed, few, if any, labs had done the same for mesoderm. So the UCSD team systematically tested thousands of combinations of nutrients and chemicals for both growing and differentiating hPSCs into mesoderm. Using this approach, they successfully tracked down a recipe that gave rise to mesoderm progenitor cells with the potential to multiply and grow in population yet lacking the ability to form tumors when transplanted into mice.

Color tagged surface proteins indicate a kidney fate for activated mesodermal progenitors (Fig 7c Kumar et al. eLife 2015;4:e08413)

Color tagged surface proteins indicate a kidney fate for activated mesodermal progenitors (Fig 7c Kumar et al. eLife 2015;4:e08413)

The research team planned to work out the various conditions to specialize the progenitor cells into a wide range of mesoderm tissues. But to their surprise, when triggered to differentiate, the progenitors only gave rise to cells of the kidney. This very limited specialization is actually desired for clinical applications since purity of cell therapies is a requirement for testing in humans.

Our kidneys thank you
Putting it all together, the team has identified a cell source with unlimited self renewal capacity that can differentiate into a very specific cell type and doesn’t carry a risk of tumor formation when transplanted. These qualities make the mesoderm progenitor cell an exciting tool for developing future kidney repair or replacement treatments. And as Dr. Karl Willert, senior author and associate professor at UC San Diego, states in a UCSD press release, there is also reason to be excited about near-term applications:

“Our cells can serve as building blocks to generate kidneys that may one day be suitable for cell replacement and transplantation. I think such a therapeutic application is still a few years in the future, but engineered kidney tissue can serve as a powerful model system to study how the human kidney interacts with and filters drugs. Such an application would be of tremendous value to the pharmaceutical industry.”

New Video: Spinal Cord Injury and a CIRM-Funded Stem Cell-Based Trial

Just 31 years old, Richard Lajara thought he was going to die.

Picture1

Richard Lajara, the 4th participant in Geron’s stem cell-based clinical trial for spinal cord injury.

On September 9, 2011 he slipped on some rocks at a popular swimming hole and was swept down a waterfall headfirst into a shallow, rocky pool of water. Though he survived, the fall left him paralyzed from the waist down due to a severed spinal cord.

Patient Number Four
At that same time period, Geron Inc. had launched a clinical trial CIRM helped fund testing the safety of a stem cell-based therapy for spinal cord injury (SCI). It was the world’s first trial using cells derived from human embryonic stem cells and Lajara was an eligible candidate. Speaking to CIRM’s governing Board this past summer for a Spotlight on Disease seminar, he recalled his decision to participate:

“When I participated with the Geron study, I was honored to be a part of it. It was groundbreaking and the decision was pretty easy. I understood that it was very early on and I wasn’t looking for any improvement but laying the foundation [for future trials].”

A few months after his treatment, Geron discontinued the trial for business reasons. Lajara was devastated and felt let down. But this year the therapy got back on track with the announcement in June by Asterias Biotherapeutics that they had treated their first spinal cord injury patient after having purchased the stem cell assets of Geron.

Getting Hope Back on Track
Dr. Jane Lebkowski, Asterias’ President of R&D and Chief Scientific Officer, also spoke at the Spotlight on Disease seminar to provide an overview and update on the company’s clinical trial. A video recording of Lebkowski’s and Lajara’s presentations is now available on our web site and posted here:

As Dr. Lebkowski explains in the video, Asterias didn’t have to start from scratch. The Geron study data showed the therapy was well tolerated and didn’t cause any severe safety issues. In that trial, five people (including Richard Lajara) with injuries in their back received an injection of two million stem cell-derived oligodendrocyte progenitor cells into the site of spinal cord damage. The two million-cell dose was not expected to show any effect but was focused on ensuring the therapy was safe.

Oligodendrocyte Precursors: Spinal Cord Healers
As the former Chief Scientific Officer at Geron, Lebkowski spoke first hand about why the oligodendrocyte precursor was the cell of choice for the clinical trial. Previous animal studies showed that oligodendrocyte progenitors, a cell type normally found in the spinal cord, have several properties that make them ideal cells for treating SCI: first, they help stimulate the growth of damaged neurons, the cell type responsible for transmitting electrical signals from the brain to the limbs.

Second, the oligodendrocytes produce myelin, a protein that acts as an insulator of neurons, very much like the plastic covering on a wire. In many spinal cord injuries, the nerves are still intact but lose their myelin insulation and their ability to send signals. Third, the oligodendrocytes release other proteins that help reduce the size of cysts that often form at the injury site and damage neurons. In preclinical experiments, these properties of oligodendrocyte progenitors improved limb movement in spinal cord-severed rodents.

Together, the preclinical animal studies and the safety data from the Geron clinical trial helped Asterias win approval from the Food and Drug Administration (FDA) to start their current trial, also funded by CIRM, this time treating patients with neck injuries instead of back injuries.

The Asterias trial is a dose escalation study with the first group of three patients again receiving two million cells. The trial was designed such that if this dose shows a good safety profile in the neck, as it did in the Geron trial in the back, then the next cohort of five patients will receive 10 million cells. In fact, Asterias reported in August that the lower dose was not only safe but also showed some encouraging results in one of the patients. And just two days ago Asterias announced their data monitoring committee recommended to begin enrolling patients for the 10 million cell dose.  If all continues to go well with safety, the dose will be escalated to 20 million cells in the third cohort of five patients. While two million cells was a very low safety dose, Asterias anticipates seeing some benefit from the 10 and 20 million cell doses.

Changing Lives by Increasing Independence
Does Lebkowski’s team expect the patients to stand up out of their wheelchairs post-treatment? No, but they do hope to see a level of improvement that could dramatically increase quality of life and decrease the level of care needed. Specifically, they are looking to see a so-called “two motor level improvement.” In her talk Lebkowski explained this quantitative measure with the chart below:

“If a patient is a C4 [meaning their abilities are consistent with someone with a spinal cord injury at the fourth cervical, or neck, bone] they will need anywhere from 18 to 24 hours of attendant care for daily living. If we could improve their motor activity such that they become a C6, that is just two motor levels, what you can see is independence tremendously increases and we go from 18 to 24 hour attendant care to having attendant care for about four hours of housework.”

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Small improvements in movement abilities can be life changing for people with spinal cord injuries.

It’s so exciting the field is at a point in time that scientists like Dr. Lebkowski are discussing real stem cell-based clinical trials that are underway in real patients who could achieve real improvements in their lives that otherwise would not be possible.

And we have people like Richard Lajara to thank. I think Dr. Oswald Stewart, the Board’s spinal cord injury patient advocate, summed it up well when speaking to Lajara at the meeting:

“Science and discovery and translation [into therapies] doesn’t happen without people like you who are willing to put yourselves on the line to move things forward. Thank you for being in that first round of people testing this new therapy.”

Don Reed Reflects on the California Stem Cell Initiative

StemCellBattlesCoverYesterday was stem cell awareness day. In honor of this important event, Don Reed held a book reading at CIRM for his newly released book, STEM CELL BATTLES: Proposition 71 and Beyond: How Ordinary People Can Fight Back Against the Crushing Burden of Chronic Disease.

Don has worn many hats during his life. He’s been a power lifter, a diver at Sea World, and is one of California’s most tenacious stem cell research advocates. His stem cell journey began when his son, Roman Reed, was seriously injured in a football accident, leaving him mostly paralyzed from the neck down.

Both Don and Roman didn’t let this tragic event ruin their lives or steal their hope. In fact, both Don and his son were instrumental for getting proposition 71 to pass, leading to the birth of CIRM and new hope for patients with uncured diseases.

At yesterday’s book reading, Don chronicled the early battles to get human stem cell research off the ground in California, the progress that’s been made so far and the promise for future therapies. It was truly an inspiring event, bringing together patients, friends of Don and his wife Gloria, and CIRM scientists to celebrate the stem cell research accomplishments of the past ten years.

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Enjoy more pictures of the event below and a short video of Jonathan Thomas, Chair of the Governing Board of CIRM, who said a few words in praise of Don Reed’s efforts to fight for stem cell research in California.

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Don Reed and his wife Gloria share a smile with CIRM’s Pat Olson.

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Jonathan Thomas and Don Reed.


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