A Tale of Two Stem Cell Treatments for Growing New Bones

Got Milk?

GotmilkIf you grew up during the 90’s, you most certainly will remember the famous “Got Milk?” advertising campaign to boost milk consumption. The plug was that milk was an invaluable source of calcium, a mineral that’s essential for growing strong bones. Drinking three glasses of the white stuff a day, supposedly would help deter osteoporosis, or the weakening and loss of bone with old age.

Research has proven that calcium is essential for growing and maintaining healthy bones. But milk isn’t the only source of calcium in the human diet, and a diet rich in calcium alone won’t prevent everyone from experiencing some amount of bone loss as they grow older. It also won’t help patients who suffer from bone skeletal defects grow new bone.

So whatever are we to do about bone loss and bone abnormalities? Here, we tell the “Tale of two stem cell treatments” where scientists tackle these problems using stem cell-derived therapies.

Protein Combo Boosts Bone Growth

Osteoporosis. (Image source)

Osteoporosis. (Image source)

Our first story comes from a CIRM-funded team of UCLA scientists. This team is interested in developing a better therapy to treat bone defects and osteoporosis. The current treatment for bone loss is an FDA-approved bone regenerating therapy involving the protein BMP-2 (bone morphogenetic protein-2). The problem with BMP-2 is that it can cause serious side effects when given in high doses. Two of the major ones are abnormal bone growth and also making stem cells turn into fat cells as well as bone cells.

The UCLA group attempted to improve the BMP-2 treatment by adding a second protein called NELL-1 (which they knew was good at stimulating bone growth from previous studies).  The combination of BMP-2 and NELL-1 resulted in bone growth and also prevented stem cells from making fat cells.

Upon further exploration, they found that NELL-1 acts as a signaling switch that controls whether a stem cell becomes a bone cell or a fat cell. Thus, with NELL-1 present, BMP-2 can only turn stem cells into bone cells.

Kang Ting, a lead author on the study, explained the significance of their new strategy to improve bone regeneration in a UCLA press release:

Kang Ting, UCLA

Kang Ting, UCLA

“Before this study, large bone defects in patients were difficult to treat with BMP2 or other existing products available to surgeons. The combination of NELL-1 and BMP2 resulted in improved safety and efficacy of bone regeneration in animal models — and may, one day, offer patients significantly better bone healing.”

Chia Soo, another lead author on the study, emphasized the importance of using NELL-1 in combination with BMP-2:

“In contrast to BMP2, the novel ability of NELL-1 to stimulate bone growth and repress the formation of fat may highlight new treatment approaches for osteoporosis and other therapies for bone loss.”

Stem cells that could fix deformed skulls

Our second story comes from a group at the University of Rochester. Their goal is to repair bones in the face and skull of patients suffering from congenital deformities, or damage due to injury or cancer surgery.

In a report published in Nature Communications, the scientists identified a population of skeletal stem cells that orchestrate the formation of the skull and can promote craniofacial bone repair in mice.

They identified this special population of skeletal stem cells by their expression of a protein called Axin2. Genetic mutations in the Axin2 gene can cause a birth defect called craniosynostosis. This condition causes the bone plates of a baby’s skull to fuse too early, causing skull deformities and impaired brain development.

1651177064_WeiHsu-stem cell photo_4487_275x200

Axin2 stem cells shown in red and blue generated new bones cells after transplantation.

According to a news release from the University of Rochester, the group’s “latest evidence shows that stem cells central to skull formation are contained within Axin2 cell populations, comprising about 1 percent—and that the lab tests used to uncover the skeletal stem cells might also be useful to find bone diseases caused by stem cell abnormalities.”

Additionally, senior author on the study, Wei Hsu, “believes his findings contributee to an emerging field involving tissue engineering that uses stem cells and other materials to invent superior ways to replace damaged craniofacial bones in humans due to congenital disease, trauma, or cancer surgery.”

Two different studies, one common goal

Both studies have a common goal: to repair or regenerate bone to treat bone loss, damage, or deformities. I can’t help but wonder whether these different strategies could be combined in a way to that would bring more benefit to the patient than using either strategy alone.

Could we use BMP-2 and NELL-1 treatment along with Axin2 skeletal stem cells to treat craniosynostosis or repair damaged skulls? Or could we identify new stem cell populations in bone that would help patients suffering from osteoporosis?

I’m sure scientists will answer these questions sooner rather than later, and when they do, you’ll be sure to read about it on the Stem Cellar!


Related Links:

If you want to accelerate stem cell therapies then create an Accelerating Center

Buckle up

Buckle up, we’re about to Accelerate

“You can’t teach fish to fly,” is one of the phrases that our CIRM President & CEO, Randy Mills, likes to throw out when asked why we needed to create new centers to help researchers move their most promising therapies out of the lab and into clinical trials.

His point is that many researchers are terrific at research but not so great at the form filling and other process-oriented skills needed to get approval from the Food and Drug Administration (FDA) for a clinical trial.

So instead of asking them to learn how to do all those things, why don’t we, CIRM, create a system that will do it for them? And that’s where we came up with the idea for the Accelerating Center (we’re also creating a Translating Center – that’s a topic for a future blog but if you can’t wait to find out the juicy details you can find them here.)

The Accelerating Center will be a clinical research organization that provides regulatory, operational and other support services to researchers and companies hoping to get their stem cell therapies into a clinical trial. The goal is to match the scientific skills of researchers with the regulatory and procedural skills of the Accelerating Center to move these projects through the review process as quickly as possible.

But it doesn’t end there. Once a project has been given the green light by the FDA, the Accelerating Center will help with actually setting up and running their clinical trial, and helping them with data management to ensure they get high quality data from the trial. Again these skills are essential to run a good clinical trial but things researchers may not have learned about when getting a PhD.

We just issued what we call an RFA (Request for Applications)  for people interested in partnering with us to help create the Accelerating Center. To kick-start the process we are awarding up to $15 million for five years to create the Center, which will be based in California.

To begin with, the Accelerating Center will focus on supporting CIRM-funded stem cell projects. But the goal is to eventually extend that support to other stem cell programs.

Now, to be honest, there’s an element of self-interest in all this. We have a goal under our new Strategic Plan of funding 50 new clinical trials over the next five years. Right now, getting a stem cell-related project approved is a slow and challenging process. We think the Accelerating Center is one tool to help us change that and give the most promising projects the support they need to get out of the lab and into people.

There’s a lot more we want to do to help speed up the approval process as well, including working with the FDA to create a new, streamlined regulatory process, one that is faster and easier to navigate. But that may take some time. So in the meantime, the Accelerating Center will help “fish” to do what they do best, swim, and we’ll take care of the flying for them.

 

 

 

Protective cell therapy could mean insulin independence for diabetic patients

This has already been a productive year for diabetes research. Earlier this month, scientists from UCSF and the Gladstone Institutes successfully made functional human pancreatic beta cells from skin, providing a new and robust method for generating large quantities of cells to replace those lost in patients suffering from type 1 diabetes.

Today marks another breakthrough in the development of stem cell therapies for diabetes. Scientists from MIT and the Harvard Stem Cell Institute published a new method in Nature Medicine that encapsulates and protects stem cell-derived pancreatic beta cells in a way that prevents them from being attacked by the immune system after transplantation.

Protecting transplanted cells from the immune system

Stem cell therapy holds promise for diabetes for a number of reasons. First, scientists now have the ability to generate large numbers of insulin producing pancreatic beta cells from human skin and stem cells. This obviates the need for donor beta cells, which are always in short supply and high demand. Second, there’s the issue of the immune system. Transplanting beta cells from a donor into a patient will trigger an immunological reaction, which can only be abated by a lifetime regimen of immunosuppressive drugs.

One way that scientists have addressed the issue of immune rejection is to transplant stem cell-derived beta cells in a protected capsule. A CIRM-funded company called ViaCyte has developed a medical device that acts like a replacement pancreas but is surgically implanted under the skin. It contains human beta cells derived from embryonic stem cells and has a membrane barrier that allows only certain molecules to pass in and out of the device. This way, the foreign pancreatic cells are shielded from the immune system, but they can still respond to changing blood sugar levels in the patient by secreting insulin into the blood stream.

Another way that scientists trick the immune system in diabetes patients uses a similar strategy but instead of a medical device that protects a large population of cells, they encapsulate individual islets (clusters of beta cells) using biomaterials.

However, previous attempts using a biomaterial called alginate to encapsulate islets caused an immune response in the form of fibrosis, or scar tissue, and cell death. Additionally, transplanted alginate microspheres were only able to achieve glycemic control, or control of blood sugar levels, temporarily in animal models.

In the Nature Medicine study, the scientists developed a new method for beta cell encapsulation where they used a chemically modified version of the alginate microspheres – triazole-thiomorpholine dioxide (TMTD) – that didn’t cause an immune reaction and was able to maintain glycemic control in mice that had diabetes.

New protective method makes diabetic mice insulin independent

The scientists tested the conventional alginate microspheres and the modified TMTD-alginate microspheres containing embryonic stem cell-derived human beta islets in diabetic mice.

Encapsulated beta islets were transplanted into diabetic mice. (Nature Medicine)

Encapsulated beta islets were transplanted into diabetic mice. (Nature Medicine)

They found that the conventional smaller alginate microspheres caused fibrosis while larger TMTD-alginate microspheres did not. They observed that the modified TMTD-alginate microspheres were able to achieve glycemic control for over 70 days after transplantation while conventional microspheres didn’t perform as well.

The scientists also looked at the immune response to both types of alginate spheres. They saw lower numbers of immune cells and less fibrosis surrounding the transplanted TMTD microspheres compared to the conventional microspheres.

The final studies were the icing on the cake. The asked whether the modified TMTD microspheres were able to maintain long-term glycemic control or insulin independence, which would mean sustaining blood glucose levels in diabetic mice for over 100 days. They studied diabetic mice that received TMTD microspheres for 174 days. At 150 days, they performed a glucose test and saw that the diabetic mice were just as good at regulating glucose levels as normal mice. Furthermore, after 6 months, these mice showed no build up of fibrotic tissue, indicating that the modified microspheres weren’t causing an immune response and these mice didn’t need immunosuppressive drugs.

What the experts had to say…

This study was picked up by STATnews, which also mentioned another related study published in Nature Biotechnology that tested various alginate derivatives in rodent and monkey models of diabetes.

Julia Greenstein, vice president of discovery research at JDRF, discussed the implications of both studies with STATnews:

“This is really the first demonstration of the ability of these novel materials in combination with a stem-cell derived beta cell to reverse diabetes in an animal model. Our goal is to bring that kind of biological cure across the spectrum of type 1 diabetes.”

First author on both studies, Arturo Vegas, also gave his thoughts and discussed future applications:

Arturo Vegas

Arturo Vegas

“From very early on, we were getting great success. Everything kind of fell into place. You saw less foreign body response. The human beta cells survived exquisitely well. I think we’ve advanced the ball pretty far, almost as far you could get in an academic environment. The talk is shifting toward doing something clinically.”

According to STATnews, Vegas and his team are working on tests now in monkey models. “Vegas said that if the primate studies are successful, the next step will be developing a therapy to be used in people.”


Related Links:

New Stem Cell Treatment for ALS May Slow Disease Progression

Exciting news was published this week that will give patients suffering from ALS, also known as Lou Gehrig’s disease, something to cheer about. The journal JAMA Neurology reported that a new stem cell treatment was successful in slowing disease progression in a small group of ALS patients in a Phase 2 clinical trial.

This is big news for a fatal, incurable disease that is well known for its progressive, degenerating effects on nerve cells in the brain and spinal cord. We’ve written about ALS a lot in the Stem Cellar, so if you want more background on the disease, read our “Progress to a Cure for ALS” blog.

A patient’s own stem cells can help

The stem cell therapy involves extracting mesenchymal stem cells from the bone marrow of ALS patients. These stem cells are then manipulated in culture into cells that secrete a growth factor called NeuroTrophic Factor (NTF), which helps keep nerve cells in the brain and spinal cord healthy and alive. The NTF-secreting stem cells (called NurOwn cells) are then transplanted back into the same ALS patient (making this an autologous stem cell therapy) by injection into either the spinal fluid or the muscles.

logoThe NurOwn method was developed by BrainStorm Cell Therapeutics, a biotech company based in the US and Israel. Clinical trials to test the safety and efficacy of NurOwn stem cells began in 2011 at the Hadassah Medical Organization (HMO). So far, 26 patients have participated in the trials both in the US and in Israel.

According to the JAMA publication, patients were monitored 3 months before and 6 months after they received stem cell transplants and 6 months after. Twelve of the 26 patients participated in an early stage of the trial (phase 1/2) to test the safety and tolerability of the stem cell therapy. The other 14 patients participated in a later stage (phase 2a), dose-escalating study where their modified stem cells were injected into both their spinal fluid and muscles. Following the treatment, the scientists looked at the safety profile of the transplanted stem cells and for signs of clinical improvement in patients such as their ease of breathing or ability to control their muscle movement.

Stem cell treatment is effective in most ALS patients

Results from the clinical trial showed that a majority of the patients benefitted from the NurOwn stem cell therapy. HMO Principle scientist and senior author on the study, Dr. Dimitrios Karussis, explained:

Dr. Dimitrios Karussis (Image credit: Israel21c)

Dimitrios Karussis (Israel21c)

“The results are very encouraging.  Close to 90% of patients who were injected intrathecally through the spinal cord fluid were regarded as responders to the treatment either in terms of their respiratory function or their motor disability.  Almost all of the patients injected in this way showed less progression and some even improved in their respiratory functions or their motor functions.”

A PRNewswire press release covering this study called the stem cell therapy the “first-of-its-kind treatment for treating neurodegenerative diseases.”

Not a cure just yet

This stem cell therapy will need to be tested in more patients before the it can be determined truly effective in slowing progression of ALS. And Dr. Karussis was quick to note that the NurOwn stem cell therapy isn’t a cure for ALS, but rather an early-stage therapy that will provide significant benefit to patients by slowing disease progression.

“I am optimistic that within the foreseeable future, we may provide a treatment to ALS patients that can slow down or stop the progression. I believe we are in the early stages of something new and revolutionary with this harvested stem cell infusion therapy.  While this is absolutely by no means a cure, it is the first step in a long process in that direction.  I see this treatment as being potentially one of the major future tools to treat degenerative diseases of the brain and spinal cord, in general.”

Other stem cell treatments for ALS in the works

A single stem cell therapy that could treat multiple neurodegenerative diseases would be extremely valuable to patients and doctors. However, it’s not clear that the “one ring to rule them all” scenario (couldn’t help making a Lord of the Rings reference) will play out well for all diseases that affect the brain and spinal cord. Luckily, Dr. Karussis and Brainstem Cell Therapeutics are not the only ones pursuing stem cell therapies for ALS.

Clive Svendsen has been on a 15-year quest to develop an ALS therapy

Clive Svendsen

CIRM is currently funding 21 studies (a total of $56.6 million) that use stem cells to either study ALS or to develop therapies to treat the disease. We wrote about one recent study by Clive Svendsen at Cedars Sinai which is using a combination of gene therapy and brain stem cells to deliver growth factors to protect nerve cells in the brain and spinal cord of ALS patients. Currently, Svendsen and his team are in the latter stages of research and hope to apply for FDA approval to test their therapy in patients in the near future. Svendsen told CIRM, “we will begin recruiting patients the first week we have approval.”


Related Links:

National honor for helping “the blind see”

Those of us fortunate to have good health take so many things for granted, not the least of which is our ability to see. But, according to the World Health Organization, there are 39 million people worldwide who are blind, and another 246 million who are visually impaired. Any therapy, any device, that can help change that is truly worthy of celebration.

Dr.MarkHumayun2 copy

Dr. Mark Humayun: Photo courtesy USC

That’s why we are celebrating the news that Professor Mark Humayun has been awarded the National Medal of Technology and Innovation, the nation’s top technology honor, by President Obama.

Humayun, a researcher at USC’s Keck School of Medicine and a CIRM grantee, is being honored for his work in developing an artificial retina, one that enables people with a relatively rare kind of blindness to see again.

But we are also celebrating the potential of his work that we are funding that could help restore sight to millions of people suffering from the leading cause of blindness among the elderly. But we’ll get back to that in a minute.

First, let’s talk about the invention that has earned him this prestigious award. It’s called the Argus II and it can help people with retinitis pigmentosa, an inherited degenerative disease that slowly destroys a person’s vision. It affects around 100,000 Americans.

The Argus II uses a camera mounted on glasses that send signals to an electronic receiver that has been implanted inside the eye. The receiver then relays those signals through the optic nerve to the brain where they are interpreted as a visual image.

In a story posted on the USC website, USC President C. L. Max Nikias praised Humayun’s work:

“He dreamed the impossible: to help the blind see. With fearless imagination, bold leadership and biomedical expertise, he and his team made that dream come true with the world’s first artificial retina. USC is tremendously proud to be Professor Humayun’s academic home.”

At CIRM we are tremendously proud to be funding the clinical trial that Humayun and his team are running to find a stem cell therapy for age-related macular degeneration (AMD), the leading cause of vision loss in the world.  It’s estimated that by 2020 more than 6 million Americans will suffer from AMD.

Humayun’s team is using embryonic stem cells to produce the support cells, or RPE cells, needed to replace those lost in AMD. We recently produced this video that highlights this work, and other CIRM-funded work that targets vision loss.

In a statement released by the White House honoring all the winners, President Obama said:

“Science and technology are fundamental to solving some of our nation’s biggest challenges. The knowledge produced by these Americans today will carry our country’s legacy of innovation forward and continue to help countless others around the world. Their work is a testament to American ingenuity.”

Which is why we are honored to be partners with Humayun and his team in advancing this research and, hopefully, helping find a treatment for millions of people who dream of one day being able to see again.

 

 

 

 

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.


Related links:

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

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


Related Links:

3D Printing Cells with DNA Velcro

Print

The complex, 3D micro-anatomy of the human liver. (Image source: WikiMedia Commons)

One of the Holy Grails of stem cell research is growing body parts to replace those damaged by disease or injury. Enormous strides have been made in a key first step: mastering recipes for maturing stem cells into various specialized cell types. But a lawn of, say, liver cells in a petri dish is not a functioning liver. Organs have complex, three-dimensional structures with intricate communication between multiple cell types.

Scientists are actively devising methods to overcome this challenge. For instance, cultivating cells onto biological scaffolds help mold the cells into the shape of a particular organ or tissue. And retooled 3D printers using “bio ink” can seed layers of different cells onto these scaffolds to create specified structures.

This week, a UCSF team added an ingenious new tool to this tissue engineering tool kit.  As reported on Monday in Nature Methods, the lab of Zev Gartner took advantage of DNA’s Velcro-like chemistry to build layers of different cell types in a specified pattern.

DNA – it’s not just for genetics anymore

DNAbasepairing

A DNA fragment is made of two complimentary strands that bind together with high specificity. (Image source: Visionlearning)

DNA is a molecule made of two thin strands. Each strand is specifically attracted to the other based on a unique sequence of genetic information. So if two strands of a short DNA fragment are peeled apart, they will only rejoin to each other and not some other fragment with a different sequence.  While DNA usually resides in the nucleus of a cell, the team worked out a method to temporarily attach copies of a strand of DNA on the outside of, let’s call it, “cell A”. The opposite strand of that DNA fragment was attached to “cell B”. When mixed together the two cells became attached to each other via the matching DNA sequences. Other cells with different DNA fragments floated on by.

The screen shot below from a really neat time-lapse video, which accompanies the research publication, shows how a rudimentary 3D cell structure could be built with a series of different cell-DNA fragment combinations. In this case, the team first attached DNA fragments onto a petri dish in a specific pattern. At the thirty-second mark in the video, you can see that cells with matching DNA fragments have attached to the DNA on the dish.

Screen Shot 2015-09-02 at 8.48.16 AM

This video demonstrates the assembly of 3D cell structures with the help of DNA “Velcro” (image source: Todhunter et al. Nature Methods 2015 Aug 31st)

The new technique, dubbed DNA programmed assembly of cells (DPAC), opens up a lot possibilities according to Gartner in a UCSF press release:

 “We can take any cell type we want and program just where it goes. We can precisely control who’s talking to whom and who’s touching whom at the earliest stages. The cells then follow these initially programmed spatial cues to interact, move around, and develop into tissues over time.”

The Quest still continues with possible victories along the way

 Of course, this advance is still a far cry from the quest for whole organs derived from stem cells. The cell assemblies using DPAC can only be grown up to about 100 microns, the thickness of a human hair. Beyond that size, the innermost cells get starved of oxygen and nutrients. Gartner says that obstacle is a current focus in the lab:

“We’re working on building functional blood vessels into these tissues. We can get the right cells in the right positions but haven’t figured out how to perfuse them with blood or a substitute efficiently yet.”

In the meantime, building these small 3D “organoids” from stem cells certainly could be put to good use as a means to test drug toxicity on human tissue or as a way to study human disease.

Related Links: