Scientists develop immune evading pancreas organoids to treat type 1 diabetes

By Stephen Lin, PhD., CIRM Senior Science Officer

A diabetic child is checking her blood sugar level (self glycaemia).

Type 1 diabetes affects millions of people.  It is a disease where beta islet cells in the pancreas are targeted by the body’s own immune system, destroying the ability to produce insulin.  Without insulin, the body cannot break down sugars from the bloodstream that produce energy for organs and that can lead to many significant health problems including damage to the eyes, nerves, and kidneys.  It is a life-long condition, most commonly triggered in children and teenagers.  However, type 1 diabetes can manifest at any time.  I have a family member who developed type 1 diabetes well into adulthood and had to dramatically alter his lifestyle to live with it. 

Fortunately most people can now live with the disease.  There was a time, dating back to ancient civilizations when getting type 1 diabetes meant early death.  Thankfully, over the past hundred years, treatments have been developed to address the disease.  The first widespread treatment developed in the 1920s was injections of animal insulin isolated from pancreatic islets in cattle and pigs.  Over 50 years later the first genetically engineered human insulin was produced using E. coli bacteria, and variations of this are still used today. However, the disease is still very challenging to manage.  My family member constantly monitors his blood sugar and gives himself injections of insulin to regulate his blood sugar. 

A therapy that can self-regulate blood sugar levels for diabetes would greatly improve the lives of millions of people that deal with the disease.  Pancreatic islet cells transplanted into patients can act as a natural rheostat to continually control blood sugar levels.  Pancreas organ transplantation and islet cell transplantation are treatment options that will accomplish this.  Both options are limited in supply and patients must be kept on life-long immunosuppression so the body does not reject the transplant.  Pancreatic beta cells are also being developed from pluripotent stem cells (these are cells that have the ability to be turned into almost any other kind of cell in the body). 

Now in an advance using pluripotent stem cells, Dr. Ronald Evans and his team at the Salk Institute have created cell clusters called organoids that mimic several properties of the pancreas.  Previously, in work supported by CIRM, the team discovered that a genetic switch called ERR-gamma caused the cells to both produce insulin and be functional to respond to sugar levels in the bloodstream.  They incorporated these findings to create their functional islet clusters that they term “human islet-like islet organoids” (HILOs).  Knowing that the immune system is a major barrier for long term cell replacement therapy, Dr. Evans’ team engineered the HILOs, in work also funded by CIRM, to be resistant to immune cells by expressing the checkpoint protein PD-L1.   PD-L1 is a major target for immunotherapies whose discovery led to a Nobel Prize in 2018.  Expressing PD-L1 acts as an immune blocker.  

When the PD-L1 engineered HILOs were transplanted into diabetic mice with functioning immune systems, they were able to sustain blood glucose control for time periods up to 50 days.  The researchers also saw significantly less mobilization of immune cells after transplantation.  The hope is that these engineered HILOs can eventually be developed as a long term therapy for type 1 diabetes patients without the need for lifelong immunosuppression. 

In a press release, the Salk researchers acknowledge that more research needs to be done before this system can be advanced to clinical trials.  For example, the transplanted organoids need to be tested in mice for longer periods of time to confirm that their effects are long-lasting. More work needs to be done to ensure they would be safe to use in humans, as well. However, the proof of concept has now been established to move forward with these efforts.  Concludes Dr. Evan’s in the announcement, “We now have a product that could potentially be used in patients without requiring any kind of device.”

The full study was published in Nature.

Human immune cells made using pluripotent stem cells in world first

Dr. Andrew Elfanty (left) and Dr. Ed Stanley (right), Murdoch Children’s Research Institute in Melbourne, Australia

Our immune system is the first line of defense our bodies use to fight off infections and disease. One crucial component of this defense mechanism are lymphocytes, which are specialized cells that give rise to various kinds of immune cells, such as a T cell, designed to attack and destroy harmful foreign bodies. Problems in how certain immune cells are formed can lead to diseases such as leukemia and other immune system related disorders.

But how exactly do immune cells form early on in the body?

Dr. Andrew Elfanty and Dr. Ed Stanley at Murdoch Children’s Research Institute in Australia have reproduced and visualized a method in the laboratory used to create human immune cells from pluripotent stem cells, a kind of stem cell that can make virtually any kind of cell in the body. Not only can this unlock a better understanding of leukemia and other immune related diseases, it could potentially lead to a patient’s own skin cells being used to produce new cells for cancer immunotherapy or to test autoimmune disease therapies.

Dr. Elefanty and Dr. Stanley used genetic engineering and a unique way of growing stem cells to make this discovery.

As observed in this video, the team was able to engineer pluripotent stem cells to glow green when they expressed a specific protein found in early immune cells. These cells can be seen migrating along blood vessels outlined in red. These cells go on to populate the thymus, which as we discussed in an earlier blog, is an organ that is crucial in developing functional T cells.

In a press release from Murdoch Children’s Research Institute, Dr. Stanley talks about the important role these early immune cells might play.

“We think these early cells might be important for the correct maturation of the thymus, the organ that acts as a nursery for T-cells”

In addition to this, the team also isolated the green, glowing pluripotent stem cells and showed that they could be used for multiple immune cell types, including those necessary for shaping the development of the immune system as a whole.

In the same press release, Dr. Elefanty discusses the future direction that their research could lead to.

“Although a clinical application is likely still years away, we can use this new knowledge to test ideas about how diseases like childhood leukemia and type 1 diabetes develop. Understanding more about the steps these cells go through, and how we can more efficiently nudge them down a desired pathway, is going to be crucial to that process.”

The full results to this study were published in Nature Cell Biology.

The Top CIRM Blogs of 2019

This year the most widely read blog was actually one we wrote back in 2018. It’s the transcript of a Facebook Live: “Ask the Stem Cell Team” event about strokes and stroke recovery. Because stroke is the third leading cause of death and disability in the US it’s probably no surprise this blog has lasting power. So many people are hoping that stem cells will help them recover from a stroke.

But of the blogs that we wrote and posted this year there’s a really interesting mix of topics.

The most read 2019 blog was about a potential breakthrough in the search for a treatment for type 1 diabetes (T1D).  Two researchers at UC San Francisco, Dr. Matthias Hebrok and Dr. Gopika Nair developed a new method of replacing the insulin-producing cells in the pancreas that are destroyed by type 1 diabetes. 

Dr. Matthias Hebrok
Dr. Gopika Nair

Dr. Hebrok described it as a big advance saying: “We can now generate insulin-producing cells that look and act a lot like the pancreatic beta cells you and I have in our bodies. This is a critical step towards our goal of creating cells that could be transplanted into patients with diabetes.”

It’s not too surprising a blog about type 1 diabetes was at the top. This condition affects around 1.25 million Americans, a huge audience for any potential breakthrough. However, the blog that was the second most read is the exact opposite. It is about a rare disease called cystinosis. How rare? Well, there are only around 500 children and young adults in the US, and just 2,000 worldwide diagnosed with this condition.  

It might be rare but its impact is devastating. A genetic mutation means children with this condition lack the ability to clear an amino acid – cysteine – from their body. The buildup of cysteine leads to damage to the kidneys, eyes, liver, muscles, pancreas and brain.

Dr. Stephanie Cherqui

UC San Diego researcher Dr. Stephanie Cherqui and her team are taking the patient’s own blood stem cells and, in the lab, genetically re-engineering them to correct the mutation, then returning the cells to the patient. It’s hoped this will create a new, healthy blood system free of the disease.

Dr. Cherqui says if it works, this could help not just people with cystinosis but a wide array of other disorders: “We were thrilled that the stem cells and gene therapy worked so well to prevent tissue degeneration in the mouse model of cystinosis. This discovery opened new perspectives in regenerative medicine and in the application to other genetic disorders. Our findings may deliver a completely new paradigm for the treatment of a wide assortment of diseases including kidney and other genetic disorders.”

Sickled cells

The third most read blog was about another rare disease, but one that has been getting a lot of media attention this past year. Sickle cell disease affects around 100,000 Americans, mostly African Americans. In November the Food and Drug Administration (FDA) approved Oxbryta, a new therapy that reduces the likelihood of blood cells becoming sickle shaped and clumping together – causing blockages in blood vessels.

But our blog focused on a stem cell approach that aims to cure the disease altogether. In many ways the researchers in this story are using a very similar approach to the one Dr. Cherqui is using for cystinosis. Genetically correcting the mutation that causes the problem, creating a new, healthy blood system free of the sickle shaped blood cells.

Two other blogs deserve honorable mentions here as well. The first is the story of James O’Brien who lost the sight in his right eye when he was 18 years old and now, 25 years later, has had it restored thanks to stem cells.

The fifth most popular blog of the year was another one about type 1 diabetes. This piece focused on the news that the CIRM Board had awarded more than $11 million to Dr. Peter Stock at UC San Francisco for a clinical trial for T1D. His approach is transplanting donor pancreatic islets and parathyroid glands into patients, hoping this will restore the person’s ability to create their own insulin and control the disease.

2019 was certainly a busy year for CIRM. We are hoping that 2020 will prove equally busy and give us many new advances to write about. You will find them all here, on The Stem Cellar.

The Most Important Gift of All

Photo courtesy American Hospital Association

There are many players who have a key role in helping make a stem cell therapy work. The scientists who develop the therapy, the medical team who deliver it and funders like CIRM who provide the money to make this all happen. But vital as they are, in some therapies there is another, even more important group; the people who donate life-saving organs and tissues for transplant and research.

Organ and tissue donation saves lives, increases knowledge of diseases, and allow for the development of novel medications to treat them. When individuals or their families authorize donation for transplant or medical research, they allow their loved ones to build a long-lasting legacy of hope that could not be accomplished in any other way.

Four of CIRM’s clinical trials involve organ donations – three kidney transplant programs (you can read about those here, here and here) and one targeting type 1 diabetes.

Dr. Nikole Neidlinger, the Chief Medical Officer with Donor Network West – the federally designated organ and tissue recovery organization for Northern California and Nevada – says it is important to recognize the critical contribution made in a time of grief and crisis by the families of deceased donors. 

“For many families who donate, a loved one has died, and they are in shock. Even so, they are willing to say yes to giving others a second chance at life and to help others to advance science. Without them, none of this would be possible. It’s the ultimate act of generosity and compassion.”

The latest CIRM-funded clinical trial involving donated tissue is with Dr. Peter Stock and his team at UCSF. They are working on a treatment for type 1 diabetes (T1D), where the body’s immune system destroys its own pancreatic beta cells. These cells are necessary to produce insulin, which regulates blood sugar levels in the body.

In the past people have tried transplanting beta cells, from donated pancreatic islets, into patients with type 1 diabetes to try and reverse the course of the disease. However, this requires islets from multiple donors and the shortage of organ and tissue donors makes this difficult to do.

Dr. Stock’s clinical trial at UCSF aims to address these limitations.  He is going to transplant both pancreatic islets and parathyroid glands, from the same donor, into T1 patients. It’s hoped this combination approach will increase beta cell survival, potentially boosting long-term insulin production and removing the need for multiple donors.  And because the transplant is placed in the patient’s forearm, it makes it easier to monitor the effectiveness and accessibility of the islet transplants. Of equal importance, the development of this site will facilitate the transplantation of stem cell derived beta cells, which are very close to clinical application.

“As a transplant surgeon, it is an absolute privilege to be able to witness the life-saving organ transplants made possible by the selfless generosity of the donor families. It is hard to imagine how families have the will to think about helping others at a time of their greatest grief. It is this willingness to help others that restores my faith in humanity”

Donor Network West plays a vital role in this process. In 2018 alone, the organization recovered 702 donor samples for research. Thanks to the generosity of the donors/donor families, the donor network has been able to provide parathyroid and pancreas tissue essential to make this clinical trial a success”

“One organ donor can save the lives of up to eight people and a tissue donor can heal more than 75 others,” says Dr. Neidlinger. “For families, the knowledge that they are transforming someone’s life, and possibly preventing another family from experiencing this same loss, can serve as a silver lining during their time of sorrow. .”

Organs that can be donated

Kidney (x2), Heart, Lungs (x2), Liver, Pancreas, Intestine

Tissue that can be donated

Corneas, Heart valves, Skin, Bone, Tendons, Cartilage, Veins

Currently, there are over 113,000 people in the U.S. waiting for an organ transplant, of which 84 % are in need of kidneys.  Sadly, 22 people die every day waiting for an organ transplant that does not come in time. The prospect of an effective treatment for type 1 diabetes means hope for thousands of people living with the chronic condition.

The challenges of living with IPEX

Last week the CIRM Board awarded $5.53 million to Dr. Rosa Bacchetta at Stanford to complete the work necessary to conduct a clinical trial for IPEX syndrome. This is a rare disease caused by mutations in the FOXP3 gene which leaves people with the condition vulnerable to immune system attacks on their organs and tissues. These attacks can be devastating, even fatal.

At the Board meeting Taylor Lookofsky, a young man with IPEX syndrome, talked about the impact the condition has had on his life. The transcript of his talk is below.

It’s a powerful reminder that syndromes like this, because they affect a small number of people, are often overlooked and have few resources devoted to finding new treatments and cures. After reading Taylor’s story you come to appreciate his courage and determination, and why the funding CIRM provides is so important in helping researchers like Dr. Bacchetta find therapies to help people like Taylor.

Brian Lookofsky (Taylor’s father), Taylor Lookofsky and Dr. Rosa Bacchetta at the CIRM Board meeting

“Good morning, my name is Taylor Lookofsky and I would first like to thank Rosa, who is one of the many doctors in my life. Rosa presented me with this amazing opportunity to come and speak to you today about my life and the challenges living with IPEX.

  • I’d like to give you some background into my health challenges I’ve faced my entire life. Now to give some context to my years of struggle, I am 28 years old, not 10 years younger as some may have assumed.
  • My first diagnosis came at the age of 1 ½ years old -type 1 diabetes.
  • Soon after being diagnosed with type 1 diabetes, I had to have a feeding tube inserted in my abdomen as I was restricted from eating almost all foods due to unknown food allergies. I was not allowed to ingest ANY food until the age of 6 years old. When I was finally introduced to food, any food ingested was tasteless and felt like sandpaper on my tongue since I had to train myself to eat.
  • Around age 10, I would be faced with the beginning of a never-ending battle with my dermatitis. I remember specific details where my mother had taken me to a dermatologist to try and figure out what was happening to my skin as it was red, blotchy, oozing. I remember shivering so badly that my mom had to ask the doctor’s office to turn the air down.
  • At age 18 I had been formally diagnosed with IPEX. I lost my hair and my skin started a battle that was more intense than any previous episode. I remember taking showers and clumps of my hair would fall out, and I would cry in the shower not knowing what was going on.
  • At age 20, I would go through the most horrific episode with my skin to date. I was bed ridden, on pain meds and could not sleep. I had gone to all of my doctors trying to figure out what had triggered this event, and no doctor could figure out what was happening, leaving me extremely frustrated, depressed and drained of all energy. I went to the burn center as a last resort and was then treated like a burn patient. To care for these wounds, I would bathe, take a sponge and physically scrape these wounds to keep them infection free and as clean as possible. When I would exit the bath, I felt like a dried-up sponge and my skin was so tight that any movement would make my skin crack open and start bleeding. To add to this, I had to use medicated wraps to help with the healing process.
  • In an ongoing attempt to treat my many symptoms, I took a series of medications that came with side effects. I have had at least 15 surgeries to remove squamous cells caused by one of the medications: In 2018, my colon perforated. As a result, I now have a colostomy bag.

The IPEX symptoms have affected me not just physically, but mentally as well. I had lost all my hair and growth has been permanently stunted, and I have not reached the point in puberty as my male counterparts. I would go day by day and see all my peers and be envious that they were tall, had beards and hair, had relationships, and the confidence that I was lacking and admittedly, still lack to this day at times.

I’ve felt hopeless because there have been so few treatment options and with the treatment currently available, I have tried hundreds of medications and creams, and have had my blood drawn countless times in hopes of finding a medication that works for me, or a cure for this insufferable disease. However, nothing. As a result, I have been battling depression singe age 20. There were days that went by where I thought “I just don’t want to be here if this is what life is going to be like.” 

The funding needed for Dr. Rosa’s therapy would be life changing in the way of new treatment options and potentially lead to a cure for this horrific disease.

I am determined to see that there is so much more to life than what society is telling me. I’ve decided that I would not conform to societies rules, and instead, tell society how I am going to live my unique and authentic life with IPEX.

I appreciate your time and consideration to fund this important research.”

Rare Disease, Type 1 Diabetes, and Heart Function: Breakthroughs for Three CIRM-Funded Studies

This past week, there has been a lot of mention of CIRM funded studies that really highlight the importance of the work we support and the different disease areas we make an impact on. This includes important research related to rare disease, Type 1 Diabetes (T1D), and heart function. Below is a summary of the promising CIRM-funded studies released this past week for each one of these areas.

Rare Disease

Comparison of normal (left) and Pelizaeus-Merzbacher disease (PMD) brains (right) at age 2. 

Pelizaeus-Merzbacher disease (PMD) is a rare genetic condition affecting boys. It can be fatal before 10 years of age and symptoms of the disease include weakness and breathing difficulties. PMD is caused by a disruption in the formation of myelin, a type of insulation around nerve fibers that allows electrical signals in the brain to travel quickly. Without proper signaling, the brain has difficulty communicating with the rest of the body. Despite knowing what causes PMD, it has been difficult to understand why there is a disruption of myelin formation in the first place.

However, in a CIRM-funded study, Dr. David Rowitch, alongside a team of researchers at UCSF, Stanford, and the University of Cambridge, has been developing potential stem cell therapies to reverse or prevent myelin loss in PMD patients.

Two new studies, of which Dr. Rowitch is the primary author, published in Cell Stem Cell, and Stem Cell Reports, respectively report promising progress in using stem cells derived from patients to identify novel PMD drugs and in efforts to treat the disease by directly transplanting neural stem cells into patients’ brains. 

In a UCSF press release, Dr. Rowitch talks about the implications of his findings, stating that,

“Together these studies advance the field of stem cell medicine by showing how a drug therapy could benefit myelination and also that neural stem cell transplantation directly into the brains of boys with PMD is safe.”

Type 1 Diabetes

Viacyte, a company that is developing a treatment for Type 1 Diabetes (T1D), announced in a press release that the company presented preliminary data from a CIRM-funded clinical trial that shows promising results. T1D is an autoimmune disease in which the body’s own immune system destroys the cells in the pancreas that make insulin, a hormone that enables our bodies to break down sugar in the blood. CIRM has been funding ViaCyte from it’s very earliest days, investing more than $72 million into the company.

The study uses pancreatic precursor cells, which are derived from stem cells, and implants them into patients in an encapsulation device. The preliminary data showed that the implanted cells, when effectively engrafted, are capable of producing circulating C-peptide, a biomarker for insulin, in patients with T1D. Optimization of the procedure needs to be explored further.

“This is encouraging news,” said Dr. Maria Millan, President and CEO of CIRM. “We are very aware of the major biologic and technical challenges of an implantable cell therapy for Type 1 Diabetes, so this early biologic signal in patients is an important step for the Viacyte program.”

Heart Function

Although various genome studies have uncovered over 500 genetic variants linked to heart function, such as irregular heart rhythms and heart rate, it has been unclear exactly how they influence heart function.

In a CIRM-funded study, Dr. Kelly Frazer and her team at UCSD studied this link further by deriving heart cells from induced pluripotent stem cells. These stem cells were in turn derived from skin samples of seven family members. After conducting extensive genome-wide analysis, the team discovered that many of these genetic variations influence heart function because they affect the binding of a protein called NKX2-5.

In a press release by UCSD, Dr. Frazer elaborated on the important role this protein plays by stating that,

“NKX2-5 binds to many different places in the genome near heart genes, so it makes sense that variation in the factor itself or the DNA to which it binds would affect that function. As a result, we are finding that multiple heart-related traits can share a common mechanism — in this case, differential binding of NKX2-5 due to DNA variants.”

The full results of this study were published in Nature Genetics.

Moving a great idea targeting diabetes out of the lab and into a company

Tejal Desai in her lab at UCSF: Photo courtesy Todd Dubnicoff

It’s always gratifying to see research you have helped support go from being an intriguing idea to something with promise to a product that is now the focus of a company. It’s all the more gratifying if the product in question might one day help millions of people battling diabetes.

That’s the case with a small pouch being developed by a company called Encellin. The pouch is the brainchild of Tejal Desai, Ph.D., a professor of bioengineering at UCSF and a CIRM grantee.

Encellin’s encapsulation device

“It’s a cell encapsulation device, so this material can essentially protect beta cells from the immune system while allowing them to function by secreting insulin. We are placing stem cell-derived beta cells into the pouch which is then implanted under the skin. The cells are then able to respond to changes in sugar or glucose levels in the blood by pumping out insulin.  By placing the device in a place that is accessible we can easily remove it if we have to, but also we can recharge it and put in new cells as well.”

While the pouch was developed in Dr. Desai’s lab, the idea to take it from a promising item and try to turn it into a real-world therapy came from one of Dr. Desai’s former students, Crystal Nyitray, Ph.D.

Crystal Nyitray: Photo courtesy FierceBiotech

After getting her PhD, Nyitray went to work for the pharmaceutical giant Sanofi. In an article in FierceBiotech she says that’s where she realized that the pouch she had been working on at UCSF had real potential.

“During that time, I started to realize we really had something, that everything that pharma or biotech was looking at was something we had been developing from the ground up with those specific questions in mind,”

So Dr. Nyitray went to work for QB3, the institute created by UC San Francisco to help startups develop their ideas and get funding. The experience she gained there gave her the confidence to be the co-founder and CEO of Encellin.

Dr. Desai is a scientific advisor to Encellin. She says trying to create a device that contains insulin-secreting cells is not new. Many previous attempts failed because once the device was placed in the body, the immune system responded by creating fibrosis or scarring around it which blocked the ability of the cells to get out.

But she thinks their approach has an advantage over previous attempts.

“This is not a new idea, the idea has been around for 40 or more years but getting it to work is hard. We have a convergence of getting the right cell types and combining that with our knowledge of immunology and then the material science where we can design materials at this scale to get the kind of function that we need.

Dr. Nyitray ““If we can reduce fibrosis, it really helps the cells get nutrients better, survive better and signal more effectively. It’s really critical to their success.”

Dr. Desai says the device is still in the early stages of being tested, but already it’s showing promise.

“We have done testing in animals. Where the company is taking this is now to see if we can take this to larger animals and then ultimately people.”

She says without CIRM’s support none of this would have happened.

“CIRM has been really instrumental in helping us refine the cell technology piece of it, to get really robust cells and also to support the development to push the materials, to understand the biology, to really understand what was happening with the cell material interface. We know we have a lot of challenges ahead, but we are really excited to see if this could work.”

We are excited too. We are looking forward to seeing what Encellin does in the coming years. It could change the lives of millions of people around the world.

No pressure. 

Stem Cell Agency Board Approves New Clinical Trial for Type 1 Diabetes

Dr. Peter Stock at the capitol in Sacramento in May 2016.
Photo courtesy of Steve German.

Today the governing Board of the California Institute for Regenerative Medicine (CIRM) awarded $11.08 Million to Dr. Peter Stock at the University of California San Francisco (UCSF) to conduct a clinical trial for treatment of Type 1 Diabetes (T1D).

The award brings the total number of CIRM funded clinical trials to 54. 

T1D is a chronic autoimmune disease that affects approximately 1.25 million Americans, with 40,000 new diagnoses each year.  T1D occurs as a result of the body’s immune system destroying its own pancreatic beta cells.  These cells are necessary to produce the vital hormone insulin, which regulates blood sugar levels in the body.  As a result of a lack of insulin, there is no blood sugar control in T1D patients, gradually causing disabling and life-threatening complications such as heart disease, nerve damage, and vision problems.

There is no cure for T1D.  Current treatments consist of blood sugar monitoring and multiple daily injections of insulin.  Transplantation of beta cells, contained in donor pancreatic islets, can reverse the symptoms of diabetes.  However, due to a poor islet survival rate, transplants require islets from multiple donors.  Furthermore, since islet cells are transplanted directly into the vessels that enter the liver, it is extremely difficult to monitor and retrieve these cells should the need arise. 

Dr. Stock’s clinical trial at UCSF aims to address these limitations.  The trial will be using parathyroid glands to aid in the success and viability of the transplant procedure.  Co-transplantation of islets and parathyroid glands, from the same donor, substantially increases beta cell survival, potentially enabling adequate long-term insulin production and removing the need for multiple donors.  Additionally, the co-transplantation will occur in the patient’s forearm, which allows for easier monitoring and improves the effectiveness and accessibility of islet transplants for patients.

“This team’s innovative approach to develop a definitive cell-based treatment for Type 1 Diabetes has the potential to address an unmet medical need that exists despite advancements in diabetes therapy.” says Maria T. Millan, M.D., the President and CEO of CIRM.  “The success of this clinical trial could enable the successful application of islet cell transplants but also of future stem-cell based approaches for diabetes.”

CIRM has funded three other clinical trials for T1D.  One of these was conducted by Caladrius Biosciences and two by ViaCyte, Inc.

Breakthrough for type 1 diabetes: scientist discovers how to grow insulin-producing cells

Matthias Hebrok, PhD, senior author of new study that transformed human stem cells into mature, insulin-producing cells. Photo courtesy of UCSF.

More often than not, people don’t really think about their blood sugar levels before sitting down to enjoy a delicious meal, partake in a tasty dessert, or go out for a bicycle ride. But for type 1 diabetes (T1D) patients, every minute and every action revolves around the readout from a glucose meter, a device used to measure blood sugar levels.

Normally, the pancreas contains beta cells that produce insulin in order to maintain blood sugar levels in the normal range. Unfortunately, those with T1D have an immune system that destroys their own beta cells, thereby decreasing or preventing the production of insulin and in turn the regulation of blood sugar levels. Chronic spikes in blood sugar levels can lead to blindness, nerve damage, kidney failure, heart disease, stroke, and even death.

Those with T1D manage their condition by injecting themselves with insulin anywhere from two to four times a day. A light workout, slight change in diet, or even an exciting event can have a serious impact that requires a glucose meter check and an insulin injection.

There are clinical trials involving transplants of pancreatic “islets”, clusters of cells containing healthy beta cells, but these rely on pancreases from deceased donors and taking immune suppressing drugs for life.

But what if there was a way to produce healthy beta cells in a lab without the need of a transplant?

Dr. Matthias Hebrok, director of the UCSF diabetes center, and Dr. Gopika Nair, postdoctoral fellow, have discovered how to transform human stem cells into healthy, insulin producing beta cells.

In a news release written by Dr. Nicholas Weiler of UCSF, Dr. Hebrok is quoted as saying “We can now generate insulin-producing cells that look and act a lot like the pancreatic beta cells you and I have in our bodies. This is a critical step towards our goal of creating cells that could be transplanted into patients with diabetes.”

For the longest time, scientists could only produce cells at an immature stage that were unable to respond to blood sugar levels and secrete insulin properly. Dr. Hebrok and Dr. Nair discovered that mimicking the “islet” formation of cells in the pancreas helped the cells mature. These cells were then transplanted into mice and found that they were fully functional, producing insulin and responding to changes blood sugar levels.

Dr. Hebrok’s team is already in collaboration with various colleagues to make these cells transplantable into patients.

Gopika Nair, PhD, postdoctoral fellow that led the study for transforming human stem cells into mature, insulin-producing cells. Photo courtesy of UCSF.

Dr. Nair in the article is also quoted as saying “Current therapeutics like insulin injections only treat the symptoms of the disease. Our work points to several exciting avenues to finally finding a cure.”

“We’re finally able to move forward on a number of different fronts that were previously closed to us,” Hebrok added. “The possibilities seem endless.” 

Dr. Hebrok, who is also a member of the CIRM funded UCSF Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, was senior author of the new study, which was published February 1, 2019 in Nature Cell Biology.

CIRM has funded three separate human clinical trials for T1D that total approximately $37.8 million in awards. Two of these trials are being conducted by ViaCyte, Inc. and the third trial is being conducted by Caladrius Biosciences.

CIRM-supported Type I Diabetes treatment enters clinical trials in Europe

Viacyte images

ViaCyte’s President & CEO, Paul Laikind

ViaCyte, a company that CIRM has supported for many years, has announced international expansion of a clinical trial to test their therapeutic PEC-Direct product in patients with Type I Diabetes.

The first European patient in Brussels was implanted with the PEC-Direct product candidate that, in animal models, is able to form functional beta cells. Patients with Type I Diabetes are unable to control blood glucose levels because their immune system attacks insulin-producing beta cells, which are responsible for regulating blood sugar.

viacyte device

ViaCyte PEC-Direct product candidate

The hope is that PEC-Direct would eliminate the need for patients to take daily doses of insulin, the current treatment standard to prevent the side effects of high blood glucose levels, such as heart disease, kidney damage and nerve damage.

The PEC-Direct product is implanted under the skin. The progenitor cells inside it are designed to mature in to human pancreatic islet cells, including glucose-responsive insulin-secreting beta cells, following implant. These are the cells destroyed by Type 1 Diabetes

In this first phase of the clinical trial, patients are administered a subtherapeutic dose of the drug to ensure that that the implants are able to generate beta cells in the body. The next part of the trial will determine whether or not the formed beta cells are able to produce appropriate levels of insulin and modulate blood glucose levels. A sister trial is currently underway in North America as well. This work is a collaboration between ViaCyte and The Center for Beta Cell Therapy in Diabetes.

Separately, ViaCyte has also made important headway to make stem cells more effective in different types of diseases by programming them to evade the immune system. This progress has been cited by the Global Human Embryonic Stem Cells Market report as a key development in growing the overall global stem cell market.

CIRM is proud to be a supporter of companies such as ViaCyte that are conducting groundbreaking research to make stem cell therapy an effective and realistic treatment option for many different diseases.