pancreatic cells

Producing insulin for people who can’t

/ Kevin McCormack / 1 Comment

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ViaCyte’s implantable stem cell pouch

One of the huge advantages of a stem cell agency like CIRM (not that there is anything out there quite like us, but anyway) is our ability to support projects as they progress from a great idea to a therapy actually being tested in people.

Exhibit A on that front came via a news release from ViaCyte, a company that is developing a new approach to helping people with severe Type 1 Diabetes (T1D).

Unlike type 2 diabetes, which is largely diet & lifestyle related and develops over time, T1D is an autoimmune condition where the person’s immune system attacks and destroys the insulin-producing cells in the pancreas. Without those cells and insulin the body is not able to regulate blood sugar levels and that can lead to damage to the heart, kidneys, eyes and nerves. In severe cases it can be fatal.

ViaCyte (which has been supported with more than $72 million from CIRM) has developed a pouch that can be implanted under the skin in the back. This pouch contains stem cells that over a period of a few months turn into insulin-producing pancreatic islet cells, the kind destroyed by T1D. The goal is for these cells to monitor blood flow and when they detect blood sugar or glucose levels are high, can secrete insulin to restore them to a safe level.

They tested this approach in 15 patients in a Phase 1 clinical trial in Canada. Their findings, published in the journals Cell Stem Cell and Cell Reports Medicine, show that six months after implantation, the cells had turned into insulin-producing islet cells. They also showed a rise in C-peptide levels after patients ate a meal. C-peptides are a sign your body is producing insulin so the rise in that number was a good indication the implanted cells were boosting insulin production.

As Dr. James Shapiro, the Chair of Canada Research and one of the lead authors of the study says, that’s no small achievement: “The data from these papers represent a significant scientific advance. It is the first reported evidence that differentiated stem cells implanted in patients can generate meal-regulated insulin secretion, offering real hope for the incredible potential of this treatment.”

And that wasn’t all. The researchers say that patients spent 13 percent more time in the target range for blood sugar levels than before the treatment, and some were even able to reduce the amount of insulin they injected.

Now this is only a Phase 1 clinical trial so the goal was to test the safety of the pouch, called PEC-Direct (VC-02), to see if the body would tolerate it being implanted and to see if it is effective. The beauty of this method is that the device is implanted under the skin so it can be removed easily if any problems emerge. So far none have.

Ultimately the hope is that this approach will help patients with T1D better regulate their blood sugar levels, improve their health outcomes, and one day even achieve independence from the burden of daily insulin injections.

Scientists develop immune evading pancreas organoids to treat type 1 diabetes

/ Kevin McCormack / 1 Comment

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.

The Most Important Gift of All

/ Kevin McCormack / Leave a comment
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.

Stories that caught our eye: How dying cells could help save lives; could modified blood stem cells reverse diabetes?; and FDA has good news for patients, bad news for rogue clinics

/ Kevin McCormack / Leave a comment

Gunsmoke

Growing up I loved watching old cowboy movies. Invariably the hero, even though mortally wounded, would manage to save the day and rescue the heroine and/or the town.

Now it seems some stem cells perform the same function, dying in order to save the lives of others.

Researchers at Kings College in London were trying to better understand Graft vs Host Disease (GvHD), a potentially fatal complication that can occur when a patient receives a blood stem cell transplant. In cases of GvHD, the transplanted donor cells turn on the patient and attack their healthy cells and tissues.

Some previous research had found that using bone marrow cells called mesenchymal stem cells (MSCs) had some success in combating GvHD. But it was unpredictable who it helped and why.

Working with mice, the Kings College team found that the MSCs were only effective if they died after being transplanted. It appears that it is only as they are dying that the MSCs engage with the individual’s immune system, telling it to stop attacking healthy tissues. The team also found that if they kill the MSCs just before transplanting them into mice, they were just as effective.

In a news article on HealthCanal, lead researcher Professor Francesco Dazzi, said the next step is to see if this will apply to, and help, people:

“The side effects of a stem cell transplant can be fatal and this factor is a serious consideration in deciding whether some people are suitable to undergo one. If we can be more confident that we can control these lethal complications in all patients, more people will be able to receive this life saving procedure. The next step will be to introduce clinical trials for patients with GvHD, either using the procedure only in patients with immune systems capable of killing mesenchymal stem cells, or killing these cells before they are infused into the patient, to see if this does indeed improve the success of treatment.”

The study is published in Science Translational Medicine.

Genetically modified blood stem cells reverse diabetes in mice (Todd Dubnicoff)

When functioning properly, the T cells of our immune system keep us healthy by detecting and killing off infected, damaged or cancerous cells in our body. But in the case of type 1 diabetes, a person’s own T cells turn against the body by mistakenly targeting and destroying perfectly normal islet cells in the pancreas, which are responsible for producing insulin. As a result, the insulin-dependent delivery of blood sugar to the energy-hungry organs is disrupted leading to many serious complications. Blood stem cell transplants have been performed to treat the disease by attempting to restart the immune system. The results have failed to provide a cure.

Now a new study, published in Science Translational Medicine, appears to explain why those previous attempts failed and how some genetic rejiggering could lead to a successful treatment for type 1 diabetes.

An analysis of the gene activity inside the blood stem cells of diabetic mice and humans reveals that these cells lack a protein called PD-L1. This protein is known to play an important role in putting the brakes on T cell activity. Because T cells are potent cell killers, it’s important for proteins like PD-L1 to keep the activated T cells in check.

Cell based image for t 1 diabetes

Credit: Andrea Panigada/Nancy Fliesler

Researchers from Boston Children’s Hospital hypothesized that adding back PD-L1 may prevent T cells from the indiscriminate killing of the body’s own insulin-producing cells. To test this idea, the research team genetically engineered mouse blood stem cells to produce the PD-L1 protein. Experiments with the cells in a petri dish showed that the addition of PD-L1 did indeed block the attack-on-self activity. And when these blood stem cells were transplanted into a diabetic mouse strain, the disease was reversed in most of the animals over the short term while a third of the mice had long-lasting benefits.

The researchers hope this targeting of PD-L1 production – which the researchers could also stimulate with pharmacological drugs – will contribute to a cure for type 1 diabetes.

FDA’s new guidelines for stem cell treatments

Gottlieb

FDA Commissioner Scott Gottlieb

Yesterday Scott Gottlieb, the Commissioner at the US Food and Drug Administration (FDA), laid out some new guidelines for the way the agency regulates stem cells and regenerative medicine. The news was good for patients, not so good for clinics offering unproven treatments.

First the good. Gottlieb announced new guidelines encouraging innovation in the development of stem cell therapies, and faster pathways for therapies, that show they are both safe and effective, to reach the patient.

At the same time, he detailed new rules that provide greater clarity about what clinics can do with stem cells without incurring the wrath of the FDA. Those guidelines detail the limits on the kinds of procedures clinics can offer and what ways they can “manipulate” those cells. Clinics that go beyond those limits could be in trouble.

In making the announcement Gottlieb said:

“To be clear, we remain committed to ensuring that patients have access to safe and effective regenerative medicine products as efficiently as possible. We are also committed to making sure we take action against products being unlawfully marketed that pose a potential significant risk to their safety. The framework we’re announcing today gives us the solid platform we need to continue to take enforcement action against a small number of clearly unscrupulous actors.”

Many of the details in the announcement match what CIRM has been pushing for some years. Randy Mills, our previous President and CEO, called for many of these changes in an Op Ed he co-wrote with former US Senator Bill Frist.

Our hope now is that the FDA continues to follow this promising path and turns these draft proposals into hard policy.

 

Throwback Thursday: Progress to a Cure for Type 1 Diabetes

/ Karen Ring / Leave a comment

Welcome back to our “Throwback Thursday” series on the Stem Cellar. Over the years, we’ve accumulated an arsenal of valuable stem cell stories on our blog. Some of these stories represent crucial advances towards stem cell-based cures for serious diseases and deserve a second look.

novemberawarenessmonthThis week in honor of Diabetes Awareness Month, we are featuring type 1 diabetes (T1D), a chronic disease that destroys the insulin-producing beta cells in your pancreas. Without these important cells, patients cannot maintain the proper levels of glucose, a fancy name for sugar, in their blood and are at risk for many complications including heart disease, blindness, and even death.

Cell replacement therapy is evolving into an attractive option for patients with T1D. Replacing lost beta cells in the pancreas is a more permanent and less burdensome solution than the daily insulin shots (or insulin pumps) that many T1D patients currently take.

So let’s take a look at the past year’s advances in stem cell research for diabetes.

Making Insulin-Producing Cells from Stem Cells and Skin

This year, there were a lot of exciting studies that improved upon previous methods for generating pancreatic beta cells in a dish. Here’s a brief recap of a few of the studies we covered on our blog:

  • Make pancreatic cells from stem cells. Scientists from the Washington University School of Medicine in St. Louis and the Harvard Stem Cell Institute developed a method that makes beta cells from T1D patient-derived induced pluripotent stem cells (iPSCs) that behave very similarly to true beta cells both in a dish and when transplanted into diabetic mice. Their discovery has the potential to offer personalized stem cell treatments for patients with T1D in the near future and the authors of the study predicted that their technology could be ready to test in humans in the next three to five years.
  • Making functional pancreatic cells from skin. Scientists from the Gladstone Institutes 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 pancreatic cells looked and acted like the real thing in a dish (they were able to secrete insulin when exposed to glucose), and they functioned normally when transplanted into diabetic mice. This study is exciting because it offers a new and more efficient method to make functioning human beta cells in mass quantities.

    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)

  • Challenges of stem cell-derived diabetes treatments. At this year’s Ogawa-Yamanaka Stem Cell Award ceremony Douglas Melton, a well-renowned diabetes researcher from Harvard, spoke about the main challenges for developing stem cell-derived diabetes treatments. The first is the need for better control over the methods that make beta cells from stem cells. The second was finding ways to make large quantities of beta cells for human transplantation. The last was finding ways to prevent a patient’s immune system from rejecting transplanted beta cells. Melton and other scientists are already working on improving techniques to make more beta cells from stem cells. As for preventing transplanted beta cells from being attacked by the patient’s immune system, Melton described two possibilities: using an encapsulation device or biological protection to mask the transplanted cells from an attack.

Progress to a Cure: Clinical Trials for Type 1 Diabetes

Speaking of encapsulation devices, CIRM is funding a Phase I clinical trial sponsored by a San Diego-based company called ViaCyte that’s hoping to develop a stem cell-based cure for patients with T1D. The treatment involves placing a small encapsulated device containing stem cell-derived pancreatic precursor cells under the skin of T1D patients. Once implanted, these precursor cells should develop into pancreatic beta cells that can secrete insulin into the patient’s blood stream. The goal of this trial is first to make sure the treatment is safe for patients and second to see if it’s effective in improving a patient’s ability to regulate their blood sugar levels.

To learn more about this exciting clinical trial, watch this fun video made by Youreka Science.

ViaCyte is still waiting on results for their Phase 1 clinical trial, but in the meantime, they are developing a modified version of their original device for T1D called PEC-Direct. This device also contains pancreatic precursor cells but it’s been designed in a way that allows the patient’s blood vessels to make direct connections to the cells inside the device. This vascularization process hopefully will improve the survival and function of the insulin producing beta cells inside the device. This study, which is in the last stage of research before clinical trials, is also being funded by CIRM, and we are excited to hear news about its progress next year.

ViaCyte's PEC-Direct device allows a patient's blood vessels to integrate and make contact with the transplanted beta cells.

ViaCyte’s PEC-Direct device allows a patient’s blood vessels to integrate and make contact with the transplanted beta cells.

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The best scientists always want to know more

/ Kevin McCormack / 1 Comment

Sir Isaac Newton

Sir Isaac Newton

Some years ago I was in the Wren Library at Trinity College, Cambridge in England when I noticed a display case with a cloth over it. Being a naturally curious person, downright nosy in fact, I lifted the cloth. In the display case was a first edition of Sir Isaac Newton’s Principia Mathematica and in the margins were notes, corrections put there by Newton for the second edition.

It highlighted for me how the best scientists never stop working, never stop learning, never stop trying to improve what they do.

That came back to me when I saw a news release from ViaCyte, a company we are funding in a Phase 1 clinical trial to treat type 1 diabetes.  The news release announced results of a study showing that insulin-producing cells, created in the lab from embryonic stem cells, can not only mature but also function properly after being implanted in a capsule-like device and placed under the skin of an animal model.

VC-01-cross-section-5

Now the clinical trial we are funding with ViaCyte uses a similar, but slightly different set of cells in people. The device in the trial contains what ViaCyte calls PEC-01™ pancreatic progenitor cells. These are essentially an earlier stage of the mature pancreatic cells that our body uses to produce insulin. The hope is that when implanted in the body, the cells will mature and then behave like adult pancreatic cells, secreting insulin and other hormones to keep blood glucose levels stable and healthy.

Those cells and that device are being tested in people with type 1 diabetes right now.

Learning more

But in this study ViaCyte wanted to know if beta cells, a more mature version of the cells they are using in our trial, would also work or have any advantages over their current approach.

The good news, published in the journal Stem Cells Translational Medicine,  is that these cells did work. As they say in their news release:

“The animal study also demonstrated for the first time that when encapsulated in a device and implanted into mice, these more mature cells are capable of producing functional pancreatic beta cells. ViaCyte is also the first to show that these further differentiated cells can function in vivo following cryopreservation, a valuable process step when contemplating clinical and commercial application.”

This does not mean ViaCyte wants to change the cells it uses in the clinical trial. As President and CEO Paul Laikind, PhD, makes clear:

“For a number of reasons we believe that the pancreatic progenitor cells that are the active component of the VC‐01 product candidate are better suited for cell replacement therapy. However, the current work has expanded our fundamental knowledge of beta cell maturation and could lead to further advances for the field.”

And that’s what I mean about the best scientists are the ones who keeping searching, keeping looking for answers. It may not help them today, but who knows how important that work will prove in the future.