Treatments, cures and clinical trials: an in-person update on CIRM’s progress

Patients and Patient Advocates are at the heart of everything we do at CIRM. That’s why we are holding three free public events in the next few months focused on updating you on the stem cell research we are funding, and our plans for the future.

Right now we have 33 projects that we have funded in clinical trials. Those range from heart disease and stroke, to cancer, diabetes, ALS (Lou Gehrig’s disease), two different forms of vision loss, spinal cord injury and HIV/AIDS. We have also helped cure dozens of children battling deadly immune disorders. But as far as we are concerned we are only just getting started.

Over the course of the next few years, we have a goal of adding dozens more clinical trials to that list, and creating a pipeline of promising therapies for a wide range of diseases and disorders.

That’s why we are holding these free public events – something we try and do every year. We want to let you know what we are doing, what we are funding, how that research is progressing, and to get your thoughts on how we can improve, what else we can do to help meet the needs of the Patient Advocate community. Your voice is important in helping shape everything we do.

The first event is at the Gladstone Institutes in San Francisco on Wednesday, September 6th from noon till 1pm. The doors open at 11am for registration and a light lunch.

Gladstone Institutes

Here’s a link to an Eventbrite page that has all the information about the event, including how you can RSVP to let us know you are coming.

We are fortunate to be joined by two great scientists, and speakers – as well as being CIRM grantees-  from the Gladstone Institutes, Dr. Deepak Srivastava and Dr. Steve Finkbeiner.

Dr. Srivastava is working on regenerating heart muscle after it has been damaged. This research could not only help people recover from a heart attack, but the same principles might also enable us to regenerate other organs damaged by disease. Dr. Finkbeiner is a pioneer in diseases of the brain and has done ground breaking work in both Alzheimer’s and Huntington’s disease.

We have two other free public events coming up in October. The first is at UC Davis in Sacramento on October 10th (noon till 1pm) and the second at Cedars-Sinai in Los Angeles on October 30th (noon till 1pm). We will have more details on these events in the coming weeks.

We look forward to seeing you at one of these events and please feel free to share this information with anyone you think might be interested in attending.

Stem cell stories that caught our eye: skin grafts fight diabetes, reprogramming the immune system, and Asterias expands spinal cord injury trial sites

Here are the stem cell stories that caught our eye this week.

Skin grafts fight diabetes and obesity.

An interesting new gene therapy strategy for fighting type 1 diabetes and obesity surfaced this week. Scientists from the University of Chicago made genetically engineered skin grafts that secrete a peptide hormone called glucagon-liked peptide-1 (GLP-1). This peptide is released by cells in the intestine and can lower blood sugar levels by stimulating pancreatic islet cells to secrete insulin (a hormone that promotes the absorption of glucose from the blood).

The study, which was published in the journal Cell Stem Cell, used CRISPR gene editing technology to introduce a mutation to the GLP-1 gene in mouse and human skin stem cells. This mutation stabilized the GLP-1 peptide, allowing it to hang around in the blood for longer. The team matured these stem cells into skin grafts that secreted the GLP-1 into the bloodstream of mice when treated with a drug called doxycycline.

When fed a high-fat diet, mice with a skin graft (left), genetically altered to secrete GLP-1 in response to the antibiotic doxycycline, gained less weight than normal mice (right). (Image source: Wu Laboratory, the University of Chicago)

On a normal diet, mice that received the skin graft saw a rise in their insulin levels and a decrease in their blood glucose levels, proving that the gene therapy was working. On a high fat diet, mice with the skin graft became obese, but when they were treated with doxycycline, GLP-1 secreted from their grafts reduced the amount of weight gain. So not only does their engineered skin graft technology look like a promising new strategy to treat type 1 diabetes patients, it also could be used to control obesity. The beauty of the technology is in its simplicity.

An article in Genetic Engineering and Biotechnology News that covered this research explained that Xiaoyang Wu, the senior author on the study, and his team “worked with skin because it is a large organ and easily accessible. The cells multiply quickly and are easily transplanted. And, transplanted cells can be removed, if needed. “Skin is such a beautiful system,” Wu says, noting that its features make it a perfect medium for testing gene therapies.”

Wu concluded that, “This kind of therapy could be potentially effective for many metabolic disorders.” According to GenBio, Wu’s team “is now testing the gene-therapy technique in combination with other medications.” They also hope that a similar strategy could be used to treat patients that can’t make certain proteins like in the blood clotting disorder hemophilia.

How to reprogram your immune system (Kevin McCormack)

When your immune system goes wrong it can cause all manner of problems, from type 1 diabetes to multiple sclerosis and cancer. That’s because an overactive immune system causes the body to attack its own tissues, while an underactive one leaves the body vulnerable to outside threats such as viruses. That’s why scientists have long sought ways to correct those immune dysfunctions.

Now researchers at the Gladstone Institutes in San Francisco think they have found a way to reprogram specific cells in the immune system and restore a sense of health and balance to the body. Their findings are published in the journal Nature.

The researchers identified a drug that targets effector T cells, which get our immune system to defend us against outside threats, and turns them into regulatory T cells, which control our immune system and stops it from attacking our own body.

Why would turning one kind of T cell into another be helpful? Well, in some autoimmune diseases, the effector T cells become overly active and attack healthy tissues and organs, damaging and even destroying them. By converting them to regulatory T cells you can prevent that happening.

In addition, some cancers can hijack regulatory T cells and suppress the immune system, allowing the disease to spread. By turning those cells into effector T cells, you can boost the immune system and give it the strength to fight back and, hopefully, kill the cancer.

In a news release, Gladstone Senior Investigator Sheng Ding, the lead scientists on the study, said their findings could have several applications:

“Our findings could have a significant impact on the treatment of autoimmune diseases, as well as on stem cell and immuno-oncology therapies.” 

Gladstone scientists Sheng Ding (right) and Tao Xu (left) discovered how to reprogram cells in our immune system. (Gladstone Institutes)

CIRM-funded spinal cord injury trial expands clinical sites

We have another update from CIRM’s clinical trial front. Asterias Biotherapeutics, which is testing a stem cell treatment for complete cervical (neck) spinal cord injury, is expanding its clinical sites for its CIRM-funded SCiStar Phase 1/2a trial. The company is currently treating patients at six sites in the US, and will be expanding to include two additional sites at Thomas Jefferson University Hospital in Philadelphia and the UC San Diego Medical Center, which is part of the UCSD Health CIRM Alpha Stem Cell Clinic.

In a company news release, Ed Wirth, Chief Medical Officer of Asterias said,

Ed Wirth

“We are excited about the clinical site openings at Thomas Jefferson University Hospital and UC San Diego Health. These sites provide additional geographical reach and previous experience with spinal cord injury trials to our SCiStar study. We have recently reported completion of enrollment in four out of five cohorts in our SCiStar study so we hope these institutions will also participate in a future, larger study of AST-OPC1.”

The news release also gave a recap of the trial’s positive (but still preliminary) results this year and their plans for completing trial enrollment.

“In June 2017, Asterias reported 9 month data from the AIS-A 10 million cell cohort that showed improvements in arm, hand and finger function observed at 3-months and 6-months following administration of AST-OPC1 were confirmed and in some patients further increased at 9-months. The company intends to complete enrollment of the entire SCiStar study later this year, with multiple safety and efficacy readouts anticipated during the remainder of 2017 and 2018.”

ViaCyte treats first patients in PEC-Direct stem cell trial for type 1 diabetes

Today, ViaCyte shared an update on its latest clinical trial for type 1 diabetes (T1D). The company is based in San Diego and is developing two stem cell-based products that attempt to replace the pancreatic beta islet cells that are attacked by the immune system of patients with T1D.

Their first product, called VC-01 or PEC-Encap, is an implantable device containing embryonic stem cells that develop into pancreatic progenitor cells, which are precursors to the islet cells destroyed by T1D. The hope is that when this device is transplanted under a patient’s skin, the progenitor cells will develop into mature insulin-secreting cells that can properly regulate the glucose levels in a patient’s blood. Because the cells are encapsulated in a protective semi-permeable membrane, hormones and nutrients can pass in and out of the device, but the implanted cells are guarded against the patient’s immune system. VC-01 is currently being tested in a Phase 1 clinical trial that is funded CIRM.

ViaCyte now has a second product called VC-02, or PEC-Direct, that also transplants pancreatic progenitors but in a device that allows a patient’s blood vessels to make direct contact with the implanted cells. This “direct vascularization” approach is being tested in patients that are at high risk for severe complications associated with T1D including hypoglycemia unawareness – a condition where patients fail to recognize when their blood glucose level drops to dangerously low levels because the typical symptoms of hypoglycemia fail to appear.

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

In May, ViaCyte announced that the US Food and Drug Administration (FDA) approved their Investigational New Drug (IND) application for PEC-Direct, which gave the company the green light to proceed with a Phase 1 safety trial to test the treatment in patients. ViaCyte’s pre-IND work on PEC-Direct was supported in part by a late stage preclinical grant from CIRM.

Today, the ViaCyte announced in a press release that it has treated its first patients with PEC-Direct in a Phase 1/2 trial at the University of Alberta Hospital in Edmonton, Alberta and at the UCSD Alpha Stem Cell Clinic in San Diego, California.

“The first cohort of type 1 diabetes patients is receiving multiple small-format cell-filled devices called sentinels in order to evaluate safety and implant viability.  These sentinel units will be removed at specific time points and examined histologically to provide early insight into the progression of engraftment and maturation into pancreatic islet cells including insulin-producing beta cells.”

The news release also revealed plans for enrollment of a larger cohort of patients by the end of 2017.

“A second cohort of up to 40 patients is expected to begin enrolling later this year to evaluate both safety and efficacy.  The primary efficacy measurement in the trial will be the clinically relevant production of insulin, as measured by the insulin biomarker C-peptide, in a patient population that has little to no ability to produce endogenous insulin at the time of enrollment.  Other important endpoints will be evaluated including injectable insulin usage and the incidence of hypoglycemic events.  ViaCyte’s goal is to demonstrate early evidence of efficacy in the first half of 2018 and definitive efficacy 6 to 12 months later.”

President and CEO of ViaCyte, Dr. Paul Laikind, is hopeful that PEC-Direct will give patients with high-risk T1D a better treatment option than what is currently available.

ViaCyte’s President & CEO, Paul Laikind

“There are limited treatment options for patients with high-risk type 1 diabetes to manage life-threatening hypoglycemic episodes. We believe that the PEC-Direct product candidate has the potential to transform the lives of these patients and we are excited to move closer to that goal with the initiation of clinical evaluation announced today.  This also represents a step towards a broader application of the technology.  We remain fully committed to developing a functional cure for all patients with insulin-requiring diabetes.  To that end, we are hard at work on next-generation approaches as well, and expect the work with PEC-Direct to further advance our knowledge and drive progress.”


Related links:

Novel diabetes therapy uses stem cell “teachers” to calm immune cells

Type 1 diabetes is marked by a loss of insulin-producing beta cells in the pancreas. Without insulin, blood sugar can’t shuttle into the body’s energy-hungry organs and tissues. As a result, sugar accumulates in the blood which, over time, causes many serious complications such as kidney disease, heart disease and stroke.  An over-reactive immune system is to blame which mistakes the beta cells for foreign invaders and attacks them.

Much of the focus on diabetes therapy development is turning stem cells into beta cells in order to replace the lost cells.  But a recent Stem Cell Translational Medicine publication describes a different approach that uses umbilical cord blood stem cells to tame the immune system and preserve the beta cells that are still intact.

Stem+Cell+Educator+Therapy+Process

Schematic diagram of the Stem Cell Educator therapy procedure.
Image: Tianhe Stem Cell Biotechnologies

The research team, composed of scientists from the U.S., China and Spain, devised a technology they call Stem Cell Educator (SCE) therapy that draws blood from a diabetic patient then separates out the lymphocytes – the white blood cells of the immune system – which trickle through a series of stacked petri dishes that contains cord blood stem cells. Because the stem cells are attached to the surface of the device, only the lymphocytes are recovered and returned to the patient’s blood.  The idea is that through this forced interaction with the cord blood stem cells – which have been shown to blunt immune cell activity – the patient’s own lymphocytes “learn” to quiet their damaging response to beta cells.

In a series of clinical trials in China and Spain from 2010 to 2014, the researchers showed that a single treatment of the SCE therapy restored beta cell function and blood sugar control in patients. Though the treatment appeared safe and effective after one year, how exactly it worked remained unclear. So, in this current study, the team aimed to better understand cord blood stem cell function and to perform a 4-year follow up on the patients.

Shortly after the SCE therapy, the researchers had observed elevated levels of platelets in the blood. They examined these cells more closely to see if they contained any factors that would dampen the immune response. Sure enough, the platelets carried a protein called autoimmune regulator (AIRE) which plays a role in inhibiting immune cells that react against the body.

Now, platelets do not contain a nucleus or nuclear DNA but they do have mitochondria – a cell’s energy producers – which contain their own DNA and genetic code. An analysis of the mitochondrial DNA revealed that it encoded proteins associated with the regeneration and growth of pancreatic beta cells. In an unusual finding in the lab, the researchers showed that the platelets release their mitochondria, which can be taken up by pancreatic beta cells where these beta cell associated proteins can exert their effects.

HealthDay reporter Serena Gordon interviewed Julia Greenstein, vice president of discovery research at JDRF, to get her take on these results:

“The platelets seem to be having a direct effect on the beta cells. This research is intriguing, but it needs to be reproduced.”

For the four-year follow up study, nine of the type 1 diabetes patients from the original trial in China were examined. Two patients who were treated less than a year after being diagnosed with diabetes still had normal levels of insulin in their blood and were still free of needing insulin injections. In the other seven patients, the single treatment had gradually lost its effectiveness. Team leader Dr. Yong Zhao of the University of Hackensack in New Jersey, felt that a single treatment possibly isn’t enough in those patients:

“Because this was a first trial, patients just got one treatment. Now we know it’s very safe so patients can receive two or three treatments.”

I imagine Dr. Zhao will be testing out multiple treatments in a clinical trial that is now in the works here in the states at Hackensack Medical Center. Stay tuned.

Stories that caught our eye: smelling weight gain, colon cancer & diet and diabetes & broken bones

How smelling your food could cause weight gain (Karen Ring).
Here’s the headline that caught my eye this week: “Smelling your food first can make you fat…”

It’s a bizarre statement, but the claim is backed by scientific research coming from a new study in Cell Metabolism by researchers at the University of California Berkeley. The team found that obese mice who smelled their food before eating it were more likely to gain weight compared to obese mice that couldn’t smell their food.

Their experiments revealed a connection between the olfactory system, which is responsible for our sense of smell, and how the mice metabolize food into energy. Obese mice that lost their ability to smell actually lost weight on a high-fat diet, burned more fat, and became more sensitive to the hormone insulin. Insulin regulates how much glucose, or sugar, is in the blood by facilitating the absorption of glucose by fat, liver and muscle cells. In obese individuals, insulin resistance can occur where their cells are no longer sensitive to the hormone and therefore can’t regulate how much glucose is in the blood.

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Both mice in this picture were fed the same high-fat diet. The only difference: the lower mouse’s sense of smell was temporarily blocked. Image: UC Berkeley

For obese mice that could smell their food, the same high fat diet given to the “no-smellers” resulted in massive weight gain in the “smellers” because their metabolism was impaired. Even more interesting is the fact that other types of smells unrelated to food, such as the scent of other mice, influenced weight gain in the “smellers”.

The authors concluded that the centers in our brain that are responsible for smell (the olfactory system) and metabolism (the hypothalamus) are connected and that manipulating smell could be a future strategy to influence how the brain controls the balance of energy during food consumption.

In an interview with Tech Times, senior author on the study, Dr. Andrew Dillin, explained how their research could potentially lead to a new strategy to promote weight loss,

Dillin-345x239

Andrew Dillin. Image: HHMI

“Sensory systems play a role in metabolism. Weight gain isn’t purely a measure of the calories taken in; it’s also related to how those calories are perceived. If we can validate this in humans, perhaps we can actually make a drug that doesn’t interfere with smell but still blocks that metabolic circuitry. That would be amazing.”

A link between colorectal cancer and a Western diet identified
Weight gain isn’t the only concern of a eating a high-fat diet. It’s thought that 80% of colorectal cases are associated with a high-fat, Western diet. The basis for this connection hasn’t been well understood. But this week, researchers at the Cleveland Clinic report in Stem Cell Reports that they’ve pinpointed a protein signaling network within cancer stem cells as a possible source of the link.

highfatdiet_shutterstock_285533255

Cancer stem cells have properties that resemble embryonic stem cells and are thought to be the source of a cancer’s unlimited growth and spread. A cancer stem cell maintains its properties by exploiting various cell signaling processes that when functioning abnormally can lead to inappropriate cell division and tumor growth. In this study, the team focused on one cell signaling process carried out by a protein called STAT3, known to promote tumor growth in a mouse model of colon cancer. When the team blocked STAT3 activity, high fat diet-induced cancer stem cell growth subsided.

In a press release, Dr. Matthew Kalady, a colorectal surgeon at the Cleveland Clinic and an author on this study, explained how this new insight can open new therapeutic avenues:

kalady

Matthew Kalady. Image: Cleveland Clinic

“We have known the influence of diet on colorectal cancer. However, these new findings are the first to show the connection between high-fat intake and colon cancer via a specific molecular pathway. We can now build upon this knowledge to develop new treatments aimed at blocking this pathway and reducing the negative impact of a high-fat diet on colon cancer risk.”

 

 

Scientists connect dots between diabetes and broken bones.
Type 2 diabetes carries a whole host of long-term complications including heart disease, nerve damage, kidney dysfunction and even an increased risk for bone fractures. The connection between diabetes and fragile bones has not been well understood. But this week, researchers at New York University of Dentistry, Stanford University and China’s Dalian Medical University published a report, funded in part by CIRM, in this week’s Nature Communications showing a biochemical basis for this connection. The new insight may lead to treatment options to prevent fractures.

succinate.png

Chemical structure of succinate.
Image: Wikimedia Commons.

Fundamentally, diabetes is a disease that causes hyperglycemia, or abnormally high levels of blood sugar. The team ran a systematic analysis of hyperglycemia’s effects on bone metabolism using bone marrow samples from diabetic and healthy mice. They found that the levels of succinate, a key molecule involved in energy production, are over 20 times higher in the diabetic mice. In turns out that succinate also acts as a stimulator of bone breakdown. Now, bone is continually in a process of turnover and, in a healthy state, the breakdown of old bone is balanced with the formation of new bone. So, it appears that the huge increase of succinate is tipping the balance of bone turnover. In fact, the team found that the porous, yet strong inner region of bone, called trabecular bone, was significantly reduced in the diabetic mice, making them more susceptible to fractures.

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The density of spongy bone, or trabecular bone, is reduced in type 2 diabetes.
Image: Wikimedia commons

Dr. Xin Li, the study’s lead scientist, explained the importance of these new insights for people living with type 2 diabetes in a press release:

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Xin Li.
Image: NYU Dentistry

“The results are important because diabetics have a significantly higher fracture risk and their healing process is always delayed. In our study, the hyperglycemic mice had increased bone resorption [the breakdown and absorption of old bone], which outpaced the formation of new bone. This has implications for bone protection, as well as for the treatment of diabetes-associated collateral bone damage.”

 

Wall Street Journal features CIRM-funded clinical trials aiming for a diabetes cure

We think CIRM-funded clinical trials hold so much promise that it doesn’t surprise us when major news organizations publish stories about these projects that aim to provide stem cell treatments to patients with unmet medical needs. But we certainly don’t mind the attention!

This past Saturday, for example, the Wall Street Journal featured two CIRM-funded clinical trials, run by ViaCyte and Caladrius, in an article covering cutting-edge research approaches to tackling type 1 diabetes. Also mentioned was Semma Therapeutics, who have a CIRM-funded pre-clinical diabetes research grant.

ViaCyte is tackling diabetes with implantable devices containing stem cell-based products that release insulin on demand rather than requiring continual monitoring of blood sugar level. Image: ViaCyte.

People with type 1 diabetes lack insulin, a hormone that’s critical for transporting blood sugar, digested from the food we eat, into our energy-hungry organs and tissues. They lack insulin because the insulin-producing beta cells in the pancreas have been attacked and killed off by the body’s own immune system. Without insulin, blood sugar levels go through the roof and over time that build up can cause vision loss, kidney disease, nerve damage, heart disease and the list goes on.

Families unaffected by type 1 diabetes often mistake insulin injections as a cure for diabetes. But they’re not. Julia Greenstein, vice president of discovery research for the JDRF, states injected insulin’s limitation very concisely but clearly in the WSJ article:

“It is [in] no way an easy life trying to manage blood glucose.”

Her statement echoes the thoughts of Chris Stiehl who we interviewed for a video a few years ago:

“It’s a 24-hour a day job, 7 days a week you never get a day off. I would give anything for a day off. Just to not have to think about it. Besides all the things you have to do for your work and your family and everything, you have to be constantly thinking: “What’s my blood sugar? What have I eaten? Have I exercised too much or too little? How much insulin should I take based on the exercise I just did? Gee by the way is my insulin pump running out of insulin?

The WSJ article points out that a pancreas or beta cell transplant, received from a deceased donor, is currently the best option for long-term treatment of type 1 diabetes. But there are big drawbacks and limitations to this approach: the pancreas transplant requires major surgery, both require life-long immunosuppressing drugs that can cause serious infection and cancer and donor organs and cells are hard to come by.

That’s where regenerative medicine technology comes into the picture. The article goes on to highlight ViaCyte’s therapeutic product, PEC-EncapTM which is composed of embryonic stem cell-derived insulin-producing beta cells that are encased by a capsule that is transplanted under the skin. The capsule has pores that allow blood glucose and insulin to flow freely but protects the cell product from destruction from the body’s immune cells.

Because the cell product stems from, er, stem cells, there’s the potential of a limitless supply that doesn’t rely on cadavers.

Dr. Gordon Weir, a Harvard Medical School professor and diabetes researcher at the Joslin Diabetes Center in Boston, spoke about the excitement of such a device along with a reality check:

“Everyone’s waiting for the next generation of beta-cell replacement that hopefully will change the whole way in which we treat diabetes. In spite of the excitement and extraordinary things that have happened in the last 10 years, there are still a lot of challenges.”

Indeed, since beginning the clinical trial in 2014, ViaCyte has encountered some speed bumps. They had hoped that blood vessels growing around but not into the device would facilitate the transfer of blood sugar into the device where the beta cells would sense the level of sugar and release the appropriate amount of insulin. But it turns out that some cells of the immune system cells mucked up the blood vessel network. The company is working on improvements to the device to get the clinical trial back on track in the next 24 months. To jump start that effort they recently secured a partnership with the makers of Gore-Tex fabrics who also specialize in medical implantable devices.

That collaboration is also motivating a next generation device called PEC-DirectTM which contains larger pores that would allow direct interaction between the body’s blood vessels and the beta cells inside the device. Because of the larger openings, immune cells could infiltrate the device and so immunosuppressive drugs would be needed in this case. But for patients with severe type 1 diabetes, this approach would be a more available treatment source compared to cadaver cells or organs.

The WSJ article also discusses the CIRM-funded Caladrius clinical trial that takes quite a different approach to treating type 1 diabetes. The company is trying to disarm the T cells that attack the body’s own pancreatic beta cells. Because diabetics don’t lose all their beta cells at once, this approach could help maintain the insulin-producing cells that are still intact. The company’s strategy is to reprogram these attacking T-cells to convert them into so-called regulatory T-cells that act as a natural inhibitor of the immune response.

While each company works diligently on their own approach, eager patients are routing for both. Dara Melnick, of Woodbury, N.Y., who was diagnosed with type 1 diabetes at 8 years old and is now 36, summed up the patient’s perspective perfectly in the article:

“A cure would be the sweetest thing I could ever taste.”

ViaCyte Advances Cell Replacement Therapy for High Risk Type 1 Diabetes

San Diego regenerative medicine company ViaCyte announced this week that the Food and Drug Administration (FDA) approved their Investigational New Drug (IND) Application for PEC-Direct, a cell-based therapy to treat patients at risk for severe complications caused by type 1 diabetes. In the US, IND approval is the final regulatory step required before a therapy can be tested in clinical trials.

PEC-Direct is a combination therapy consisting of cells encapsulated in a device that aims to replace the insulin-producing islet cells of the pancreas destroyed in patients with type 1 diabetes. The device contains human stem cell-derived pancreatic progenitor cells that develop into insulin-secreting cells when the device is placed under the patient’s skin. Ports on the surface of the device allow blood vessels from the host to directly contact the cells within, allowing for engraftment of the transplanted cells and for their maturation into islet cells.  These cells can sense and regulate blood glucose levels by secreting the hormones found in islets, including insulin.

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

Because PEC-Direct allows for “direct vascularization”, in effect connecting the device to the blood system, patients will need to take immunosuppressive drugs to prevent rejection of the donor cells. ViaCyte is therefore testing this therapy in patients who are at risk for serious complications associated with type 1 diabetes like severe hypoglycemia where a patient’s blood sugar is so low they need immediate medical assistance.

Severe hypoglycemia can occur because people with diabetes must inject insulin to control elevated blood sugar, but the injections can exceed the patients’ needs. The resulting low blood sugar can lead to dizziness, irregular heartbeat, and unconsciousness, even death. In some cases, sufferers are not aware of their hypoglycemia symptoms, putting them at increased risk of these life-threatening complications.

ViaCyte’s President and CEO, Dr. Paul Laikind, explained in a news release,

Paul Laikind

“While insulin therapy transformed type 1 diabetes from a death sentence to a chronic illness, it is far from a cure. Type 1 diabetes patients continue to deal with the daily impact of the disease and remain at risk for often severe long-term complications.  This is especially true for the patients with high-risk type 1 diabetes, who face challenges such as hypoglycemia unawareness and life-threatening severe hypoglycemic episodes.  These patients have a particularly urgent unmet medical need and could benefit greatly from cell replacement therapy.”

Approximately 140,000 people in the US and Canada suffer from this form of high-risk diabetes. These patients qualify for islet transplants from donated cadaver tissue. But because donor islets are in limited supply, ViaCyte Clinical Advisor, Dr. James Shapiro at the University of Alberta, believes PEC-Direct will address this issue by providing an unlimited supply of cells.

“Islet transplants from scarce organ donors have offered great promise for those with unstable, high-risk type 1 diabetes, but the procedure has many limitations.  With an unlimited supply of new islets that the stem cell-derived therapy promises, we have real potential to benefit far more patients with islet cell replacement.”

The company’s preclinical research on PEC-Direct, leading up to the FDA’s IND approval, was funded by a CIRM late stage preclinical grant. ViaCyte now plans to launch a clinical trial this year that will evaluate the safety and efficacy of PEC-Direct in the US and Canada. They will enroll approximately 40 patients at multiple clinical trial centers including the University of Alberta in Edmonton, the University of Minnesota, and UC San Diego. The trial will test whether the device is safe and whether the transplanted cells can produce enough insulin to relieve patients of insulin injections and hypoglycemic events.

ViaCyte has another product called PEC-Encap, a different implantable device that contains the same cells but protects these cells from the patient’s immune system. The device is being tested in a CIRM-funded Phase 1/2a trial, and ViaCyte is currently collaborating with W. L. Gore & Associates to improve the design of PEC-Encap to improve consistency of engraftment in patients.

Creating partnerships to help get stem cell therapies over the finish line

Lewis, Clark, Sacagawea

Lewis & Clark & Sacagawea:

Trying to go it alone is never easy. Imagine how far Lewis would have got without Clark, or the two of them without Sacagawea. Would Batman have succeeded without Robin; Mickey without Minnie Mouse? Having a partner whose skills and expertise complements yours just makes things easier.

That’s why some recent news about two CIRM-funded companies running clinical trials was so encouraging.

Viacyte Gore

First ViaCyte, which is developing an implantable device to help people with type 1 diabetes, announced a collaborative research agreement with W. L. Gore & Associates, a global materials science company. On every level it seems like a natural fit.

ViaCyte has developed a way of maturing embryonic stem cells into an early form of the cells that produce insulin. They then insert those cells into a permeable device that can be implanted under the skin. Inside the device, the cells mature into insulin-producing cells. While ViaCyte has experience developing the cells, Gore has experience in the research, development and manufacturing of implantable devices.

Gore-tex-fabricWhat they hope to do is develop a kind of high-tech version of what Gore already does with its Gore-Tex fabrics. Gore-Tex keeps the rain out but allows your skin to breathe. To treat diabetes they need a device that keeps the immune system out, so it won’t attack the cells inside, but allows those cells to secrete insulin into the body.

As Edward Gunzel, Technical Leader for Gore PharmBIO Products, said in a news release, each side brings experience and expertise that complements the other:

“We have a proven track record of developing and commercializing innovative new materials and products to address challenging implantable medical device applications and solving difficult problems for biologics manufacturers.  Gore and ViaCyte began exploring a collaboration in 2016 with early encouraging progress leading to this agreement, and it was clear to us that teaming up with ViaCyte provided a synergistic opportunity for both companies.  We look forward to working with ViaCyte to develop novel implantable delivery technologies for cell therapies.”

AMD2

How macular degeneration destroys central vision

Then last week Regenerative Patch Technologies (RPT), which is running a CIRM-funded clinical trial targeting age-related macular degeneration (AMD), announced an investment from Santen Pharmaceutical, a Japanese company specializing in ophthalmology research and treatment.

The investment will help with the development of RPT’s therapy for AMD, a condition that affects millions of people around the world. It’s caused by the deterioration of the macula, the central portion of the retina which is responsible for our ability to focus, read, drive a car and see objects like faces in fine details.

RPE

RPT is using embryonic stem cells to produce the support cells, or RPE cells, needed to replace those lost in AMD. Because these cells exist in a thin sheet in the back of the eye, the company is assembling these sheets in the lab by growing the RPE cells on synthetic scaffolds. These sheets are then surgically implanted into the eye.

In a news release, RPT’s co-founder Dennis Clegg says partnerships like this are essential for small companies like RPT:

“The ability to partner with a global leader in ophthalmology like Santen is very exciting. Such a strong partnership will greatly accelerate RPT’s ability to develop our product safely and effectively.”

These partnerships are not just good news for those involved, they are encouraging for the field as a whole. When big companies like Gore and Santen are willing to invest their own money in a project it suggests growing confidence in the likelihood that this work will be successful, and that it will be profitable.

As the current blockbuster movie ‘Beauty and the Beast’ is proving; with the right partner you can not only make magic, you can also make a lot of money. For potential investors those are both wonderfully attractive qualities. We’re hoping these two new partnerships will help RPT and ViaCyte advance their research. And that these are just the first of many more to come.

Stem Cell Stories That Caught Our Eye: Plasticity in the pancreas and two cool stem cell tools added to the research toolbox

There’s more plasticity in the pancreas than we thought. You’re taught a lot of things about the world when you’re young. As you get older, you realize that not everything you’re told holds true and it’s your own responsibility to determine fact from fiction. This evolution in understanding happens in science too. Scientists do research that leads them to believe that biological processes happen a certain way, only to sometimes find, a few years later, that things are different or not exactly what they had originally thought.

There’s a great example of this in a study published this week in Cell Metabolism about the pancreas. Scientists from UC Davis found that the pancreas, which secretes a hormone called insulin that helps regulate the levels of sugar in your blood, has more “plasticity” than was originally believed. In this case, plasticity refers to the ability of a tissue or organ to regenerate itself by replacing lost or damaged cells.

The long-standing belief in this field was that the insulin producing cells, called beta cells, are replenished when beta cells actively divide to create more copies of themselves. In patients with type 1 diabetes, these cells are specifically targeted and killed off by the immune system. As a result, the beta cell population is dramatically reduced, and patients have to go on life-long insulin treatment.

UC Davis researchers have identified another type of insulin-producing cell in the islets, which appears to be an immature beta cell shown in red. (UC Davis)

But it turns out there is another cell type in the pancreas that is capable of making beta cells and they look like a teenage, less mature version of beta cells. The UC Davis team identified these cells in mice and in samples of human pancreas tissue. These cells hangout at the edges of structures called islets, which are clusters of beta cells within the pancreas. Upon further inspection, the scientists found that these immature beta cells can secrete insulin but cannot detect blood glucose like mature beta cells. They also found their point of origin: the immature beta cells developed from another type of pancreatic cell called the alpha cell.

Diagram of immature beta cells from Cell Metabolism.

In coverage by EurekAlert, Dr Andrew Rakeman, the director of discovery research at the Juvenile Diabetes Research Foundation, commented on the importance of this study’s findings and how it could be translated into a new approach for treating type 1 diabetes patients:

“The concept of harnessing the plasticity in the islet to regenerate beta cells has emerged as an intriguing possibility in recent years. The work from Dr. Huising and his team is showing us not only the degree of plasticity in islet cells, but the paths these cells take when changing identity. Adding to that the observations that the same processes appear to be occurring in human islets raises the possibility that these mechanistic insights may be able to be turned into therapeutic approaches for treating diabetes.”

 

Say hello to iPSCORE, new and improved tools for stem cell research. Stem cells are powerful tools to model human disease and their power got a significant boost this week from a new study published in Stem Cell Reports, led by scientists at UC San Diego School of Medicine.

The team developed a collection of over 200 induced pluripotent stem cell (iPS cell) lines derived from people of diverse ethnic backgrounds. They call this stem cell tool kit “iPSCORE”, which stands for iPSC Collection for Omic Research (omics refers to a field of study in biology ending in -omics, such as genomics or proteomics). The goal of iPSCORE is to identify particular genetic variants (unique differences in DNA sequence between people’s genomes) that are associated with specific diseases and to understand why they cause disease at the molecular level.

In an interview with Phys.org, lead scientist on the study, Dr. Kelly Frazer, further explained the power of iPSCORE:

“The iPSCORE collection contains 75 lines from people of non-European ancestry, including East Asian, South Asian, African American, Mexican American, and Multiracial. It includes multigenerational families and monozygotic twins. This collection will enable us to study how genetic variation influences traits, both at a molecular and physiological level, in appropriate human cell types, such as heart muscle cells. It will help researchers investigate not only common but also rare, and even family-specific variations.”

This research is a great example of scientists identifying a limitation in stem cell research and expanding the stem cell tool kit to model diseases in a diverse human population.

A false color scanning electron micrograph of cultured human neuron from induced pluripotent stem cell. Credit: Mark Ellisman and Thomas Deerinck, UC San Diego.

Stem cells that can grow into ANY type of tissue. Embryonic stem cells can develop into any cell type in the body, earning them the classification of pluripotent. But there is one type of tissue that embryonic stem cells can’t make and it’s called extra-embryonic tissue. This tissue forms the supportive tissue like the placenta that allows an embryo to develop into a healthy baby in the womb.

Stem cells that can develop into both extra-embryonic and embryonic tissue are called totipotent, and they are extremely hard to isolate and study in the lab because scientists lack the methods to maintain them in their totipotent state. Having the ability to study these special stem cells will allow scientists to answer questions about early embryonic development and fertility issues in women.

Reporting this week in the journal Cell, scientists from the Salk Institute in San Diego and Peking University in China identified a cocktail of chemicals that can stabilize human stem cells in a totipotent state where they can give rise to either tissue type. They called these more primitive stem cells extended pluripotent stem cells or EPS cells.

Salk Professor Juan Carlos Izpisua Bemonte, co–senior author of the paper, explained the problem their study addressed and the solution it revealed in a Salk news release:

“During embryonic development, both the fertilized egg and its initial cells are considered totipotent, as they can give rise to all embryonic and extra-embryonic lineages. However, the capture of stem cells with such developmental potential in vitro has been a major challenge in stem cell biology. This is the first study reporting the derivation of a stable stem cell type that shows totipotent-like bi-developmental potential towards both embryonic and extra-embryonic lineages.”

Human EPS cells (green) can be detected in both the embryonic part (left) and extra-embryonic parts (placenta and yolk sac, right) of a mouse embryo. (Salk Institute)

Using this new method, the scientists discovered that human EPS stem cells were able to develop chimeric embryos with mouse stem cells more easily than regular embryonic stem cells. First author on the study, Jun Wu, explained why this ability is important:

“The superior chimeric competency of both human and mouse EPS cells is advantageous in applications such as the generation of transgenic animal models and the production of replacement organs. We are now testing to see whether human EPS cells are more efficient in chimeric contribution to pigs, whose organ size and physiology are closer to humans.”

The Salk team reported on advancements in generating interspecies chimeras earlier this year. In one study, they were able to grow rat organs – including the pancreas, heart and eyes – in a mouse. In another study, they grew human tissue in early-stage pig and cattle embryos with the goal of eventually developing ways to generate transplantable organs for humans. You can read more about their research in this Salk news release.

Stem cells stories that caught our eye: switching cell ID to treat diabetes, AI predicts cell fate, stem cell ALS therapy for Canada

Treating diabetes by changing a cell’s identity. Stem cells are an ideal therapy strategy for treating type 1 diabetes. That’s because the disease is caused by the loss of a very specific cell type: the insulin-producing beta cell in the pancreas. So, several groups are developing treatments that aim to replace the lost cells by transplanting stem cell-derived beta cells grown in the lab. In fact, Viacyte is applying this approach in an ongoing CIRM-funded clinical trial.

In preliminary animal studies published late last week, a Stanford research team has shown another approach may be possible which generates beta cells inside the body instead of relying on cells grown in a petri dish. The CIRM-funded Cell Metabolism report focused on alpha cells, another cell type in pancreas which produces the hormone glucagon.

glucagon

Microscopy of islet cells, round clusters of cells found in the pancreas. The brown stained cells are glucagon-producing alpha cells. Credit: Wikimedia Commons

After eating a meal, insulin is critical for getting blood sugar into your cells for their energy needs. But glucagon is needed to release stored up sugar, or glucose, into your blood when you haven’t eaten for a while. The research team, blocked two genes in mice that are critical for maintaining an alpha cell state. Seven weeks after inhibiting the activity of these genes, the researchers saw that many alpha cells had converted to beta cells, a process called direct reprogramming.

Does the same thing happen in humans? A study of cadaver donors who had been recently diagnosed with diabetes before their death suggests the answer is yes. An analysis of pancreatic tissue samples showed cells that produced both insulin and glucagon, and appeared to be in the process of converting from beta to alpha cells. Further genetic tests showed that diabetes donor cells had lost activity in the two genes that were blocked in the mouse studies.

It turns out that there’s naturally an excess of alpha cells so, as team lead Seung Kim mentioned in a press release, this strategy could pan out:

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Seung Kim. Credit: Steve Fisch, Stanford University

“This indicates that it might be possible to use targeted methods to block these genes or the signals controlling them in the pancreatic islets of people with diabetes to enhance the proportion of alpha cells that convert into beta cells.”

Using computers to predict cell fate. Deep learning is a cutting-edge area of computer science that uses computer algorithms to perform tasks that border on artificial intelligence. From beating humans in a game of Go to self-driving car technology, deep learning has an exciting range of applications. Now, scientists at Helmholtz Zentrum München in Germany have used deep learning to predict the fate of cells.

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Using deep learning, computers can predict the fate of these blood stem cells.
Credit: Helmholtz Zentrum München.

The study, published this week in Nature Methods, focused on blood stem cells also called hematopoietic stem cells. These cells live in the bone marrow and give rise to all the different types of blood cells. This process can go awry and lead to deadly disorders like leukemia, so scientists are very interested in exquisitely understanding each step that a blood stem cell takes as it specializes into different cell types.

Researchers can figure out the fate of a blood stem cells by adding tags, which glow with various color, to the cell surface . Under a microscope these colors reveal the cells identity. But this method is always after the fact. There no way to look at a cell and predict what type of cell it is turning into. In this study, the team filmed the cells under a microscope as they transformed into different cell types. The deep learning algorithm processed the patterns in the cells and developed cell fate predictions. Now, compared to the typical method using the glowing tags, the researchers knew the eventual cell fates much sooner. The team lead, Carsten Marr, explained how this new technology could help their research:

“Since we now know which cells will develop in which way, we can isolate them earlier than before and examine how they differ at a molecular level. We want to use this information to understand how the choices are made for particular developmental traits.”

Stem cell therapy for ALS seeking approval in Canada. (Karen Ring) Amyotrophic lateral sclerosis (ALS) is a progressive neuromuscular disease that kills off the nerve cells responsible for controlling muscle movement. Patients with ALS suffer from muscle weakness, difficulty in speaking, and eventually breathing. There is no cure for ALS and the average life expectancy after diagnosis is just 2 – 5 years. But companies are pursuing stem cell-based therapies in clinical trials as promising treatment options.

One company in particular, BrainStorm Cell Therapeutics based in the US and Israel, is testing a mesenchymal stem cell-based therapy called NurOwn in ALS patients in clinical trials. In their Phase 2 trials, they observed clinical improvements in slowing down the rate of disease progression following the stem cell treatment.

In a recent update from our friends at the Signals Blog, BrainStorm has announced that it is seeking regulatory approval of its NurOwn treatment for ALS patients in Canada. They will be working with the Centre for Commercialization of Regenerative Medicine (CCRM) to apply for a special regulatory approval pathway with Health Canada, the Canadian government department responsible for national public health.

In a press release, BrainStorm CEO Chaim Lebovits, highlighted this new partnership and his company’s mission to gain regulatory approval for their ALS treatment:

“We are pleased to partner with CCRM as we continue our efforts to develop and make NurOwn available commercially to patients with ALS as quickly as possible. We look forward to discussing with Health Canada staff the results of our ALS clinical program to date, which we believe shows compelling evidence of safety and efficacy and may qualify for rapid review under Canada’s regulatory guidelines for drugs to treat serious or life-threatening conditions.”

Stacey Johnson who wrote the Signals Blog piece on this story explained that while BrainStorm is not starting a clinical trial for ALS in Canada, there will be significant benefits if its treatment is approved.

“If BrainStorm qualifies for this pathway and its market authorization request is successful, it is possible that NurOwn could be available for patients in Canada by early 2018.  True access to improved treatments for Canadian ALS patients would be a great outcome and something we are all hoping for.”

CIRM is also funding stem cell-based therapies in clinical trials for ALS. Just yesterday our Board awarded Cedars-Sinai $6.15 million dollars to conduct a Phase 1 trial for ALS patients that will use “cells called astrocytes that have been specially re-engineered to secrete proteins that can help repair and replace the cells damaged by the disease.” You can read more about this new trial in our latest news release.