Genetic discovery may help better identify children at risk for type 1 diabetes

Six novel chromosomal regions identified by scientists leading a large, prospective study of children at risk for type 1 diabetes will enable the discovery of more genes that cause the disease and more targets for treating or even preventing it.

The TEDDY study’s international research team has identified the new gene regions in young people who have already developed type 1 diabetes or who have started making antibodies against their insulin-producing cells, often a precursor state to the full-blown disease that leads to a lifetime of insulin therapy.

Their analysis of 5,806 individuals published in the Journal of Autoimmunity also confirmed three regions already associated with one of those related conditions.

“We want to build a more precise profile of who will get this disease and when,” says Dr. Jin-Xiong She, director of the Center for Biotechnology and Genomic Medicine at the Medical College of Georgia at Augusta University, principal investigator of TEDDY’s Georgia/Florida site and the study’s corresponding author.

In keeping with their theory that two subtypes of type 1 diabetes will become clear from longitudinal studies of those at risk, the international TEDDY team also found different chromosomal regions were associated with which autoantibody shows up first in a patient, a sign his immune system is turning on his pancreas.

They looked at two top autoantibodies: one directly against insulin, called IAA, and one called GADA, against the enzyme glutamate decarboxylase, which regulates the insulin-producing beta cells in the pancreas. About 90 percent of patients with type 1 diabetes have one or the other autoantibody first and many eventually end up with both, She says. The second autoantibody may surface in a few days or even years later.

“There is mounting evidence that we have at least two major subtypes of type 1 diabetes, based on the autoantibodies children have. Now we have found a genetic basis that supports that,” says She, Georgia Research Alliance Eminent Scholar in Genomic Medicine.

TEDDY – The Environmental Determinants of Diabetes in the Young – is an international initiative following almost 9,000 children for 15 years in a strategic and rare opportunity to watch how genetics and environmental factors collide to cause disease, She says. An original goal of TEDDY was to better determine which genetic variations correlate with progression or lack of progression to type 1 diabetes.

For this particular pursuit, they focused on the 5,806 Caucasian TEDDY participants, because of genetic differences in different ethnic groups. They also focused on non-HLA genes, says Dr. Ashok Sharma, MCG bioinformatics expert and the study’s first author.

Most genes known to be associated with type 1 diabetes – including those currently considered the top two high-risk genes, which are the ones TEDDY screens for – are classified as human leukocyte antigen, or HLA genes. It’s a logical association since HLA genes regulate our immune system, says Sharma.

But in their comprehensive effort to better identify children at highest risk of disease – and ideally one day intervene – this particular search focused on non-HLA genes. “By study design we were looking for them,” Sharma says.

“With HLA genes you can achieve a certain level of accuracy in identifying high-risk individuals,” says She. “But if we can add additional genes into the screening, we can refine the prediction of the disease, we can increase the accuracy, we can probably even identify higher percentages of at-risk individuals.”

“It’s not monogenic, there are many genes involved,” Sharma says of type 1 diabetes, a condition that affects 1 in 300 people in the United States by age 18, according to the National Institutes of Health.

Which of those genes are involved also varies by individual. Sharma and She note the reality that not all patients with the high-risk genes even get the disease, although they still don’t know why.

One of the many points they hope TEDDY clarifies is if or how these genetics along with environmental factors – like childhood infections or even what children eat – conspire to cause actual disease. Genetic factors are comparatively easier to identify, and should also help identify environmental factors, they say.

For this study, the scientists also started with 176,586 SNPs, or single nucleotide polymorphisms. A nucleotide is a basic building block of our genetic information. In the case of DNA, those are A, C, T and G, chemical bases that can be arranged in seemingly endless potential orders. SNPs are genetic variations – one letter replaced by another – that scientists are using increasingly to figure out which occur more or less often in people with a certain condition or disease.

The SNPs examined by TEDDY scientists were already associated with other autoimmune diseases like rheumatoid arthritis or celiac disease, but not type 1 diabetes, Sharma says. They determined which of these SNPs are different in TEDDY participants who had developed type 1 diabetes versus those who had Islet cell autoantibodies versus those who still had neither.

Previous research has shown that the same genes are not always associated with IA and actual type 1 diabetes.

In fact, while Islet cell autoantibodies, or IA, are considered a red flag for type 1 diabetes, not every child with IA will progress to full-blown disease, She says, although multiple autoantibodies definitely increase that risk. In fact, different genes may play a role in IA development while others play a role in disease progression, the TEDDY scientists write.

While the SNPs themselves may or may not have a direct functional consequence, they are in close proximity to a gene that does, says She. “It’s a marker,” he says, that will enable the scientists to more efficiently and effectively identify causative genes.

“We are using SNPs but not as an endpoint,” Sharma notes. “We want to find out the genes which are there,” a focal point for the work now underway.

Key to the work already complete, is how closely and long TEDDY participants are followed. Normally gene identification starts with what is called a case-control design, in which genetic variations are compared between patients with a condition and healthy individuals, to look for differences that may contribute to the disease.

While standard cross-sectional, or case-control studies haven’t shown a huge impact from non-HLA genes, they only provide a “snapshot’ of what is happening with both patients and controls alike, the scientists say. With the prospective and longitudinal TEDDY, the scientists are literally watching the disease occur – or not – in high-risk young people.

In fact, this is the first major study regarding gene identification for any disease that uses this sort of longitudinal information, She says.

As with many things, timing is everything, and the TEDDY perspective sharpens the search, particularly for important non-HLA genes by adding the “time to disease” perspective, She says.

Photographed: Drs. Jin-Xiong She (left) and Ashok Sharma

Pain-Free Skin Patch Responds to Sugar Levels for Management of Type 2 Diabetes

Researchers with NIH’s National Institute of Biomedical Imaging and Bioengineering (NIBIB) have devised an innovative biochemical formula of mineralized compounds that interacts in the bloodstream to regulate blood sugar for days at a time. In a proof-of-concept study performed with mice, the researchers showed that the biochemically formulated patch of dissolvable microneedles can respond to blood chemistry to manage glucose automatically.

“This experimental approach could be a way to take advantage of the fact that persons with type 2 diabetes can still produce some insulin,” said Richard Leapman, Ph.D., NIBIB scientific director. “A weekly microneedle patch application would also be less complicated and painful than routines that require frequent blood testing.”

Insulin is a hormone made in the pancreas and secreted into the bloodstream to regulate glucose in response to food intake. It is needed to move glucose from the bloodstream into cells where the sugar can be converted to energy or stored. In type 1 diabetes, usually diagnosed in children and young adults, the body does not make insulin at all. Type 2 diabetes, which can be diagnosed at any age but more commonly as an adult, progressively lessens the body’s ability to make or use insulin. Untreated, diabetes can result in both vascular and nerve damage throughout the body, with debilitating impacts on the eyes, feet, kidneys, and heart.

Global incidence of all types of diabetes is about 285 million people, of which 90 percent have type 2 diabetes. Many require insulin therapy that is usually given by injection just under the skin in amounts that are calculated according to the deficit in naturally generated insulin in the blood. Insulin therapy is not managed well in half of all cases.

NIBIB researchers led by Xiaoyuan (Shawn) Chen, senior investigator in the Laboratory of Molecular Imaging and Nanomedicine, are working on an alternate therapy approach to regulate blood sugar levels in type 2 diabetes using a painless skin patch. In a Nov. 24, 2017, study published online in Nature Communications, the team applied the treatment to mice to demonstrate its potential effectiveness.

The base of the experimental patch is material called alginate, a gum-like natural substance extracted from brown algae. It is mixed with therapeutic agents and poured into a microneedle form to make the patch. “Alginate is a pliable material—it is soft, but not too soft,” Chen said. “It has to be able to poke the dermis, and while not a commonly used material for needles, it seems to work pretty well in this case.”

Chen’s team infused the alginate with a formula of biochemical particles that stimulates the body’s own insulin production when needed and curtails that stimulation when normal blood sugar concentration is reached. The responsive delivery system of the patch can meet the body’s need for days instead of being used up all at once.

“Diabetes is a very serious disease and affects a lot of people,” Chen said, explaining that his group is part of a crowded field of drug research and developers with competing ideas. “Everybody is looking for a long-acting formula.”

Pain-free skin patch responds to sugar levels for management of type 2 diabetes | National Institute of Biomedical Imaging and Bioengineering

Chen’s formula puts two drug compounds—exendin-4 and glucose oxidase—into one patch. The two compounds react with the blood chemistry to trigger insulin secretion. Each is matched with a phosphate mineral particle, which stabilizes the compound until it is needed. Acidity that occurs when sugar concentrations rise weakens the bond with the drug being held by one, but not the other mineral.

Exendin-4 is similar in genetic makeup to a molecule the body produces and secretes in the intestine in response to food intake. Though it is somewhat weaker than the naturally occurring molecule, the team chose exendin-4 for its application because exendin-4 does not degrade in the bloodstream for an hour or more, so can have long-lasting effect after being released. However, it can induce nausea when too much is absorbed. To control how quickly it is absorbed, the researchers combined exendin-4 with mineral particles of calcium phosphate, which stabilize it until another chemical reaction occurs. That chemical reaction is caused by the second drug compound in the patch—glucose oxidase— that is held in its mineral buffer of copper phosphate.

Chen explained that when blood sugar is elevated beyond a precise point, it triggers a reaction with copper phosphate and glucose oxidase to produce slight acidity, which causes calcium phosphate to release some exendin-4. Rising glucose levels trigger the release of exendin-4; but exendin-4 then gets insulin flowing to reduce the glucose level, which slows down and stops release of exendin-4. “That’s why we call it responsive, or smart, release,” said Chen. “Most current approaches involve constant release. Our approach creates a wave of fast release when needed and then slows or even stops the release when the glucose level is stable.”

The researchers demonstrated that a patch about half an inch square contained sufficient drug to control blood sugar levels in mice for a week. For the approach to advance as an application that people with type-2 diabetes can use, the team will need to perform tests to treat larger animals with a patch that contains proportionately more therapeutic compound. In addition to its size, the patch would need to be altered for application on human skin, likely requiring longer needles.

“We would need to scale up the size of the patch and optimize the length, shape, and morphology of the needles,” Chen said. “Also, the patch needs to be compatible with daily life, for instance allowing for showering or sweating.”

Chen is encouraged by the success of his experiments, and by research reports of steady progress by other experimental microneedle patch developers.  For instance, others have completed early human studies with microneedle patch devices that contain insulin and that would benefit people with type 1 as well as type 2 diabetes. He hopes there will be lessons from development of those devices that can be applied to the microneedle patch that his team tested in this study.

Sernova Tackles both Diabetes and Hemophilia with one Technology

contributed by Richard (Rick) Mills
Editor, Ahead of the Herd

As a general rule, the most successful man in life is the man who has the best information.

Paul Lacey was a researcher at Washington University when, in 1972, he cured some diabetic rats by transplanting the islet cells from healthy rats into diabetic ones.

Over the next two decades researchers made many attempts to apply the procedure to humans. Unfortunately no one was successful. By the early 1990’s most scientists had come to the conclusion that islet-cell transplantation was a lost cause.

Drs. James Shapiro, Jonathan Lakey and colleagues from the University of Alberta in Edmonton were successful at improving the treatment of a select group with severe diabetes through development of the Edmonton protocol in the late 1990s.

The Edmonton Protocol is a method of transplantation of pancreatic islets into the portal vein of the recipient’s pancreas. These pancreatic islets are sourced/extracted from pancreases removed from recently deceased adults.

Each recipient receives islets from one to three donors. The islets are infused into the patient’s portal vein, and are then protected from the recipient’s immune system through the use of two immunosuppressant drugs as well as an antibody drug specifically used in transplant patients.

35886507 - pancreatic gland
35886507 – pancreatic gland

Since 2000 close to a thousand people have received islet transplants – but by five years after the procedure, on average fewer than 10% of all patients are free of daily insulin supplementation. Thus, while islet cell transplantation has demonstrated exciting success and the potential for cell therapy as a treatment for diabetes has great promise, further technology developments are required.

Exactly what is Diabetes?

Diabetes is a condition in which the sugar levels in the blood are too high on a constant basis. Without tight blood sugar control to normal levels, this can result in severe long term medical consequences.

Much of the food one eats is broken down into a simple sugar called glucose. In response to a rise in glucose levels after a meal the islet’s beta-cells in the pancreas detect blood glucose levels and secrete insulin into the blood. Insulin acts to open the gates of cells allowing the glucose to move from the blood stream into the cells where it can be utilized for energy.

A Type 1 diabetes diagnosis means the pancreatic beta cells that read glucose levels and secrete insulin have been damaged or destroyed. Thus, glucose cannot move from the bloodstream into the cells allowing blood sugars to rise.

A Type 2 (insulin resistance) diabetes diagnosis is a far more common verdict for people than Type 1. Insulin resistance occurs as a result of chronically elevated blood sugar and insulin levels. These elevated levels of sugar and insulin have the effect of “numbing” the cellular processes which move the sugar from the blood stream to the cells – the body cannot respond to the insulin “requests” to move blood sugar into the cells. Approximately 27% of the people who start out as Type 2 diabetics, will, in the future require insulin injections similar to Type 1 diabetics.

Diabetic complications, which occur even in individuals taking insulin injections, include irreversible damage to the heart, blood vessels, eyes, kidneys, skin, feet and hearing. In individuals taking insulin injections to reduce blood sugar levels, severe hypoglycemia from a single injection of too much insulin, can cause organ failure, coma and death.

Diabetes is not considered a high mortality condition, but it is a major risk factor for other causes of death and has an extremely high attributable burden of disability, for example; 2% of people with diabetes become blind, about 10% develop severe visual impairment, and 50% of people with diabetes die of cardiovascular disease.

Standard of Care

The Standard of Care for patients with reduced or missing critical hormones or proteins, such as insulin, is often monitoring and injecting these proteins multiple times a day.

A search has been on for an alternative site for islet transplantation as well as for an optimal medical device in which to implant the islets (therapeutic cells). Several subcutaneous devices have previously been developed for islet transplantation but from a preclinical and clinical perspective the results from these products have been generally disappointing.

Current cell therapy is limited to poor cell survival, inappropriate delivery of hormones and a lack of available donors and cells. At this time there is no approved device to house and protect therapeutic cells in the body.

Sernova Corp. (TSX-V: SVA) (OTCQB: SEOVF) (FSE: PSH)

Sernova Corp is a Phase I/II clinical stage company developing medical technologies for the treatment of chronic debilitating metabolic diseases to replace proteins or hormones in short supply within the body.

The first proprietary platform technology is the Cell Pouch System™. Think of SVA’s Cell Pouch System™ as a potential natural insulin producing pump with the added benefit of fine-tuned glucose control with no need to replenish the insulin. When placed under the skin and filled with islets it can develop pancreas-like characteristics taking over normal blood glucose control. The device uniquely forms highly vascularized tissue chambers for the placement, survival and function of therapeutic cells. Insulin producing islets transplanted in the device have been proven to become connected to microvessels and able to produce all of the regulatory hormones to control diabetes.

Sernova is exploring the additional utility of the Cell Pouch System™ as an enabling platform for a range of therapeutic cell types and diseases. The technology could be used for a patient’s own cells (autograft), or a donor’s cells (allograft).

The therapeutic cells placed into the device may also be cells that can be a source to treat millions of patients such as stem cell derived therapeutic cells (stem cells have the ability to differentiate into other cell/tissue types) or xenogeneic (derived or obtained from an organism of a different species) cells.

Sernova’s products are also designed to allow for multiple market expansion opportunities within each therapeutic area. For example, the technology would be beneficial if it provided a simple reduction in the number of daily therapeutic injections a patient must take; however, there is the possibility that it could even essentially ‘cure’ the disease through natural release and regulation of the therapeutic proteins or hormones.

Sernova’s trials

Sernova’s products are uniquely focused on those diseases in which a protein, hormone or factor, missing or in short supply in the body, could be replaced by therapeutic cells which release those factors into the bloodstream.

Diabetes and hemophilia are but two of the multibillion dollar market opportunities where such treatments could lead to:
• A significant improvement in the quality of patient’s lives
• Reducing health care costs
• Potentially reduce the devastating side effects of disease
While other scientific laboratories around the world were advancing stem cell technologies which, if successful, would provide sources of therapeutic cells for various clinical applications, Sernova was in parallel working on their proprietary, scalable, implantable medical device (Cell Pouch System™) that creates a natural environment for the survival and function of these therapeutic cells.

Sernova is in the forefront of such technologies.

Diabetes

About 347 million people worldwide have diabetes. The World Health Organization (WHO) projects that diabetes will be the 7th leading cause of death in 2030.

July 12, 2016 – Sernova Corp. a clinical stage company developing disruptive regenerative medicine technologies for the long-term treatment of chronic diseases including diabetes and hemophilia, is pleased to announce today it has entered into a research funding agreement with JDRF, the leading global organization funding and advocating for type 1 diabetes (T1D) research.

The purpose of the funding is to advance human clinical trials of Sernova’s
Cell Pouch System(TM) (CPS) technologies for treatment of hypoglycemia unawareness patients with severe type 1 diabetes. T1D is a life-threatening disease in which the body’s immune system mistakenly attacks and kills the pancreatic cells that produce insulin—a hormone that is essential for life because of its role to help the body use glucose.

JDRF will provide Sernova up to US$2.45 million to support a clinical trial at a major transplantation center in the United States. The goal of the study is to provide patients with hypoglycemia unawareness a novel cell therapy treatment utilizing Sernova’s proprietary, highly vascularized, cell macroencapsulated implantable and scalable device to reduce or eliminate the need for injections of exogenous insulin.

“Sernova’s progression to human clinical trials is an incredible accomplishment in the global diabetes research agenda. I am particularly proud of this trial being a part of the JDRF portfolio because it supports advancements of the best and brightest research minds in Canada at Sernova. Also, this is a shining example of the international collaboration fostered by projects funded by JDRF. Working together with our global partners, we can accelerate this type of transformative research and ensure it becomes available for the T1D community.” Dave Prowten, President and CEO of JDRF Canada.

Hemophilia
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Patients with hemophilia A have a defective gene for factor VIII. Patients receive prophylaxis factor replacement therapy two to three times a week. Prophylactic therapy (prevention therapy) involves three infusions of Factor VIII each week at a hospital at a cost of about USD$200,000/yr.

December 21, 2015 – Sernova Corp. announced today that the European Commission’s Horizon 2020 program has awarded a Euro 5.6M ($8.5M CAD) grant to a consortium consisting of Sernova Corp and five European academic and private partners to advance development of a GMP clinical grade Factor VIII releasing therapeutic cell product in combination with Sernova’s Cell Pouch(TM) for the treatment of severe hemophilia A

February 16, 2016 – Sernova Corp. announced today it has received its initial € 566,500 ($875,000 CDN) installment of non-dilutive funds from the HemAcure Grant funded by the EU Horizon 2020 Program. Sernova will use the payment to fund activities related to the development of a GMP clinical grade Factor VIII releasing therapeutic cell product combined with Sernova’s Cell Pouch(TM) to treat severe hemophilia A, a serious genetic bleeding disorder caused by missing or defective factor VIII in the blood stream.

“We are excited that the HemAcure consortium partners, a group developing a therapeutic that is highly disruptive to the current standard of care treatments for hemophilia A, are already working diligently to advance the program. Together, we are working to address, with a sense of urgency, the critical challenges posed by severe hemophilia A.” Dr. Philip Toleikis, Sernova President and CEO.

Conclusion

Since late December 2015, Sernova and its collaborative partners have announced funding of joint research hemophilia and diabetes collaborations totaling Cdn$11,780,000.00.

Individually each of these collaborations is massive validation of Sernova’s technology. Taken together they show a company on the cusp of being THE paradigm changer in science and they highlight Sernova’s capability to profoundly disrupt current standard of care.For this reason Sernova Corp has to be on everyone’s radar screen.

Richard (Rick) Mills
aheadoftheherd.com
Richard owns shares of Sernova Corp. (TSX-V: SVA) (OTCQB: SEOVF) (FSE: PSH)

Richard lives with his family on a 160 acre ranch in northern British Columbia and is the owner of Aheadoftheherd.com.
Richard’s articles have been published on over 400 websites, including:  WallStreetJournal, USAToday, NationalPost, Lewrockwell, MontrealGazette, VancouverSun, CBSnews, HuffingtonPost, Beforeitsnews, Londonthenews, Wealthwire, CalgaryHerald, Forbes, Dallasnews, SGTreport, Vantagewire, Indiatimes, Ninemsn, Ibtimes, Businessweek, HongKongHerald, Moneytalks, SeekingAlpha, BusinessInsider, Investing.com, MSN.com and the Association of Mining Analysts.

Joint Research Collaboration Aims to Advance Human Clinical Trials for the Treatment of Hypoglycemic Unawareness Patients with Severe Type 1 Diabetes

A new research funding agreement between the Juvenile Diabetes Research Foundation (JDRF) and Sernova, a clinical-stage regenerative medicine biotech, aims to address people with severe type 1 diabetes (T1D) who are hypoglycemia unaware, a condition in which a person with diabetes does not experience the usual early warning symptoms of hypoglycemia (low blood sugar) following an insulin injection. The purpose of the funding is to advance human clinical trials of Sernova’s novel cell macroencapsulated implantable and scalable Cell Pouch System (CPS) with the hope to improve the quality of life and overall outcomes for these patients.

Type 1 diabetes is a disease in which the body’s immune system mistakenly attacks and kills the pancreatic cells that produce insulin—a hormone that is essential for life because of its role to help the body use glucose. People with diabetes who have hypoglycemia unawareness are at a higher risk of acute life threatening consequences that can lead to coma and death following an insulin injection that reduces blood glucose to dangerously low levels.

JDRF will provide Sernova $2.45 million USD to support a clinical trial at a major transplantation center in the United States. “JDRF has previously provided funding to advance the development of Sernova’s technologies through a preclinical collaboration with Massachusetts General Hospital, and we are proud to continue our support as Sernova’s technologies progress into new safety and efficacy clinical trials,” said Derek Rapp, JDRF President and CEO. “JDRF is excited about this collaboration, which advances research in encapsulated cell therapies, and will continue to drive progress toward our mission to accelerate life-changing breakthroughs to cure, prevent and treat T1D and its complications.”

“Sernova and JDRF are tightly aligned in our vision to see cell-based therapies developed to reduce disease burden and significantly increase the quality of life for people living with T1D,” remarked Dr. Philip Toleikis, Sernova’s President and CEO. “We see our work with JDRF on this important clinical trial as an exciting opportunity to more rapidly advance Sernova’s therapies to treat people with diabetes and address many of the shortcomings and challenges of current insulin therapy.”

Understanding Hypoglycemia Unawareness

17727298 - type 1 diabetes

There is no cure for T1D, and people living with the disease are dependent on insulin therapy to help keep their blood-sugar levels from spiking too high, which can lead to long-term complications such as kidney and heart diseases or an acute, potentially deadly health crisis. Present-day insulin therapy is, however, an imperfect treatment method that requires people with T1D to monitor their blood sugar throughout the day and take multiple, calculated doses of insulin based on food intake, exercise, stress, illness and other factors. A miscalculation or unexpected variable leading to high or low blood sugar episodes are daily threats, and only a third of people with T1D achieve their long-term blood glucose targets, placing them at risk for T1D-related health complications.

Many patients with diabetes who experience insulin-induced drops in blood sugar levels which could reach acute dangerous levels have the typical early warning signs of hypoglycemia, which include sweating, trembling, butterflies in the stomach, tingling, numbness, and rapid pulse.

People with diabetes who have hypoglycemia unawareness don’t experience these symptoms in reaction to a severe drop in blood sugar levels. Instead, without warning, they can lapse into severe hypoglycemia, becoming confused or disoriented or falling unconscious into a coma followed by death. It has been shown that transplantation of new islets can reduce the incidence and severity of hypoglycemia unawareness.

“Sernova’s progression to human clinical trials is an incredible accomplishment in the global diabetes research agenda,” said Dave Prowten, President and CEO of JDRF Canada. “I am particularly proud of this trial being a part of the JDRF portfolio because it supports advancements of the best and brightest research minds in Canada at Sernova. Also, this is a shining example of the international collaboration fostered by projects funded by JDRF. Working together with our global partners, we can accelerate this type of transformative research and ensure it becomes available for the T1D community.”

Cell Pouch System Technology vs Existing Islet Transplant Technology

Currently, islet cell transplantation is a procedure that involves transplanting islet cells from a donor’s pancreas into a diabetic patient’s liver through a blood vessel, basically a “big injection” into the portal vein of the liver. In this procedure infused islets can result in toxicities such as liver hypertension resulting from blockage of small blood vessels where the islets lodge. In addition, a large proportion of infused islet cells die during or after the process often requiring multiple treatments to achieve efficacy. Because of these and other issues as well as the low number of available islet donors in addition to diminishing efficacy over time, the procedure is available to only a small fraction of the most severely ill T1D patients.

 “We hope with these trials to accomplish an improved quality of life for people with diabetes who also experience hypoglycemia unawareness, and to potentially increase the number of patients that could be treated,” remarked Dr. Toleikis. “This work will also lend important information as we continue our development of Cell Pouch System cell-based technologies to treat the broader T1D community.”

Stem Cells From Diabetic Patients Coaxed to Become Insulin-Secreting Cells

Signaling a potential new approach to treating diabetes, researchers at Washington University School of Medicine in St. Louis and Harvard University have produced insulin-secreting cells from stem cells derived from patients with type 1 diabetes.

People with this form of diabetes can’t make their own insulin and require regular insulin injections to control their blood sugar. The new discovery suggests a personalized treatment approach to diabetes may be on the horizon — one that relies on the patients’ own stem cells to manufacture new cells that make insulin.

The researchers showed that the new cells could produce insulin when they encountered sugar. The scientists tested the cells in culture and in mice, and in both cases found that the cells secreted insulin in response to glucose.

The research is published May 10 in the journal Nature Communications.

“In theory, if we could replace the damaged cells in these individuals with new pancreatic beta cells — whose primary function is to store and release insulin to control blood glucose — patients with type 1 diabetes wouldn’t need insulin shots anymore,” said first author Jeffrey R. Millman, PhD, an assistant professor of medicine and of biomedical engineering at Washington University School of Medicine. “The cells we’ve manufactured sense the presence of glucose and secrete insulin in response. And beta cells do a much better job controlling blood sugar than diabetic patients can.”

Millman, whose laboratory is in the Division of Endocrinology, Metabolism and Lipid Research, began his research while working in the laboratory of Douglas A. Melton, PhD, Howard Hughes Medical Institute investigator and a co-director of Harvard’s Stem Cell Institute. There, Millman had used similar techniques to make beta cells from stem cells derived from people who did not have diabetes. In these new experiments, the beta cells came from tissue taken from the skin of diabetes patients.

“There had been questions about whether we could make these cells from people with type 1 diabetes,” Millman explained. “Some scientists thought that because the tissue would be coming from diabetes patients, there might be defects to prevent us from helping the stem cells differentiate into beta cells. It turns out that’s not the case.”

Millman said more research is needed to make sure that the beta cells made from patient-derived stem cells don’t cause tumors to develop — a problem that has surfaced in some stem cell research — but there has been no evidence of tumors in the mouse studies, even up to a year after the cells were implanted.

He said the stem cell-derived beta cells could be ready for human research in three to five years. At that time, Millman expects the cells would be implanted under the skin of diabetes patients in a minimally invasive surgical procedure that would allow the beta cells access to a patient’s blood supply.

“What we’re envisioning is an outpatient procedure in which some sort of device filled with the cells would be placed just beneath the skin,” he said.

The idea of replacing beta cells isn’t new. More than two decades ago, Washington University researchers Paul E. Lacy, MD, PhD, now deceased, and David W. Scharp, MD, began transplanting such cells into patients with type 1 diabetes. Still today, patients in several clinical trials have been given beta cell transplants with some success. However, those cells come from pancreas tissue provided by organ donors. As with all types of organ donation, the need for islet beta cells for people with type 1 diabetes greatly exceeds their availability.

Millman said that the new technique also could be used in other ways. Since these experiments have proven it’s possible to make beta cells from the tissue of patients with type 1 diabetes, it’s likely the technique also would work in patients with other forms of the disease — including type 2 diabetes, neonatal diabetes and Wolfram syndrome. Then it would be possible to test the effects of diabetes drugs on the beta cells of patients with various forms of the disease.

Solving a Genetic Mystery in Type 1 Diabetes

In type 1 diabetes, the immune system attacks the body’s own insulin-producing cells. Scientists understand reasonably well how this autoimmune attack progresses, but they don’t understand what triggers the attack or how to stop it, says Stephan Kissler, Ph.D., Investigator in the Section on Immunobiology at Joslin Diabetes Center and Assistant Professor of Medicine at Harvard Medical School.

Mutations in dozens of genes raise the risk of the disease by small but significant amounts, and researchers are painstakingly uncovering how each gene might contribute. Now the Kissler lab has shown one way in which one such gene, called RGS1, may help to foster the autoimmune attack.

In the attack, immune cells called T cells infiltrate the pancreas and damage the insulin-producing beta cells. Another type of immune cells called B cells produce antibodies and are also involved. In a mouse model of type 1 diabetes, RGS1 affects the population of one type of T cell called a “T follicular helper cell” that is critical for B cells and antibody production, Dr. Kissler and his colleagues reported recently in Genes and Immunity.

“In a nutshell, what we found is that this gene has an effect on the frequency of these T follicular helper cells, which are important for the B cells and seem to be important for the disease,” says Dr. Kissler, who is also an assistant professor of medicine at Harvard Medical School.

The finding was particularly striking because clinical studies have found that the number of these cells in the blood is higher in people with type 1 diabetes.

However, Dr. Kissler’s group discovered that reducing levels of the RGS1 protein did not slow the progression of the disease in mouse models, suggesting that it may not offer much potential for human treatment.

“Inhibiting RGS1 didn’t prevent autoimmune diabetes from happening, which is slightly disappointing but not surprising because any one of these genes in humans has a very small effect on risk,” says Dr. Kissler.

His lab focuses on genes associated with higher risk of type 1 diabetes that also play a role in other autoimmune diseases. Additionally, Dr. Kissler’s group narrows in on genes such as RGS1 that help to regulate cell migration. Mutations of RGS1 are associated with several autoimmune diseases, including multiple sclerosis, and a drug targeting cell migration has been approved to treat multiple sclerosis, he notes.

While the scientists had speculated that inhibiting RGS1 would lower the migration of T cells into the pancreas, they didn’t find evidence for that movement in their mouse models. They did discover that the inhibition changes the ways cells move within lymph nodes and the spleen, organs in which T follicular helper cells interact with B cells to promote antibody production.

Several pieces of evidence suggest that B cells are major players in type 1 diabetes, Dr. Kissler says. Among them, certain antibodies that are linked to autoimmune attack and produced by B cells are the best known indicators for risk of type 1 diabetes.

Lymph nodes and the spleen have “follicular” regions full of B cells, and other regions full of T cells. “The RGS1 gene is important to allow activated T cells to move into the regions with all the B cells, where they help the B cells get activated and produce antibodies,” he explains. “These are the T follicular helper cells. If you don’t have any of these cells, the antibody production doesn’t work anymore.”

“Overall, the T follicular helper cells are important for B cells, you have more of those T cells in people with type 1 diabetes, they seem to be very important for the disease, and we have a new explanation of why RGS1 has been implicated,” Dr. Kissler sums up.

“We’re continuing to test a number of other genes to see if one strikes us as being a very potent modifier of type 1 diabetes,” he adds. ““The more pieces of this puzzle we can lay down, the better a picture we have to figure out the best ways to intervene in the disease. And this piece of information about RGS1 might become valuable down the line when we know more about other genes, because it might fall into place in the puzzle.”

Celia Caballero-Franco, PhD, a postdoctoral fellow in the Kissler lab, was first author on the paper. Lead funding came from the National Institutes of Health and the JDRF.