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Fri, Aug 14 · Leave a Comment

The Race is On – How Mayo Clinic is Using Regenerative Medicine Technology to Find a Cure for Diabetes

By Center for Regenerative Medicine Center for Regenerative Medicine

This story first appeared in Mayo Clinic Magazine.
For Caroline Schlehuber, an artificial pancreas might mean an end to finger pricks, blood reads and daily shots.
Caroline can never escape her diabetes. It was there on her first day of school, at her first communion. It's there every Halloween, every Christmas, every vacation. She's pricked her finger eight to 10 times a day since she was 3 years old, including the six birthdays she's had since she was diagnosed.

She understands that it wasn't her fault that her body turned on itself, that her immune system attacked her insulin-producing islet cells. To quote Caroline, "Diabetes doesn't care how cute you are. Diabetes doesn't care how well you play soccer. Diabetes doesn't care who your friends are or how much your family loves you."

From the outside, her life looks perfectly normal. She plays soccer, swims with friends and goes to ballgames with her family. But in the background is the relentless hum of type 1 diabetes, with vigilant blood sugar surveillance and insulin adjustments.

Her parents, Tom and Michelle Schlehuber, are thankful for the lifesaving medications and technologies that keep their daughter alive, but they pray for the day when Caroline isn't one missed reading away from the emergency room, when her life isn't dominated by glucose meters and insulin pumps.

That day may be closer than they imagined.

NEW POSSIBILITIES

The road to discovery is long and riddled with ideas proven wrong. Researchers repeatedly see the most promising ideas fail when subjected to rigorous scientific method. The experience leaves most of them hesitant to use a certain four-letter word — "cure." Instead they use euphemisms like "advancing care" and "better treatments."

But something seems to be stirring among diabetes researchers. One occasionally hears whispers of the word. Some are becoming even bolder with statements like, "It's no longer if we cure diabetes, but when."

The reason for the optimism is that one proven cure already exists. Patients with type 1 diabetes who have received pancreas transplants have seen their disease go away completely. Unfortunately, the transplant requires a lifetime of immunosuppressive drugs whose side effects can be more harmful than diabetes.

The success of transplants shows a cure is possible. But how do we get there without the full transplant? Without the drugs? Researchers are making extraordinary progress toward answering these questions. So much so that many believe the race is on to find a cure. And Mayo Clinic might have the edge.

"I genuinely believe that now is the time for diabetes, and there is a lot going on at Mayo that has major promise," says Stephen J. Russell, M.D., Ph.D., deputy director for translation in Mayo Clinic's Center for Regenerative Medicine. "We know we can turn this new stuff into clinical reality."

BUILDING A NEW PANCREAS FOR TIGHT GLUCOSE CONTROL

Mayo Clinic's Yogish C. Kudva, MBBS, and Ananda Basu, MBBS, M.D., hope to transform life for people like Caroline with a hands-free device called the artificial pancreas.

Functioning just like a biological pancreas, the artificial pancreas uses an abdominal patch that continuously measures blood sugar. A pager-sized pump then delivers exactly the right amount of insulin at exactly the right time. Precision is critical because abnormal blood sugar levels can cause disabling and life-threatening complications such as heart attacks and strokes and damage the nerves, eyes and kidneys.

The artificial pancreas will free people with diabetes from daily preoccupations over finger pricks, blood reads and daily shots. Many people with diabetes have insulin pumps already, but the artificial pancreas represents a sea change because it minimizes patient decision-making.

Looking to the future, Dr. Kudva says, "We're very excited."

Working in partnership with the University of Minnesota, Mayo investigators are developing a novel continuous blood sugar sensor to improve its performance and usability. Mayo investigators are also refining the algorithm that controls insulin delivery so that it can be individualized for each patient.

In an upcoming clinical trial, Mayo researchers will use hard data from humans with type 1 diabetes to predict insulin needs, setting Mayo's efforts apart from other studies that have relied on computer simulations. By next year, Drs. Kudva and Basu hope to test the artificial pancreas in the real world as patients use it for weeks at a time, integrating the device into their daily lives.

REPLACING DAMAGED CELLS

The immune system wages war on any virus, bacteria or fungus it considers an invader of the body. As with Caroline's type 1 diabetes, the immune system mistakenly targets the body's own islet cells, compromising the pancreas' ability to monitor blood sugar levels and release insulin.

Mayo Clinic investigator Yasuhiro Ikeda, D.V.M., Ph.D., is investigating a cutting-edge regenerative approach to replace these essential islet cells in the pancreas. Tapping the body's power to heal itself, Dr. Ikeda is working to generate new islets from the diabetic's own skin or blood.

The process extracts cells from the patient and converts them into stem cells. Dr. Ikeda has taken these bioengineered cells — known as induced pluripotent stem (iPS) cells — a step further by inducing them to grow into glucose-responsive, insulin-producing cells in the laboratory. The iPS technology and its promise for humankind have been recognized by the 2012 Nobel Prize in physiology or medicine.

"Our future goal is to make customized islets from iPS cells and then hopefully put them back into the patient," Dr. Ikeda said.

Dr. Ikeda has improved blood sugar levels in diabetic mice for short periods of time using this promising technology. His next steps are to improve the responsiveness of the bioengineered islets to blood sugar fluctuations and increase the amount of insulin they produce. Human trials could start in the next three years.

STOPPING DIABETES IN ITS TRACKS

A problem lingers even if lost islets can be replaced: The patient's body could reject them as the immune system attacks the newly transplanted islets.

In this regard, Dr. Ikeda believes that recent advances in gene therapy hold great promise in preventing the autoimmune response to islets that mark the progression of diabetes.

"If we can suppress autoimmunity, we should be able to suppress the disease," he says.

To reach islets with tremendous precision, Dr. Ikeda uses a mild, nondisease-causing virus called adeno-associated virus (AAV), which travels through the bloodstream to deliver a gene that suppresses the immune system's attack in a localized area.

Dr. Ikeda has already used the gene, called interleukin-10, to prevent the onset of diabetes in diabetes-prone mice. That success drove him to pursue an even more challenging discovery: How do you stop diabetes in its tracks once islet destruction begins?

"Once the immune response kicks in, it's very hard to reverse it," he says.

In pursuit of a landmark discovery, Dr. Ikeda is focused on stopping the progression of diabetes during its so-called "honeymoon" stage. This is the critical period — roughly two years in humans but much shorter in the lab mice Dr. Ikeda is testing — during which the immune system gradually decimates islets in the pancreas.

If diabetes can be stopped early enough, Dr. Ikeda believes a critical mass of islets will be preserved to maintain necessary insulin levels. He hopes clinical trials focused on this approach to gene therapy can start soon.

REBOOTING THE SYSTEM

Another possible treatment for diabetes, called cell therapy, also is aimed at protecting islets from the immune system.

"My hope is we reset the system: that you prevent the cells from killing the islets, the islets repair, and you go on with your life," says Allan B. Dietz, Ph.D., an investigator in Mayo Clinic's Human Cellular Therapy Laboratory, which is integral to Mayo Clinic's regenerative medicine endeavors.

Cell therapy involves the use of mesenchymal stem cells, which can be produced in large quantities from a fat biopsy and implanted back into a patient.

"When you get wounded or have an injury, these are the cells that mediate repair," Dr. Dietz says.

There's a good chance that mesenchymal stem cells can suppress the immune system safely in a targeted area to prevent the destruction of islets while helping islets repair themselves, Dr. Dietz said. He noted that new trials could start soon if funding were available.

WORKING TOWARD A CURE

Though Caroline's family began praying for a cure the day they learned she had diabetes, they began working toward it almost as soon.

Within months of the diagnosis, the family formed Team Caroline and participated in Juvenile Diabetes Research Foundation's Walk to Cure Diabetes in San Diego. About 15 friends and family members joined in. Over the past six years, their involvement has grown, and last year about 100 people donned bright green shirts and walked with them through Mall of America in Minnesota to raise awareness and funds to support research.

Their goal was $15,000. They exceeded it by more than 20 percent.

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Fri, Jul 31 · Leave a Comment

Meet the Researcher: Abba Zubair, M.D., Ph.D., Talks Stem Cells in Space

By Center for Regenerative Medicine Center for Regenerative Medicine

Abba Zubair, M.D., Ph.D.

Abba Zubair, M.D., Ph.D.

Abba C. Zubair, M.D., Ph.D., medical and scientific director of the Cell Therapy Laboratory at Mayo Clinic in Florida will present "Growing Stem Cells in Space: Medicine’s Next Big thing?” All are welcome to the Research Information Center in Rochester, Minn. (Gonda Building, Lobby Level) Tuesday August 4, at 1:30 p.m.

Dr. Zubair will discuss the possibility of growing stem cells aboard the International Space Station, a strategy that may accelerate the growth of human tissues and organs which currently require a substantial amount of time to develop due to gravity. This experiment breaks new ground as the first of its kind to be conducted in orbit.

Join Dr. Zubair to learn about this approach and its potential role in regenerative medicine, the implications of which range far, from the study of neuroregeneration, to organ transplantation, to the treatment of stroke patients. Read more about Dr. Zubair's study: Stem Cells in Space: Testing Stroke Treatment.

The presentation is open to the public.

To learn more about the Mayo Clinic Research Information Center and to view past “Meet the Researchers,” please visit: http://www.mayo.edu/research/about/information-center.

 

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Tags: Abba Zubair, Mayo Clinic, Meet the Researcher, Regenerative Medicine, Research, space, stem cells, stroke


Fri, Jul 31 · Leave a Comment

Researchers Test Bioartificial Liver Device to Treat Acute Liver Failure

By Center for Regenerative Medicine Center for Regenerative Medicine

This story first appeared on the Mayo Clinic News Network.

Approximately 30,000–40,000 people die from liver disease each year, according to the American Liver Foundation. For people who experience acute liver failure, the only proven treatment has been liver transplantation. Researchers at Mayo Clinic have developed and are testing an alternative to liver transplantation called the Spheroid Reservoir Bioartificial Liver that can support healing and regeneration of the injured liver, and improve outcomes and reduce mortality rates for patients with acute liver failure --without requiring a transplant.

bioliver slideDeveloped by Scott Nyberg, M.D., Ph.D., principal investigator in the Artificial Liver and Liver Transplantation Laboratory at Mayo Clinic, and liver transplant surgeon, the device uses healthy hepatocytes, or liver cells, from pigs to do the job of a normal, healthy liver, which aids in digestion and the removal of waste and toxins from the bloodstream. Treatment with the Spheroid Reservoir Bioartificial Liver (SRBAL) has been shown to reduce the severity of liver disease and improve survival in pigs. Future clinical studies are planned to assess the SRBAL as a less-invasive, long-term treatment option to liver transplantation. Results from a study using the device in a pivotal preclinical trial were published today in the Journal of Hepatology.

“Acute liver failure claims the lives of over 30 percent of people who are diagnosed with this condition. Liver transplantation has been the go-to option for treating acute liver failure, but it also comes with many risks and isn’t always an option, due to compatibility and availability of donor livers,” says Dr. Nyberg. “A bioartificial liver device could allow physicians to treat and extend the lives of more patients, safely and cost-effectively, with fewer risks.”

The study conducted by Dr. Nyberg was designed to serve as a preclinical trial on pigs with drug-induced acute liver failure. The animals were treated using the Spheroid Reservoir Bioartificial Liver and were injected with healthy donor hepatocytes to determine if this treatment method could reverse the severity of their disease.

“This study demonstrated that animals treated using the bioartificial liver responded to the healthy hepatocytes and reached the study endpoint with less disease severity than animals that received other forms of treatment,” said Dr. Nyberg. “Although the artificial liver is not yet cleared for use on humans, these findings show promise as an effective treatment option for diseases like liver cancer and hepatitis, which is becoming an increasingly common diagnosis.”

The rights to the SRBAL have been exclusively optioned to Liver Cell Technologies for commercial development. Mayo Clinic and Dr. Nyberg have a financial interest in the product and Liver Cell Technologies.

According to the American Liver Foundation, there are more than 100 different types of liver disease that can compromise liver function and lead to chronic and life-threatening conditions such as hepatitis, non-alcoholic fatty liver disease, and liver cancer.

 

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Tags: Bioartificial Liver, Liver Transplantation, Mayo Clinic, Regenerative Medicine, scott nyberg, stem cells


Mon, Jul 27 · Leave a Comment

Human Cell Therapy Laboratory: Developing Drugs from the Patient, for the Patient

By Center for Regenerative Medicine Center for Regenerative Medicine

This story originally appeared on the Mayo Medical Laboratories Blog.

It’s almost a crime the outside world doesn’t know about the human clinical trials occurring at Mayo Clinic’s Human Cell Therapy Laboratory (HCTL) in Rochester. Currently, there are eleven (phase I) trials underway (or just finishing), investigating the use of cellular therapies. Developed in HCTL, these therapies are designed to treat chronic wounds—particularly patients with anal fistulas secondary to Crohn’s disease—renal stenosis, and fatal neurological diseases such as amyotrophic lateral sclerosis (ALS) and multiple-system atrophy (MSA).

Dietz_Allan_B_12AP

Allan Dietz, Ph.D.

All of these trials are using autologous (derived from the patient’s own stem cells and delivered back to the patient) cell therapies. The stem cells originate from adipose (fat), bone marrow, or umbilical cord blood. Hence, rather than something synthetic and pharmaceutically manufactured, the stem cells act as “a drug from the patient, for the patient,” says Allan Dietz, Ph.D., biochemist and Director of HCTL. “We’re really driven by the fact that there are a lot of unmet patient needs out there, and lots of indications where [pharmaceutical] drugs have either continually failed or the whole patient need has been abandoned by the pharmaceutical industry. We need to come up with something else. So that’s the foundation we work off of, based in transfusion medicine.”

HCTL’s cancer vaccine platforms—currently focused on boosting the immune system against non-Hodgkin lymphoma and ovarian and brain cancers—are also showing promise in human trials. The vaccine process involves taking autologous monocytes from a patient’s blood and converting them into active, potent, mature dendritic cells. These cells “flip on a switch that really cranks up your immune system,” says Dr. Dietz. “We started this work on immune-based cancer therapies over fifteen years ago. I think the greatest change that’s occurred is that you can now affect the patient’s tumor by working on the patient—not the tumor. And I think it’s going to change how we treat cancer. It’s cheap, feasible, and extremely safe. It’s early, but we’re seeing very good evidence of improvement in cancer patients’ immune systems and evidence of long-term stable disease.”

The Human Cell Therapy Laboratory maximizes its efficiency by trying to identify broadly applicable platforms that have the most impact on the highest number of diseases. Another factor that amps up efficiency is its “one-stop shop” approach: The laboratory provides both the platforms and the research that goes into each one. It provides regulatory advice to physicians, helping to design the clinical trial and move things quickly through the U.S. Food and Drug Administration. It manufactures cells and, in some cases, helps monitor patient outcomes, performing some of the ancillary studies that happen during those trials.

Efficiency is of utmost importance because by the time patients enter a trial, they are in the eleventh hour of their disease or condition, having no other treatment options, which is why close, long-term collaborations between HCTL and Mayo physicians are paramount.

“We have really excellent, dedicated physicians who are not satisfied with what they can offer their patients,” says Dr. Dietz. “These are the men and women who are driven to provide something different for their patients. It makes us very efficient because we combine our expertise and develop the kind of teamwork that’s needed to move these cell therapies into the clinic as fast as possible. I have no way to prove it, but I think I have the best team at Mayo, period.

“We try and stay ahead of everybody by constantly improving on cell-based therapies. As our team collaborators move through phase I of trials, it becomes clearer to them how to modify these platforms for the next generation of trials. Then it comes back to our lab to work on those modifications to specialize a platform into something specific to those patient indications.”

HCTL-image-1024x200

Dr. Dietz likens his team’s work to providing Mayo physicians with a “toolbox.” And physicians who use these platform tools are beginning to combine them in innovative ways. In doing so, they’re bringing new options to the clinic. “We have one trial in which the measles virus—which is being used as an exciting technology here at the clinic—is being used to infect stem cells that home in on the tumor and deliver the measles virus to ovarian cancer,” says Dr. Dietz. “So you don’t get a measles virus/stem cell combination unless you have both tools in the toolbox.”

Meanwhile, HCTL continues to innovate cell matrix combinations, such as the recellularization of whole organs for transplant—with a goal of being the first to transplant a fully functional, recellularized liver in a human.

All of this begs the question: How soon will human cell therapies alter the practice of medicine as we know it?

“Cell-based therapies are already in the clinic now, with bone marrow transplant, for example. That’s still the foundation of our work,” say Dr. Dietz. “But I think we’re going to see these therapies creep into different parts of medicine at different rates, depending on how quickly we can demonstrate their usefulness. There will be places where it will be implemented relatively quickly, as with wound healing, because the cells seem to have a very unique and powerful capacity to heal wounds. I think in the next ten years, you’re going to be really stunned at some of the applications as cells find their place in therapy. I think it’s the next big phase of medicine.”

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Tags: Allan Dietz, Neurology, Oncology, Regenerative Medicine, Research, stem cells


Wed, Jul 15 · Leave a Comment

Repairing Mitochondrial Disease

By Center for Regenerative Medicine Center for Regenerative Medicine

A multidisciplinary team  has successfully  eliminated fatal mitochondrial DNA mutations in stem cells from patients with mitochondrial diseases. The study is published in the current issue of Nature as a collaboration between some of the top research institutions and Mayo Clinic's Center for Regenerative Medicine.

Mitochondrial diseases are a particular struggle for patients and their families as treatment options are limited, something made even more dire as many of those affected are children. Andre Terzic, M.D., Ph.D., Director of Mayo Clinic's Center for Regenerative Medicine, explains: "these are life threatening conditions where standard care is limited to alleviating  symptoms of disease. Our proof-of-concept study shows that functionally corrected stem cells can be generated from these patients, providing initial steps towards regenerative therapy for mitochondrial disease.”

Mitochondrial DNA defects impair the ability of patient's mitochondria, the body's cellular metabolic engine, to generate energy . Once the mitochondria begin to malfunction, energy production becomes insufficient to support normal functions, and the patient experiences a variety of debilitating symptoms particularly in tissues with high energy requirements.

Now, researchers at Oregon Health & Science University in collaboration with Salk Institute, Sanford Consortium for Regenerative Medicine, University of Oxford, Cincinnati Children’s Hospital Medical Center, and Mayo Clinic's Center for Regenerative Medicine have applied  methods to restore healthy mitochondria in cells derived from patients with mitochondrial disease. Through generation of pluripotent stem cells they were able to either select stem cells containing healthy mitochondria or to replace the dysfunctional mitochondria with healthy counterparts from a donor cell. “Restoration of mitochondrial function in stem cells from patients with mitochondrial disease is thus achievable” explains co-author Clifford Folmes, Ph.D.

This technique  restored  mitochondrial function in different forms of mitochondrial disease, including Leigh Syndrome and Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). Dr. Terzic concludes: "This is a transformative moment where deadly diseases are targeted and potential solutions are offered."

 

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Tags: Andre Terzic, Clifford Folmes, Mayo Clinic, mitochondrial disease, Oregon Health and Science University, Regenerative Medicine


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