Newsletter - January 2013

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Stem Cell Therapy to Prevent Type 1 Diabetes

Maria Criag, paediatric endocrinologist

Maria Craig, paediatric endocrinologist at the Children's Hospital at Westmead in Sydney, Australia

Diabetes is one of the most common chronic diseases affecting humans - the WHO estimates that around 350 million people have diabetes globally. Approximately 10% have type 1 diabetes - a disease that is often diagnosed during childhood or adolescence. In type 1 diabetes, the pancreas does not make enough of the hormone insulin that keeps blood sugar levels in the normal range. People with type 1 diabetes must frequently take finger prick tests of their blood sugar level and receive multiple daily injections of insulin or wear an implanted insulin pump. While the cause of type 1 diabetes is not fully understood, the immune system plays a major role in causing the damage to the insulin producing cells in the pancreas. There is currently no prevention or cure for type 1 diabetes - but stem cells may be a promising new approach.

The role of stem cells

Stem cells are basic cells that have the capacity to multiply - either into specialized cells or to regenerate themselves. Cord blood stem cells are particularly unique because they not only have the capacity to develop into other cell types, but are also immune tolerant - that is they are less likely to provoke an immune response. They also contain greater numbers of regulatory T cells - a particular type of white blood cell that helps to keep the immune system in balance. This makes cord blood stem cells potentially useful for treating diseases where the immune system has 'gone astray' - such as type 1 diabetes.

Can stem cells prevent or cure type 1 diabetes?

To date no studies have shown that stem cells can prevent type 1 diabetes in humans, but cord blood has been able to prevent and also cure type 1 diabetes in mice.

The first study that used cord blood to treat children with type 1 diabetes was performed by Dr. Michael Haller and colleagues at the University of Florida. They gave children their own cord blood stem cells (that had been stored at birth) within 6 months after the children had been diagnosed with type 1 diabetes. That study succeeded in increasing the number of regulatory T cells in the children's blood and demonstrated that the cord blood infusions were safe. But the study failed to cure the children of diabetes, because the increase in regulatory T cells only lasted for 6 to 9 months. It may be that once type 1 diabetes has been diagnosed, too many of the insulin producing cells in the pancreas have already been destroyed, and it is too late for the cord blood stem cells to rescue them. Perhaps cord blood stem cells could defeat diabetes if they were given early enough to protect the insulin producing cells?

Another important study on children was performed by Dr. Piotr Trzonkowski and colleagues at the Medical University of Gdansk in Poland. They harvested regulatory T cells from children who had been diagnosed with diabetes, multiplied the cell number by culturing them in the laboratory, and returned the cells to the children. This study of high dose of regulatory T cells showed a benefit compared to a control group, because the children who received the infusion continued to make insulin.

Cord blood from donors has also been used to treat diabetics as part of Stem Cell Educator therapy. This work was conducted by Dr. Yong Zhao and colleagues from both the University of Illinois and the General Hospital of Jinan Military Command in China. The study treated adults who had been diagnosed with type 1 diabetes for more than a year. The white blood cells of the patients were passed through filters holding cord blood stem cells that came from donors in a public cord blood bank. After mingling in the filter for 2 to 3 hours, the "re-educated" immune system cells were returned to the patients. Afterwards, the patients exhibited improved diabetes control, needing less insulin and making more regulatory T cells.

Testing cord blood as prevention of type 1 diabetes

In Australia, we are conducting a pilot trial called "Cord blood Reinfusion in Diabetes" (CoRD) that seeks to prevent diabetes with cord blood. The study is supported by the family cord blood bank Cell Care. To be eligible, children must: 1. have their own cord blood in storage, 2. have a relative with type 1 diabetes, and 3. have antibodies which signal that their immune system is already attacking their insulin producing cells in the pancreas. Study participants will have their own cord blood reinfused in Children's Hospital at Westmead. The hope is that a reinfusion of their cord blood stem cells will reset the immune systems of these children, before the auto-immune damage leads to a diagnosis of type 1 diabetes.

This research is one of a number of potential avenues in which scientists hope that stem cells will help patients to preserve their insulin producing cells and thereby be cured of diabetes.

Associate Professor Maria Craig MBBS PhD FRACP MMed(ClinEpid) is a paediatric endocrinologist at the Children's Hospital at Westmead, in Sydney Australia. Her major research interest is childhood diabetes. She has recently launched the world's first trial using a child's own cord blood to prevent type 1 diabetes.

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JDRF

JDRF Walk to Cure Diabetes

JDRF is the leading global organization focused on type 1 diabetes (T1D) research. T1D is an autoimmune disease that strikes both children and adults. Unrelated to diet or lifestyle, T1D causes lifelong dependence on injected or pumped insulin and carries the constant danger of life-threatening complications. It requires intensive, 24/7 management. Nobody can predict who will get T1D or prevent it. At present, there is no cure.

Parents founded JDRF in 1970 to help their children with T1D by funding research to find a cure for this poorly understood and often deadly disease. Driven by passionate, grassroots volunteers connected to children, adolescents, and adults with this disease, JDRF has grown to become the largest non-governmental funder of T1D research. JDRF has awarded more than $1.7 billion to diabetes research since our founding.

Our goal is simple: we want to create a world without T1D. JDRF is the only global organization with a strategic plan to bring a continuous stream of life-changing therapies, and ultimately, a cure for T1D. This plan is aggressive, forward-looking, and realistic:

We want to substantially lessen the daily burdens and dangers of life with T1D
Then, remove T1D completely from people's lives, returning them to normal health
Finally, eliminate the threat of T1D from every life in the future

We are uniquely positioned to carry out this plan and create a future without T1D.

We drive advances across every stage of the research pipeline from earliest research to human trials to new product launch.
We partner with academia, foundations, industry, governments, regulators, and insurers as the center of a global, coordinated effort.
We have a dedicated team of 24 PhD and MD scientists with experience translating research in academia and industry and measuring progress toward our strategic goals.
We are highly efficient - more than 80% of what we spend goes directly to research and research-related education. Forbes recently named JDRF one of its five all-star charities in fundraising efficiency.

JDRF has no endowment. Every dollar we spend every year to execute our plan is secured through the annual support of our donors. Clinical trials and clinical development are increasingly expensive. Basic research in mice is costly, but proof of effectiveness, safety, and market preparation in humans is even more so. Today, JDRF has $530 million at work around the world advancing our goals. But it is not enough.

As successful as we have been to date, the gap between where we are now and delivering life-changing therapies is large. We need to increase the number of dollars we deploy annually so that we can take full advantage of the exciting opportunities we see in T1D research. The incidence of T1D is rising. As many as 3 million Americans may have T1D, and 30,000 more are diagnosed each year. The healthcare costs are staggering. Type 1 diabetes costs $14.9 billion in the United States each year. We can't wait to fund the best strategies globally to achieve our vision of a world without T1D.

For more information or to make a donation to JDRF, please visit www.jdrf.org.

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Measuring Stem Cells in Cord Blood: The Value of the CFU Assay

Stephen J. Szilvassy, PhD

Stephen J. Szilvassy, PhD, Associate Director of Hematopoietic Products Research & Development, STEMCELL Technologies Inc. Vancouver, Canada

Imagine this scenario. I have a closed box. It contains something very precious! It may change - strike that - it may save your child's life! I will take care of the box for as long as you want, for a fee. You just tell me when you need it. If you decide later that you don't want me to store the box any longer then you can walk away at any time. You might think "this sounds pretty great! But how do I really know that what I am paying for will do what you say? It sure would be better if I had something to give me more confidence". For all its wonderful prospects and demonstrated ability to save the lives of people with blood cancers and other diseases of the bone marrow, this is essentially the conundrum of private cord blood (CB) banking.

Many parents elect to have their child's umbilical CB frozen and stored as a future source of stem cells. These rare but highly potent cells can be given to the child they came from or to a close family member, as a treatment for certain cancers, blood diseases, and developmental disorders. Parents undertake this decision in most cases, however, without really knowing if the CB cells are healthy and have the ability to do what they hope they will do when the time comes. But there are several simple tests that can measure the number and viability of stem cells in a CB unit when it is banked. When these tests indicate that there are sufficient numbers of stem cells in their child's CB unit and these cells are healthy, parents should have greater confidence in the quality of their child's CB and the soundness of their investment.

Many CB banks perform a test called the "CD34 assay". CD34 is a protein that is expressed on the surface of most stem cells. The CD34 protein can thus serve as a "marker" for counting stem cells in a CB sample. The more cells that express CD34, the more stem cells are probably present. Probably. While CD34 expression is a useful indirect indicator of stem cell numbers, only about 10-20% of CD34 positive cells can actually proliferate and produce new blood cells. This means that measuring CD34 cells alone can over-estimate the actual number of stem cells in a sample. Furthermore, analysis of CD34 expression alone does not necessarily indicate that the CD34-positive cells are healthy. Stem cells can be damaged by the procedures used in collecting and processing the CB unit.

The "colony-forming unit" or "CFU" assay is another test that can be used to measure not only the number but also the quality of stem cells in CB. In this test, a very small sample of CB cells are grown in a culture dish containing growth factors. In these cultures primitive stem cells divide. One stem cell makes two daughter cells, which then make four, eight, sixteen and so on until 1-2 weeks later the dish contains many colonies comprised of hundreds or thousands of cells, each derived from a stem cell that was present in the original sample. These colonies can be counted to indicate the number of CFUs or stem cells that were present in the original CB unit. Each colony equates to one stem cell and as with CD34-positive cells, it is better to have more.

You might ask, "Which test is better for measuring CB unit quality; the CD34 assay or the CFU assay?" The answer lies in what these tests measure. The CD34 assay counts cells according to a physical property, CD34 expression, but does not measure cell function. The primary advantage of the CD34 assay is that it is quick, giving an answer in only a few hours. The CFU assay takes 1-2 weeks to perform, but its important advantage is that it measures cell function, the ability of a stem cell to multiply and produce mature blood cells. Several clinical studies have been conducted to determine which test better predicts whether and how quickly a patient's bone marrow will be replenished after stem cell transplantation. When compared head to head, most such studies have shown that the number of CFUs in a CB unit is the single best indicator of successful engraftment and overall survival following CB transplantation.

So let's revisit the box. The wonders of CB stem cell transplantation contained inside it have transformed the practice of medicine. Parents and physicians can use two common tests to determine the quality of their CB stem cells. When the stakes are this high, wouldn't you want to use the test that gives you the best idea of what's inside your box?

For more information on the CFU assay and how it is used to measure stem cells in cord blood, please visit stemcell.com for the following resources: Potency Assays for Measuring the Engraftment Potential of Hematopoietic Stem and Progenitor Cells and The CFC Assay For Cord Blood.

Stephen J. Szilvassy, PhD, is Associate Director of Hematopoietic Products Research & Development at STEMCELL Technologies Inc., a leading company in the field of stem cells and regenerative medicine headquartered in Vancouver, Canada. He leads a group of researchers developing tools for scientists and clinicians working in the area of bone marrow and cord blood stem cell development. Dr. Szilvassy has over 27 years of experience in the field of hematopoietic stem cell biology, including 7 years as tenured Associate Professor of Medicine at the University of Kentucky Lucille P. Markey Cancer Center. He has led teams to develop new drugs for the treatment of malignant and non-malignant hematological disorders and solid tumors at several biotechnology companies. Prior to joining STEMCELL, Dr. Szilvassy was Principal Scientist in Hematology/Oncology Research at Amgen, the world's largest biotechnology company, from 2003-2011. He has authored over 40 peer-reviewed research and review articles, and book chapters on the subject of blood stem cells. He is a long-standing member of the American Society of Hematology, the International Society of Experimental Hematology, and the International Society for Stem Cell Research, and has served as an editorial board member and reviewer for the scientific journals published by these organizations.