Newswise University Hospitals Case Medical Center clinical researchers have launched an innovative clinical trial, unique in its design, which will evaluate the ability of a patients own stem cells to prevent leg amputations in end stage peripheral arterial disease (PAD).

Led by Vik Kashyap, MD, Division Chief, Vascular Surgery at University Hospitals Case Medical Centers Harrington Heart & Vascular Institute and Professor of Surgery at Case Western Reserve University School of Medicine, the clinical trial is designed to improve blood flow in legs with blocked arteries by attempting to treat diseased blood vessels. Peripheral arterial disease (PAD) is a common yet serious disease that occurs when extra cholesterol and fat circulating in the blood collects on the walls of the arteries that supply blood to the limbs.

Due to the location and extent of the blockages in certain individuals, standard treatments such as surgical bypass (insertion of a vein or synthetic graft to redirect blood flow around the blockage) and angioplasty (insertion of a balloon through the artery to open the blockage) will not improve blood flow to the leg, and amputation is the only alternative.

For patients with critical limb ischemia (CLI) revascularization procedures such as surgical bypass or percutaneous angioplasty/stenting are currently the only option to restore perfusion and maintain limb viability.

For CLI patients who are non-candidates for revascularization, amputation is often needed. It is estimated that over 160,000 amputations are performed in the United States each year.

The number of CLI patients who will not be candidates for revascularization continues to rise as the population ages and the incidence of diabetes and other vascular risk factors increase. For CLI patients who are considered unreconstructable, the amputation and mortality rates at six months approach 40% and 20%, respectively. Furthermore, nearly 30% of patients who undergo below-knee amputation will fail rehabilitation and require chronic institutional care or professional assistance at home.

The trial sponsor, Biomet Biologics (Warsaw, IN), recently completed a Phase I study of 30 subjects to evaluate the safety of autologous concentrated bone marrow aspirate for critical limb ischemia. The results of this study were used to advance the companys MarrowStim concentration technology into the FDA-approved, pivotal IDE trial described here. Overall, the trial will enroll 152 subjects at up to 20 investigational sites.

This trial offers an opportunity to save a patients leg when there are no remaining options to improve blood supply, said Dr. Kashyap. We are pleased to add this capability at UH and provide hope for patients facing the risk of limb loss.

Subjects will be randomized to receive either the investigational treatment involving the MarrowStim P.A.D. Kit (75% chance), or a placebo control involving a sham procedure (25% chance). The trials primary end point of time to treatment failure, defined as major amputation or death, will be evaluated over a oneyear followup period. Secondary end points, including rest pain, perfusion measurements, quality of life, and safety, will also be evaluated for one year.

Only those patients meeting the pre-defined approved inclusion/exclusion criteria are eligible for this clinical trial. To learn more about this clinical trial and to see the qualifications for participation, visit http://www.clinicaltrialspotlight.com or call toll-free at 877-788-3972.

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University Hospitals Case Medical Center Launches Novel Clinical Trial Using Stem Cells to Prevent Amputation

June 19, 2013 A new study examining the brains of fruit flies reveals a novel stem cell mechanism that may help explain how neurons form in humans. A paper on the study by researchers at the University of Oregon appeared in the online version of the journal Nature in advance of the June 27 publication date.

"The question we confronted was 'How does a single kind of stem cell, like a neural stem cell, make all different kinds of neurons?'" said Chris Doe, a biology professor and co-author on the paper "Combinatorial temporal patterning in progenitors expands neural diversity."

Researchers have known for some time that stem cells are capable of producing new cells, but the new study shows how a select group of stem cells can create progenitors that then generate numerous subtypes of cells.

"Instead of just making 100 copies of the same neuron to expand the pool, these progenitors make a whole bunch of different neurons in a particular way, a sequence," Doe said. "Not only are you bulking up the numbers but you're creating more neural diversity."

The study, funded by the Howard Hughes Medical Institute and the NIH National Institute of Child Health and Human Development, builds on previous research from the Doe Lab published in 2008. That study identified a special set of stem cells that generated neural progenitors. These so-called intermediate neural progenitors (INPs) were shown to blow up into dozens of new cells. The research accounted for the number of cells generated, but did not explain the diversity of new cells.

"While it's been known that individual neural stem cells or progenitors could change over time to make different types of neurons and other types of cells in the nervous system, the full extent of this temporal patterning had not been described for large neural stem cell lineages, which contain several different kinds of neural progenitors," said lead author Omar Bayraktar, a doctoral student in developmental neurobiology who recently defended his dissertation.

The cell types in the study, Bayraktar said, have comparable analogs in the developing human brain and the research has potential applications for human biologists seeking to understand how neurons form.

The Nature paper appears alongside another study on neural diversity by researchers from New York University. Together the two papers provide new insight into the processes involved in producing the wide range of nerve cells found in the brains of flies.

For their study, Bayraktar and Doe zeroed in on the stem cells in drosophila (fruit flies) known as type II neuroblasts. The neuroblasts, which had previously been shown to generate INPs, were shown in this study to be responsible for a more complex patterning of cells. The INPs were shown to sequentially generate distinct neural subtypes. The research accounted for additional neural diversity by revealing a second axis in the mechanism. Instead of making 100 neurons, as had been previously thought, a stem cell may be responsible for generating some 400 or 500 neurons.

The study concludes that neuroblasts and INP patterning act together to generate increased neural diversity within the central complex of the fruit fly and that progenitors in the human cerebral cortex may use similar mechanisms to increase neural diversity in the human brain. One long-term application of the research may be to eventually pinpoint stem cell treatments to target specific diseases and disorders.

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How neural stem cells create new and varied neurons

June 17, 2013 A team from the New York Stem Cell Foundation (NYSCF) Research Institute and the Naomi Berrie Diabetes Center of Columbia University has generated patient-specific beta cells, or insulin-producing cells, that accurately reflect the features of maturity-onset diabetes of the young (MODY).

The researchers used skin cells of MODY patients to produce induced pluripotent stem (iPS) cells, from which they then made beta cells. Transplanted into a mouse, the stem cell-derived beta cells secreted insulin in a manner similar to that of the beta cells of MODY patients. Repair of the gene mutation restored insulin secretion to levels seen in cells obtained from healthy subjects. The findings were reported today in the Journal of Clinical Investigation.

Previous studies have demonstrated the ability of human embryonic stem cells and iPS cells to become beta cells that secrete insulin in response to glucose or other molecules. But the question remained as to whether stem cell-derived beta cells could accurately model genetic forms of diabetes and be used to develop and test potential therapies.

"We focused on MODY, a form of diabetes that affects approximately one in 10,000 people. While patients and other models have yielded important clinical insights into this disease, we were particularly interested in its molecular aspects -- how specific genes can affect responses to glucose by the beta cell," said co-senior author Dieter Egli, PhD, Senior Research Fellow at NYSCF, who was named a NYSCF-Robertson Stem Cell Investigator in 2012.

MODY is a genetically inherited form of diabetes. The most common form of MODY, type 2, results in a loss-of-function mutation in one copy of the gene that codes for the sugar-processing enzyme glucokinase (GCK). With type 2 MODY, higher glucose levels are required for GCK to metabolize glucose, leading to chronic, mildly elevated blood sugar levels and increased risk of vascular complications.

MODY patients are frequently misdiagnosed with type 1 or 2 diabetes. Proper diagnosis can not only change the patient's course of treatment but affect family members, who were previously unaware that they, too, might have this genetic disorder.

NYSCF scientists took skin cells from two Berrie Center type 2 MODY patients and "reprogrammed" -- or reverted -- them to an embryonic-like state to become iPS cells. To examine the effect of the GCK genetic mutation, they also created two genetically manipulated iPS cell lines for comparison: one fully functional (two correct copies of the GCK gene) and one with complete loss of function (two faulty copies of the GCK gene). They then generated beta cell precursors from the fully functional and loss-of-function iPS cell lines and transplanted the cells for further maturation into immune-compromised mice.

"Our ability to create insulin-producing cells from skin cells, and then to manipulate the GCK gene in these cells using recently developed molecular methods, made it possible to definitively test several critical aspects of the utility of stem cells for the study of human disease," said Haiqing Hua, PhD, lead author on the paper, a postdoctoral fellow in the Division of Molecular Genetics, Department of Pediatrics and Naomi Berrie Diabetes Center at Columbia University and the New York Stem Cell Foundation Research Institute.

When given a glucose tolerance test three months later, mice with MODY beta cells had decreased sensitivity to glucose but a normal response to other molecules that stimulate insulin secretion. This is the hallmark of MODY. Mice with two faulty copies of the GCK gene secreted no additional insulin in response to glucose. When the researchers repaired the GCK mutation using molecular techniques, cells with two restored copies of GCK responded normally to the glucose stress test. Unlike other reported techniques, the researchers' approach efficiently repaired the GCK mutation without introducing any potentially harmful additional DNA.

"Generation of patient-derived beta cells with gene correction could ultimately prove to be a useful cell-replacement therapy by restoring patients' ability to regulate their own glucose. This result is truly exciting," said Susan L. Solomon, Chief Executive Officer of The New York Stem Cell Foundation.

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Researchers demonstrate use of stem cells to analyze causes, treatment of diabetes