1. Heart Disease

Adipose Stem Cells for Treatment of Heart Attack and Prevention of Heart Failure.

Keith March, M.D., Ph.D., Brian Johnstone, Ph.D., Peng-Sheng Chen, Ph.D.

Heart attacks and heart failure are major life-threatening complications of diabetes. Based on our prior findings that adipose (fat-derived) stem cells could protect leg tissue from injury due to poor blood flow, we wished to test the possibility that heart tissue would be protected in a similar way. We also have obtained data that the factors secreted by ASCs could protect nerves from injury due to low oxygen as well as other injurious factors that mimic degenerative conditions of nerves, and we hypothesized that this in turn could contribute to cardiac functional preservation. Indeed, we found that rats with heart attacks had less damage and more nerve sprouting following ASC injection. In a study of ASCs infused into normal pig coronary arteries, we also found that ASCs could self-aggregate, creating the possibility of microvascular obstructions and undesirable injury. We discovered that this problem could largely be avoided by the admixture of heparin and other selected agents with the ASC prior to infusion. This finding is potentially very important in directing future studies of ASC delivery into heart tissues.

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2. Diabetes

Diabetes: working towards a cure

Carmella Evans-Molina, M.D., Ph.D.

Nearly 24 million people in the United States are affected by diabetes. Type 2 diabetes is the most common form of diabetes. In type 2 diabetes, either the body does not produce enough insulin or the cells ignore the insulin. Insulin is necessary for the body to be able to use glucose for energy. When you eat food, the body breaks down all of the sugars and starches into glucose, which is the basic fuel for the cells in the body. Insulin takes the sugar from the blood into the cells. When glucose builds up in the blood, the body cannot make efficient use of its main source of fuel, and over time, high blood glucose levels may hurt your eyes, kidneys, nerves or heart.

Type 1 diabetes is usually diagnosed in children and young adults, and was previously known as juvenile diabetes. In type 1 diabetes, the immune system attacks the insulin-producing beta cells in the pancreas and destroys them. Insulin is a hormone that is needed to convert sugar (glucose), starches and other food into energy needed for daily life. A person who has type 1 diabetes must take insulin daily to live.

Dr. Evans-Molina and Dr. Kono, in collaboration with Dr. Keith March, have been performing the first transplantation studies using two adult stem cell types (from fat and blood vessels) in combination with pancreatic islets. They have already obtained early information suggesting that this approach can prolong beta cell (the insulin-secreting cell) survival following islet transplantation. This has the potential to provide an exciting new treatment option for patients with diabetes. Our hope is that one day a patient will receive an under the skin implant of these cells (Bio-Pump) which will be able to augment their insulin levels and reduce or eliminate the need for supplemental insulin injections.
Furthermore, this team has discovered that these fat-derived stem cells can actually block islet death in animals that are newly acquiring type 1 diabetes. They are planning experiments to help lay a foundation for clinical trials to treat children at the time of initial presentation with diabetes (or after onset in their brothers and sisters) in the hope of significantly forestalling the onset of disease. These findings may also have potential benefit for patients with type 2 diabetes.

"Targeting diabetic retinopathy with low molecular weight inhibitors".
Rajashekhar Gangaraju, Ph.D., and Matthias Clauss, Ph.D.
Over 80% of people who have had diabetes for 10 years will develop eye related complications. Current strategies for treating diabetic complications are ineffective in targeting these eye disorders which include; laser photocoagulation, VEGF (a cocktail that encourages repair), injections of steroids, and the removal of leaking blood, and a few more experimental procedures. Although some treatments are successful in slowing down or partially restoring vision loss, they do not cure diabetic retinopathy. New evidence indicates that diabetes may be an inflammatory disease. We hypothesize that endothelium (single layer of smooth, thin cells that lines the heart, blood vessels, lymphatics, and serous cavities) exposed to inflammation and high glucose, leads to a condition resulting in increased blood vessels with abnormal leakiness. In order to address this hypothesis we use a unique diabetic mouse model that over expresses TNF in endothelium. We have found that diabetes and inflammation strongly support each other for generating diabetic retinopathy. Importantly we have identified a low molecular weight signal transduction inhibitor which reduces diabetic retinopathy and can be applied in the eye without injection. It thus may be superior to anti-VEGF therapy (trade names: Lucentis, Macugen, Avastin), which needs to be injected. Most current treatments involve an injection into the eye. Have you ever had a loved one receive an eye injection? Imagine requiring an 80 an elderly great grandmother, who already has some mild dementia, to hold still while her head is placed in a vise and contraptions put on her eyelid to hold them open. Then, the only way she has to quiet the eye from moving is to try to stare at a spot on the wall. Quickly, a 2 inch needle is used to inject into the fragile back of the eye. The Grandmother can be terrified….

The potential for a new therapy offers new hope to millions. Many people elect not to receive treatment strictly because they cannot hold still long enough for the procedure, and because it usually takes multiple injections, with very little improvement. At present, this project is awaiting additional support to further improve the inhibitor

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3. Blindness

"Targeting diabetic retinopathy with low molecular weight inhibitors".

Rajashekhar Gangaraju, Ph.D., and Matthias Clauss, Ph.D.

Over 80% of people who have had diabetes for 10 years will develop eye related complications. Current strategies for treating diabetic complications are ineffective in targeting these eye disorders which include; laser photocoagulation, VEGF (a cocktail that encourages repair), injections of steroids, and the removal of leaking blood, and a few more experimental procedures. Although some treatments are successful in slowing down or partially restoring vision loss, they do not cure diabetic retinopathy. New evidence indicates that diabetes may be an inflammatory disease. We hypothesize that endothelium (single layer of smooth, thin cells that lines the heart, blood vessels, lymphatics, and serous cavities) exposed to inflammation and high glucose, leads to a condition resulting in increased blood vessels with abnormal leakiness. In order to address this hypothesis we use a unique diabetic mouse model that over expresses TNF in endothelium. We have found that diabetes and inflammation strongly support each other for generating diabetic retinopathy. Importantly we have identified a low molecular weight signal transduction inhibitor which reduces diabetic retinopathy and can be applied in the eye without injection. It thus may be superior to anti-VEGF therapy (trade names: Lucentis, Macugen, Avastin), which needs to be injected. Most current treatments involve an injection into the eye. Have you ever had a loved one receive an eye injection? Imagine requiring an 80 an elderly great grandmother, who already has some mild dementia, to hold still while her head is placed in a vise and contraptions put on her eyelid to hold them open. Then, the only way she has to quiet the eye from moving is to try to stare at a spot on the wall. Quickly, a 2 inch needle is used to inject into the fragile back of the eye. The Grandmother can be terrified…. The potential for a new therapy offers new hope to millions. Many people elect not to receive treatment strictly because they cannot hold still long enough for the procedure, and because it usually takes multiple injections, with very little improvement. At present, this project is awaiting additional support to further improve the inhibitor and test its application, as a safe and noninvasive therapeutic tool to treat diabetic retinopathy in patients

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4. COPD/LUNG DISEASE

Irina Petrache, M.D.

Emphysema as well as sleep-disordered breathing and sleep apnea are conditions associated with increased diabetes and insulin resistance (metabolic syndrome), as well as obesity, hypertension, and cardiovascular disease. In addition, the alteration in circulating endothelial progenitor cells found in respiratory disease, the metabolic syndrome and cardiovascular disease may reflect a common condition of endothelial dysfunction. Irina Petrache, M.D., and her team of investigators recently completed a study to determine if adult stem cells acquired from fat could help improve blood flow to the lungs, particularly those damaged by emphysema. In this study, mice were exposed to chronic cigarette smoke for up to 21 weeks. These "smoking mice" were then given injections of adipose (fat) derived stem cells. After injection of the cells, this study showed that the lungs were not only protected from typical damage, but that these cells even promoted repair of the lung tissue. These findings point the way to a new potential treatment option for COPD and emphysema patients; and may be helpful to diabetes in this context as well. As in the other studies, adipose (fat) stem cells used in this study are readily available and can be acquired in large amounts during liposuction.

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5. REGENERITIVE MEDICINE

A Laboratory Analysis of Endometrial Regenerative Cells (ERC).

Michael Murphy, M.D.

Dr. Murphy's team launched a new trial that evaluates a new source of stem cells; A Laboratory Analysis of Endometrial Regenerative Cells (ERC). This study collects menstrual blood. The goal is to develop a sterile laboratory technique for expanding ERCs from a single donor to reach a target population of 1 x108 cells with a normal karyotype. ERC appear to possess numerous advantages compared to other stem cell sources that make them attractive to further investigation. Firstly, the ease of collection of ERC allows for the creation of patient-specific cell banking (holding them back until needed). If the cells behave as expected, they may be expanded (multiplied) and may possess the ability to change into various tissues.

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6. Peripheral Vascular Disease

Michael Murphy, M.D.

More than 100,000 patients in the US each year undergo amputation due to advanced atherosclerotic vascular disease in the leg. Ten to fifteen million more with this disease have crippling pain that limits their walking. More than half of these patients have this disease as a complication of diabetes. There is accumulating evidence that this PAD may be effectively treated with stem cells that stimulate new blood vessel development.
Dr. Michael Murphy has completed the first Phase I trial of stem cells (derived from one's own bone marrow) that was FDA-approved in the USA to treat vascular disease in legs for patients who have been told their only hope is amputation. Thus far, only three patients of 32 treated have required amputation. The autologous bone marrow mononuclear cells "SAVE" study is now being extended to a Phase III randomized study between patients receiving cells or no cells, to compare outcomes directly. The study has received conditional FDA approval and will be conducted at 10 centers throughout the US, with the ICVBM being the lead center for the study. Duke University in North Carolina and the University of Alabama in Birmingham are among those participating. This study forms a key platform to move into treatments of heart disease; developing new therapies in legs allows testing safety in leg muscle before moving into heart muscle.

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7.Wound Healing

Keith March, M.D., Ph.D., Dmitry Traktuev, Ph.D.

Burns and wounds are often slow to heal due to poor blood supply in areas of poor circulation like the legs of diabetic patients, or such as those seen after radiation to treat cancers. We have identified that fat-derived stem cells can function along with endothelial cells to build blood vessel networks. Dmitry Traktuev would like to use this observation to build new skin-like materials from the vascular stem cells and skin cells, and then test this approach in mice and in pigs. ICVBM research demonstrating this concept in pigs for the first time was recently published in the leading journal of plastic and reconstructive surgery. This sets the stage

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8.ERECTILE DISFUNCTION

To be researched as funding becomes available.

Up to 50% of patients have erectile dysfunction after certain types of prostate surgery for cancer, and this ED does not respond to drugs like Viagra. There is significant evidence suggesting that fat-derived (vascular) stem cells could reverse this problem by enhancing nerve sprouting to the penis. We would like to attempt this concept as well, in collaboration with local Urology colleagues.

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9.Hemophilia Arthritis

To be researched as funding becomes available.

Fat-derived (vascular) stem cells may well also address certain types of arthritis, like rheumatoid arthritis. We would like to try this in initial animal studies; nd move into patients as soon as feasible, if supported by the studies. We also anticipate initiating clinical trials in the area of osteoarthritis, where substantial animal data has already been accumulated.

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