Angiogenesis: Development of a Novel Cell Separation Platform for Processing Bone Marrow and its Verification in a Prospective Randomized Clinical Trial of Critical Limb Ischemia
Tools and Technologies I
The use of stem cells derived from adult sources, specifically bone marrow, presents new opportunities in many disease areas with critical unmet medical needs. This application focuses on two major points. The first is the development of a practical and cost-effective device for preparing stem cells. The second is the conduct of a ground-breaking clinical trial using this tool to demonstrate its utility in critical limb ischemia, for which no surgical procedure or drug is currently available. Ischemia develops in the lower extremities when arteries become obstructed and blood supply is reduced. To underline the importance of this work, more patients die of vascular disease than the aggregate of all other diseases in the United States annually. Stem cell therapy is being advanced as a form of treatment for injured heart tissue, brain tissue, and skeletal muscle injured by ischemia. Success will represent the first real advance since risk factor modification and interventional procedures in the treatment of these three common manifestations of vascular disease: heart attack, stroke, and severe limb ischemia. Each of these territories have unique challenges; refinement of stem cell therapies are easy to explore in the ischemic muscle and other tissues of the leg, where disease is common and a better solution to tradition therapy is sorely needed. Diabetes mellitus and peripheral vascular disease are two of the major causes for non-traumatic amputation in the United States. Approximately 85,000 lower limb amputations are performed in diabetics in the United States yearly, with an additional 7,000 in non-diabetics with peripheral vascular disease. The U.S. is the 3rd leading country with Diabetes Mellitus (DM) in the world: 18 million people have diabetes in the U.S. and this number is expected to be double by the year 2030. Vascular bypass (surgical or interventional) fail at rates in excess of 50% @ 5 years. At least a third fails by 2 years. Revision procedures are even more costly, with even worst outcomes. Survival after major limb amputation is diminished. The cost of re-vascularization, rehabilitation, or post-amputation nursing home care is in the $100 billion range annually in the USA alone. Angiogenesis is an extremely low cost and low risk alternative that uses the body’s own cells to generate new vascularity to bypass occluded vessels. In conclusion, this research has two major objectives. The first is to focus engineering effort toward improving a medical device for practical and rapid processing of stem cells from bone marrow. It is anticipated with this achieved, this device will have applications is many areas of medicine. The second objective is to determine if systematic injection of stem cells will produce growth of new arterial vessels and improve the prognosis of patients with lower extremity ischemia who face pain, amputation, disability, and tremendous medical expenses.
Statement of Benefit to California:
California is the largest state in the union and one of the most progressive. The state is often considered a bellwether for economic and social issues for other states. The California state economy ranks with the largest countries in the world. It is fair to say that California experiences the good and bad extremes of contemporary living. The proposed research has two major goals. The first is to focus engineering effort toward improving a medical device for practical and rapid processing of stem cells from bone marrow. It is anticipated with this achieved, this device will have applications is many areas of medicine. The second objective is to determine if systematic injection of stem cells will produce growth of new arterial vessels and improve the prognosis of patients with lower extremity ischemia who face pain, amputation, disability, and tremendous medical expenses. California will benefit from the products of this research in two major ways. First, the state will be the home base for the development and manufacturing of a medical device that has the potential of saving countless lives across many disciplines in medicine. The second benefit is much more tangible. If obstruction of lower extremity arteries can be improved with stem cell injection the benefits to the citizens of California will be enormous. To put this in perspective, the cost of treating atherosclerosis with current methodologies will increase in California in the years ahead. The US Census reports that the United States population, including California is aging rapidly. The “baby-boomers” are now entering the system and predicted to consume significant resources. Traditional therapy for atherosclerosis, including distal chronic limb ischemia is especially costly and fraught with limitations. Once risk factor modification fails, therapies include morbid surgeries and costly endovascular procedures. These techniques have limited long-term patency. Patients are often subjected to redo procedures and/or amputations. Diabetes mellitus and peripheral vascular disease are two of the major causes for non-traumatic amputation in California. Nationally, 85,000 lower limb amputations are performed in diabetics yearly, with an additional 7,000 in non-diabetics with peripheral vascular disease. The U.S. is the 3rd leading country with Diabetes Mellitus (DM) in the world: 18 million people have diabetes in the U.S. and this number is expected to be double by the year 2030. In effect, cell therapies such as the one being investigated in this proposal apply the body’s own ability to generate vessels in an ischemic bed where the lack of blood flow itself significantly limits the healing process. It is cost effective and safe. This project tests the hypothesis that traditional interventions can be replaced or significantly delayed using this approach. The savings to the California health care system would be in the billions.
The first aim of this proposal is to improve a medical device to give rapid and efficient isolation of stem cells from bone marrow. The second aim of the proposal is to conduct a clinical trial using this improved device to determine if injection of bone marrow derived stem cells could benefit patients with severe limb ischemia. While acknowledging the potential impact of the proposed research and the qualifications of the Principal Investigator (PI) and the research team, the reviewers’ enthusiasm for the proposal was markedly reduced in that most of the proposed research was to conduct a clinical trial. Clinical research is outside of the scope of the RFA. The reviewers commented that the impact of the proposed research was potentially high. Isolation of pure populations and good quantities of hematopoietic stem cells is a challenging process. Developing technology that can speed the use of these cells in the clinic is a worthy goal. Reviewers also acknowledged that an efficacious therapy for limb ischemia would be important. One reviewer commented that the use of stem cells obtained from adult tissues and in particular bone marrow is one of the most promising areas in which stem cells can a have immediate application. The reviewers were of mixed opinions on the feasibility of the first aim - to improve the design of the device. One reviewer commented that it was rational and feasible. The investigators propose to improve the device in order to remove more red cells and neutrophils. Proof of concept of the original device has been done using cord blood and there are defined milestones. The other reviewers felt that the applicant does not clearly delineate the limitations of the device or precisely how the quality of the purified cells will be improved. The reviewers also had concerns with the proposed clinical trial. Their main concern was that a clinical study was outside of the scope of this RFA. In addition, they noted numerous problems with this study design. They noted that the primary endpoint was very vague and were unclear if it could be objectively assessed. They were unclear on the randomization strategy and the feasibility of adequate patient enrollment in the two year time frame given the inclusion/exclusion criteria as well as uncertainties about the effect of other interventions on patient eligibility. Overall, the reviewers found the clinical trial description presented in this proposal to be too vague and suggested that the PI needs more input from the clinical team. The PI has strong background in devices and his/her co-investigators are engineers. The clinical investigators have clinical research trial experience. Reviewers commented that most of the budget was to support the clinical studies and therefore was inappropriate,