Critical Limb Threatening Ischemia (CLTI) is the most severe form of peripheral arterial disease caused by atherosclerotic occlusion of blood vessels to the lower extremities. It is often associated with excruciating pain and leads to the development of skin ulcers or gangrene.
The standard of care for CTLI is to improve blood flow to the leg with either a surgical bypass or angioplasty with stents to open the atherosclerotic blockages. Unfortunately, about 30 percent of patients with CLTI will not be candidates for a surgical bypass or angioplasty and amputation is the only treatment available to remove a painful or infected leg. In the United States. Amputations are the sixth costliest operation to the national health care system, with over 53,000 performed each year. This cost has driven interest in cell-based therapies for wound healing and restoring blood perfusion in critical limb ischemia patients.
Murphy conducted the first trial in the U.S. using a patient’s own bone marrow cells to prevent amputations. His pioneering work culminated in the MOBILE (MarrOwStim Treatment of LimB IschemIa in Subjects with Severe Peripheral ArteriaL DiseasE) trial—a randomized, placebo-controlled trial that assessed the ability of intra-muscular injection of a patient’s bone marrow cells to prevent amputation.
The MOBILE study demonstrated that cell therapy was safe, however there was not a significant difference in amputation rates at one-year between the cell treated and placebo groups. The MOBILE trial was uniquely designed to distribute patients with diabetes and a foot ulcer evenly between study groups so that additional analyses could assess these factors on outcomes.
Murphy’s group found that diabetes and presence of a foot ulcer had a negative effect on cell therapy and they surmised that any future trials would require a potentially more potent cell population as bone marrow progenitor cells from patients with advanced disease and age are impaired in their regenerative potential.
“My moonshot is to develop an effective strategy that incorporates a multi-modal approach to limb preservation in the diabetic patient with vascular disease,” said Murphy.
To get to the moon, Murphy has teamed up with Sashwati Roy, PhD, professor of surgery and Director of Clinical Research at the IU Health Comprehensive Wound Center. Roy has been focusing on diabetic wounds and has developed a unique wound dressing, an electroceutical pad, that transmits an electrical current into the soft tissue of the wound that disrupts the biofilm produced by invading bacteria. Once the biofilm is disrupted, antibiotics and other treatments will have a more profound effect in eradicating the bacteria and stimulating the wound to heal.
Murphy also has joined forces with Emily Hopewell, PhD, Director of Cell and Gene Therapy Manufacturing at IU School of Medicine, and Erik Woods, PhD of Ossium Health, Inc. Ossium Health has isolated a unique cell, a mesenchymal stromal cell (MSC) from the vertebral bodies of young, healthy organ donors. These vertebral body MSCs (VB-MSCs) have shown a significant effect in promoting muscle and blood vessel regeneration in a diabetic mouse model of CLTI, and Murphy and Hopewell are working on getting FDA approval to use VB-MSCs in the next generation of clinical trials.
Murphy and Roy are planning a program grant through the National Institutes of Health that will explore the potential synergy of intra-muscular injection (two doses) and application of Roy’s electroceutical dressing for foot wounds in reducing amputation rates in CLTI in a multi-center clinical trial.
Murphy explained that creation of the Indiana Center for Regenerative Medicine and Engineering at IU School of Medicine has helped to advance his research. The Indiana Center for Regenerative Medicine and Engineering under Chandan K. Sen, PhD, the J. Stanley Battersby Chair and Professor of Surgery, Director of the Indiana Center for Regenerative Medicine and Engineering who is a renowned leader in regenerative medicine, has added many benefits to researchers by aiding his expertise in clinical trial design, preclinical animal models, funding mechanisms, and as a collaborator.
As an educational institute, Murphy’s lab is also creating future scientists and surgeons. Murphy hosts both medical students and residents in the laboratory under the division of vascular surgery within a two-year research fellowship.
“My laboratory, as well as some of my colleagues' laboratories, offers a two-year fellowship. During that time, residents and fellows could earn a master's degree, which I highly recommend, in biostatistics, immunology or clinical research,” said Murphy.
Murphy’s work, along with the Indiana Center for Regenerative Medicine and Engineering and IU School of Medicine, have gained prestige as leaders in their prospective fields. Murphy hopes to help Hoosiers who have been told that the only option for their condition is amputation and change their outlook and options.
The views expressed in this content represent the perspective and opinions of the author and may or may not represent the position of Indiana University School of Medicine.
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