By Nissim Mashiach
New approaches to treating diabetic foot ulcers (DFUs) and venous leg ulcers (VLUs) are sorely needed by the medical community. A review in the August 2014 issue of Advances in Therapy reports that the development of new treatments for DFUs has stalled over the past two decades, with the number of cases of foot ulcerations and amputations remaining constant during this period of time. According to lead author A. Veves, the standard of care for DFUs—including debridement, pressure offloading, infection management and revascularization—is the same as 20 years ago, and there is no particular standout among the three treatments for DFUs currently approved by the U.S. Food and Drug Administration is better than the others.
So in what directions will innovation come from? A slew of future potential therapies exist; as recently highlighted by V. Hackethal in a Medscape article, these might include stem cell-based therapies, topical neuropeptides, delivery of gene-encoding growth factors via viral vectors, and cytokine inhibition. What promise does each area hold?
A large and growing literature exists on the promise of stem cells in wound healing. Writing in Critical Reviews in Biomedical Engineering in 2009, M. Chen et al. reviewed these approaches, and suggested the availability of adult stem cells and induced pluripotent stem cells from the patient provide opportunities for eventually generating skin without the risk of immune rejection. Although it is well-known that during the inflammatory phase of wound healing, blood-borne immunocompetent cells invade the wound area, evidence cited by the authors suggests that bone marrow-derived stem cells are also recruited into the wound site.
The second approach, topical neuropeptides, is also showing promise in wound healing. For example, in a 2013 paper in Angiogenesis, K. Albrecht-Schgoer et al. conclude that topical secretoneurin gene therapy has the potential to accelerate the healing of diabetic wounds. Secretoneurin, an angiogenic neuropeptide, has been shown to improve tissue perfusion in different animal models by increasing the amount of vessels in affected areas. The study found secretoneurin significantly accelerated wound closure in mice and immunohistochemistry revealed higher capillary and arteriole density in the wounded area compared to control mice.
Promising work has also been ongoing in the area of gene transfer via viral vectors for years. In 2007, for example, a group led by A. Badillo reported in Journal of Surgical Research the positive effects of lentiviral-mediated transfection of stromal-derived growth factor-1alpha (SDGF-1α) in diabetic mice showing notable improvements in wound healing with complete epithelialization after two weeks.
As for inhibition of pro-inflammatory cytokines, one approach showing promise is transcutaneous electrical nerve stimulation (TENS). Writing in Inflammation earlier this year, S Gürgen et al., reporting on a study involving 48 rats, found that distinctive decreases of pro-inflammatory cytokines observed in the dermis in the TENS group suggest that TENS can shorten the wound healing process by inhibiting the inflammation phase.
A separate but equally interesting approach involves the treatment of DFUs and VLUs with a mixture of white blood cells including monocytes/macrophages, neutrophils and lymphocytes obtained from young healthy donor blood. If the white blood cells are properly treated, the mixture can replenish the imbalanced inflammatory environment in the non-healing wound with functionally active immune cells that release the necessary growth factors and are capable of phagocytosis of bacteria and dead cells in the wound bed. By recreating the natural environment for wound healing, the appropriate cell activities and factor secretions are maintained as required during wound healing.
More than 5,000 patients have been treated to date using this method, which is approved in Israel. An Israeli clinical trial harnessing this approach has shown that after only approximately three injections right into the wound bed, there was a 70.9 percent healing rate of chronic wounds in VLUs and DFUs, with an average time to close of 12.1 weeks. Patients included in this trial were some of the worst cases; it included those with hard-to-heal ulcers with infections, reduced blood flow and history of amputations. Among the subjects of the trial was a 58-year-old male with a DFU whose wound was closed after six weeks and two injections; a 53-year-old male with a DFU that was completely closed following two injections a month apart; and a 61-year-old male with a DFU whose wound was closed following a single treatment. Now this treatment is currently in U.S. clinical trials. Two separate Phase 3 clinical trials will evaluate approximately 500 patients with VLUs and DFUs. The DFU study will be completed by the second half 2015, and the VLU study will be completed by the second half of 2016. If results are positive, we could see this treatment available in the United States in the next few years.
DFUs and VLUs are expensive problems that can seriously affect the quality of life of diabetes patients. The five approaches highlighted above might offer physicians and their patients a new route to advanced wound care, particularly for the most difficult-to-treat patients.
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Nissim Mashiach is president and CEO of Macrocure Ltd., a clinical-stage biotechnology company focused on developing a novel therapeutic platform to address chronic and hard-to-heal wounds. Macrocure’s lead product candidate, CureXcell, is a unique combination of living human white blood cells that have been activated to facilitate the healing process and stimulate wound closure.
(Photo by By Intermedichbo via Wikimedia Commons)
