Project: Development of Carbon Monoxide-Releasing Molecules for the Treatment of Non-Healing Wounds

This project aims to develop a new class of drugs, Carbon Monoxide Releasing Molecules (CO-RMs), for the treatment of chronic wounds (CW). CW are a major source of morbidity and impact heavily on healthcare resources. CO-RMs are proposed based on the rationale that their promising pharmacological actions are applicable to the treatment of CW. _x000D_The disruption of skin and underlying tissue results in wounds in need of repair. Wound healing consists of three overlapping phases -inflammation, proliferation, tissue regeneration- involving various cell types that coordinate tissue repair (Schreml et al., 2009). Acute wounds will heal quickly in healthy people; however, the healing process can be compromised giving rise to CW. These occur mostly on the legs or feet of patients with immobilizing disorders, impaired circulation or diabetes (Sen et al., 2009). Patients suffer pain and longer hospitalization with significant morbidity and economic impact for the healthcare system. _x000D_The prevalence of wounds and treatment costs in major European countries expose dramatic trends (Posnett et al., 2009). In the population aged over 65 between 490,000-1,3 million people suffer of leg ulcers, costing approximately €6,5 billion. In diabetic patients (20,2 million in 2008) about 1,0-1,4 million suffer of foot ulcers with an annual cost of €4-6 billion. CW also affect 6,5 million patients in the USA, costing indicatively US$25 billion (Sen et al., 2009). Since the aging population and diabetes will rise substantially in the next decades, it is fair to say that CW will become a larger burden on future healthcare costs._x000D_Treatments for CW rely more on physical wound care than drugs (Fonder et al., 2008). Healing is aided by dressings that retain moisture and, as bacterial infection delays healing, topical or systemic antibiotics are used. For example, silver-based dressings are applied topically for their broad toxicity to microbes. However, a Cochrane review concluded that silver dressings do not effectively prevent wound infection (Storm et al., 2010) and topical antibiotics (such as neomycin) may induce contact sensitivity (Fonder et al., 2008). Apart from a drug based on recombinant human growth factor (Regranex, by Johnson & Johnson), approved by the FDA for the treatment of CW but severely restricted in its use, there is presently little choice in drug therapies for the medical community dealing with CW. Clearly, the need for new drugs, possibly exploiting endogenous repair mechanisms, is strong and timely. _x000D_The idea of CO-RMs originated from studies on the protective protein heme oxygenase-1 (HO-1), which produces CO intracellularly from heme. CO mediates crucial signals in inflammation, angiogenesis and cell proliferation (Motterlini and Otterbein, 2010); CO-RMs were conceived to deliver precise amounts of CO to tissues and ‘mimic’ pharmacologically the protective properties of HO-1. CO-RMs are also an attractive alternative to inhalation of CO gas (which binds to hemoglobin in blood, Foresti et al., 2008), the subject of on-going clinical trials for certain indications. Why could CO-RMs work in the treatment of CW? First, CO-RMs modulate inflammation (Sawle et al., 2005), targeting macrophages that initially coordinate wound repair. Second, HO-1/CO stimulate proliferation of endothelial cells (Grochot-Przeczek et al., 2010), which form new blood vessels. HO-1 also accelerates cutaneous wound healing in mice and rats (Grochot-Przeczek et al., 2009; Ahanger et al., 2010). Fourth, CO-RMs are anti-bacterial agents (Nobre et al., 2007; Davidge et al., 2009; Desmard et al., 2009), thus addressing another clinical complication of CW. Lastly, topical lotions containing CORM-2 inhibited the formation of tumors induced by UV in the skin of mice (Allanson and Reeve, 2007). Alfama has also internal data showing a pro-healing effect for some CO-RMs._x000D_Among the biomaterials employed in wound healing collagen is the preferred choice for drug delivery (Ruszczak and Friess, 2003). Collagen is the primary building block of most human tissues, including the skin, and its use in wound management can be optimized by biochemical techniques to fit the desired degradation rate in the wound bed. The heat-treated form of collagen, gelatin, is routinely used to prepare drug delivery vehicles such as microspheres. The interaction of CO-RM drugs with collagen can also be optimized to provide the desired release pattern._x000D__x000D_The central aim of this project -the development of CO-RM drugs for the treatment of CW- is a novel but scientifically sound application of the CO-RM technology, and needs CO-RMs for topical applications. Alfama has synthesized more than 800 CO-RMs and is working extensively on the chemistry to develop clinically acceptable, drug-like CO-RMs for parenteral or oral use. In this project Alfama and its P CollPlant will collaborate to combine CO-RMs with collagen-based biomaterials for optimal drug delivery to the wound bed._x000D_

Acronym CORM-HEAL (Reference Number: 5946)
Duration 01/02/2011 - 31/01/2013
Project Topic Chronic non-healing wounds is a major economic and medical problem, especially in diabetic patients. Carbon monoxide-releasing molecules (CO-RMs) are anti-inflammatory prodrugs that could promote wound healing. This project proposes to test promising CO-RMs for the treatment of non-healing wounds.
Network Eurostars
Call Eurostars Cut-Off 5

Project partner

Number Name Role Country
2 CollPlant Ltd. Partner Israel
2 Alfama - Investigacao e Desenvolvimento de Produtos Framaceuticos, Lda. Coordinator Portugal