Treatment & Prevention of Oxidative Injury

Summary

During open heart surgery and organ transplant, surgeons have to disrupt the blood supply to the organ. Recent studies suggest that free radical production and oxidative stress can occur when the blood supply is returned to the organ, causing complications and tissue damage. Vanderbilt researchers have identified a treatment for oxidative injury that can be administered during surgery to prevent organ damage.

Free radical production and oxidative injury have been implicated in numerous diseases. One example includes cardiac surgery where ischemia, restriction of blood supply and subsequent reperfusion cause oxidative stress and potential injury to cardiac tissue. The absence of oxygen and nutrients normally supplied by the blood results in inflammation and oxidative damage when circulation is restored. This damage is partly due to the inflammatory response which causes free radicals to be released when the tissue is damaged. In addition, membrane damage occurs which may cause even more free radicals to be released, ultimately leading to apoptosis and cell death.

Glutathione is a nutrient that functions as a scavenger of free radicals. It has been shown that intracellular levels of glutathione are crucial to a cell's viability (Chiba T et al, Eur J Immunol 26(5):1164-1169). Glutathione is a tripeptide composed of glutamate, cysteine and glycine. It is synthesized in two steps, the first of which combines glutamate and cysteine to form γ-glutamylcysteine using the rate limiting enzyme glutamate cysteine ligase. Thus the rate of glutathione production is directly dependent upon this step, and if this step could become non-limiting, then perhaps the amount of glutathione synthesized could be increased.

Vanderbilt researchers have purposed and tested the hypothesis that insufficient levels of glutathione may cause oxidative stress and lead to cellular injury. Supportive of this hypothesis, an insertion/deletion polymorphism in the gene for the glutamate cysteine ligase catalytic subunit (GCLC) has been associated with the development of postoperative pulmonary hypertension in children following bypass (Willis AS et al, Free Radic Biol Med 34:72-76). These researchers have shown that cell death was significantly reduced after exposure to H2O2 (Figure 1.a). In addition, when neuronal cells are pretreated with γ-glutamylcysteine four hours prior to exposure to H2O2, the oxidative stress is reduced. Administration of intravenous γ-glutamylcysteine is well tolerated in rats and elevates plasma γ-glutamylcysteine levels and tissue glutathione levels. Taken together, these results suggest that administration of γ-glutamylcysteine may be used to reduce oxidative injury and organ damage that can occur during surgery.

According to the American Heart Association, approximately 700,000 open heart surgeries were performed in 2008 in the United States alone. In addition, the United Network for Organ Sharing reports that 18,659 organ transplants were performed in the United States between January and August 2008. In addition to surgery, potential markets for this new technology include stroke, cardiac ischemia (heart attack) and trauma patients.

Current therapies including the use of vasodilators, anti-thrombotics/thrombolytics, β-blockers and coronary artery bypass graft are used pre- and post-MI to maintain/restore coronary blood flow and limit oxygen demand. However, most of these techniques are meant to target ischemia itself rather than the injury that reperfusion can cause. Thus there is a real clinical need to develop therapies that can be administered prior to and during surgeries where ischemia is required to directly inhibit the development of permanent cardiac injury that reperfusion injury may cause.

Animal studies to determine dosage and toxicity are currently underway. Once complete, animal studies will need to be performed to validate treatment and begin preclinical studies.

A PCT application has been filed, foreign rights are still available.