Therapeutic Applications

Bovine CuZn-SOD was marketed as an anti-inflammatory drug under the trade name "Orgotein." However, due to adverse immunological side effects, it was withdrawn from the market, and its marketing license was suspended in 1994 [124]. The product has been marketed in Spain by the company OXIS International, where it has been used in humans for the prevention and treatment of radiation-induced tissue inflammation and fibrosis [125,126]. The enzyme was marketed for use in animals in the United States as the active ingredient in Palosein, which is used for the alleviation of musculoskeletal inflammation in dogs and horses. The enzyme is also marketed as a dietary supplement [127], however, there is little evidence to support its therapeutic efficacy in this context. A recombinant CuZn-SOD (Oxsodrol) was registered with the FDA in 1991 by Savient Pharmaceuticals as an orphan drug for the treatment of bronchopulmonary dysplasia in premature infants [128]. The enzyme has undergone phase-II clinical trials for various indications and did show long-term benefits for some, but has not gained approval [125,129-131].

There are numerous pathophysiological conditions associated with the overproduction of superoxide anions and there appears to be a similarity between the tissue injuries that are observed in the various disease states. Disease pathologies arising from this tissue damage include ischemia and reperfusion injuries, radiation injury, hyperoxic lung damage, and atherosclerosis. Loss of SOD activity has also been implicated in the pathogenesis of motor neuron disease [132]. The common etiology of these pathologies provides an opportunity to treat numerous disease states with a single therapeutic for removal of superoxide anions [116]. ROS (e.g., superoxide, peroxynitrite, hydroxyl radical, and hydrogen peroxide) play a significant role in inflammation, enabling SOD to inhibit tissue injury associated with acute and chronic inflammation [117]. SOD injection to patients with osteoarthritis of the knee is one of the most impressive examples of beneficial SOD therapy. The enzyme was considered to have a positive effect in many other conditions as an anti-inflammatory agent and was seeking to gain approval for this use from regulatory authorities in the 1990s [133,134]. Although preclinical and clinical studies were promising, there were drawbacks such as immunogenicity and targeting associated with its use as a therapeutic agent. To overcome or reduce these problems, several approaches have since been attempted. These include entrapment of the enzymes in liposomes and masking of the protein surface by biocompatible natural or synthetic polymers such as PEG. These modifications were principally intended to reduce antigenicity and increase blood residence time [135].

However, these approaches have also had limited success [136]. Low-molecular-mass nonprotein-based SOD mimetics that could overcome some of the limitations of the native enzyme have been designed [137]. One such mimetic is M40403, which is currently in phase I clinical trials. In addition, the use of recombinant EC-SOD as a therapeutic enzyme in many of the conditions associated with free radicals is now being assessed. EC-SOD has a much longer half-life (20 h) than intracellular SOD, and is targeted to endothelial cells by its heparin affinity. The targeting of EC-SOD to the endothelial cells would be very beneficial in the treatment of atherosclerosis and ischemia/reperfusion injury. This beneficial effect has been demonstrated in animal models of these conditions [138]. To date, no SOD-based therapeutic has been approved in the United States.

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