In our prior study, "Dynamic Modeling in GWI," we used an exercise challenge, known to make Veterans with Gulf War Illness (GWI) suffer a degree of relapse, to map out the causes of relapse. We evaluated each subject nine times over 24 hours, looking at the patterns of over 300,000 genes as they turned on or off in response to the exercise challenge, as well as measures of inflammation, various hormones, immune messenger signals (cytokines), and chemical messengers of the central nervous system(neuropeptides). The idea was to understand the time course of relapse, and the "tag team" of signals that result in the symptoms of GWI. Then, using sophisticated computational methods that could handle many millions of data elements, our computational biologists created a virtual model of the illness, a model that showed us the key therapeutic targets that sustain GWI. The modeling suggests five key targets, and one, NF-kB, is "upstream" of several others, making this the focus of our first intervention study.

There are dozens of interventions that target NF-kB, from very expensive and potentially toxic biologic response modifiers to low toxicity nutraceuticals. Because GWI Veterans are known to be very susceptible to toxic side effects of medications, we searched for a safe but potentially effective approach. Both glutathoione and curcumin have literature demonstrating strong evidence of impact on the NF-kB pathway, with proven clinical impact. The medical literature supports their use in other illness involving chronic inflammation; this is coupled with an excellent record of drug safety. Thus, we propose to study glutathione and curcumin, both in formulations that optimize bioavailability, and compare them to placebo in a classic double blind placebo control study. These studies are termed Phase I/II, to acknowledge that the interventions have not been tested before in GWI, but they will be evaluated in a way that allows conclusions on feasibility and safety (Phase I), as well as efficacy (Phase II). Our primary goal is to test the utility of our computational model in an intervention setting. If we are successful, we will have set the stage for a series of studies that attempt to reset homeostasis in complex illnesses such as GWI. We will also deliver sufficient data to support and assist in design issues for a Phase 3 study using the better of the two nutraceuticals studied. Because these interventions target redox/mitochondrial function, we have invited Dr. Richard Deth to partner with our group and examine the role of redox/glutathione and mitochondrial status in GWI Veterans before and after treatment and add this to our virtual clinical trials modeling system.

If successful, we will gain confidence in our virtual clinical trials model and utilize this method to design additional treatment strategies for GWI. Depending upon the results of this study, we also hope to be in a position to propose a Phase 3 clinical trial of the more effective of the two treatments tested in this study.