A Basic FGF Mimetic Biobetter for Mitigation of Acute Gastrointestinal Radiation Syndrome

Speaker

Abstract

In the event of a radiological or nuclear disaster, there will be a need for therapies that can mitigate the acute hematopoietic and gastrointestinal (GI) radiation syndromes expected to develop in many of the victims of the disaster. Currently, there are FDA approved G-CSF and GM-CSF agents for mitigating the myelosuppression associated with the hematopoietic syndrome. However, an effective mitigation agent for acute GI syndrome is currently missing from our clinical armamentarium. Basic FGF (FGF2) benefits both GI and hematopoietic
syndromes in mouse models. However, natural FGF2 is severely depleted by total-body irradiation in humans, and replacement with hrFGF2 has logistical challenges and production costs that make clinical use and strategic stockpiling unrealistic. We hypothesize that FGF-P, a small FGF2 mimetic peptide, mitigates acute radiation-induced GI syndrome through a variety of cooperating mechanisms, including decreased mucosal cell loss, improved proliferation of small bowel mucosa and gut barrier function, and reduced bacterial translocation. It also helps maintain progenitor cells through signaling pathways that mimic natural FGFs. Our current preclinical studies of FGF-P in rodent survival and mechanistic studies are demonstrating these expected benefits, including improved GI barrier function, electrolyte transport, and mitogenesis for at least 30-day post-irradiation. This is resulting in increased survival time and the number of survivors when FGF-P is given subcutaneously beginning 24 hours post radiation exposure. In an effort to more fully understand the mechanisms by which FGF-P is mitigating GI-ARS we are examining a number of pro- and anti-inflammatory cytokine and chemokine beginning prior to irradiation, within the first 10 days following administration of FGF-P to 30 post-irradiation. The cytokine and chemokine studies are being conducted with the use of the Bio-Rad Bio-Plex Pro 23-plex Mouse and Rat cytokine kits, and 33-plex mouse chemokine kit, run on a Luminex 200 instrument. These multi-plex assay systems provide us with the needed breadth of cytokine and chemokine coverage for our mechanistic studies while minimizing the volume of plasma sample needed to perform the assay. From the results of the cytokine and chemokine studies in the rodent models, we will be able to identify common markers of efficacy of the FGF-P in the rodent models that could be used to translate the results of these pre-clinical studies to higher animal models and ultimately into humans as we advance our drug development efforts with the goal of gaining FDA approval of the use of FGF-P as a mitigator of GI-ARS using the Animal Rule.


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A Basic FGF Mimetic Biobetter for Mitigation of Acute Gastrointestinal Radiation Syndrome



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