For victims of gastrointestinal (GI) radiation exposure and concomitant GI syndrome, DiaCarta's fibroblast growth factor-peptide (FGF-P) is a product that will not only reduce depopulation and improve reepithelialization of the small bowel but also support bone marrow function. It could be the crucial factor that prevents mortality from GI syndrome. Our peptide is an FGF-2 mimetic;however, unlike recombinant FGF-2, it is highly stable, remarkably easier and less expensive to manufacture, and has no toxic contaminants. FGF-P has several properties that are essential for this project: 1) Most cells express FGF receptors, including those of the mucosa, skin, bone marrow, and vasculature. 2) FGFs are needed to maintain the "stem-ness" of stem and progenitor cells. 3) Unlike in the case of traumatic wounds, FGFs are decreased and not increased following irradiation, which leads to insufficient rates of recovery and the loss of stem cells needed for a subject to survive. Three tasks aimed at establishing the efficacy and fitness of FGF-P for deployment in a disaster situation must be addressed in this Phase I SBIR. 1. Quantitative measurement of the capacity of FGF-P to mitigate GI syndrome. Studies include: (1.1) Radiation and drug dose response;(1.2) Scheduling studies;(1.3) Formulation. Endpoints will be studied quantitatively for determination of the dose modification factors. Endpoints will include survival (LD50/30 and LD50/7, median lethal dose at 30 and 7 days), stool heme, weight, serum lipopolysaccharide, and crypt depletion and recovery rate. 2. Studies to document that FGF-P mechanisms transcend species. These studies are required for the FDA Animal Rule and must demonstrate that the mechanism is not species-dependent. Sub-aims include: (2.1) Chick embryo angiogenesis assays;(2.2) In vivo and in vitro measurement of dose-equivalent effect curves between human FGF-2 and FGF-P. We will perform molecular signaling and functional assays. 3. Preliminary toxicity testing and regulatory preparations. We will prepare for future development steps to demonstrate efficacy and fitness. These steps include: (3.1) Gross toxicity studies;(3.2) Preparation for good manufacturing practice agent production;(3.3) Preliminary guidance meetings with the FDA. In these meetings, we will clarify best pivotal endpoints and choice of animal species.
Gastrointestinal radiation exposures are life-threatening. Multiple in vitro and in vivo models have shown that fibroblast growth factors (FGFs) augment epithelial and endothelial healing following radiation, and randomized human trials have demonstrated that FGFs improve wound healing. Our peptide, FGF-P, mimics a natural growth factor with none of the clinical or commercial drawbacks. We will confirm the potential of FGF-P given e 24 hours after radiation to greatly impact gastrointestinal and survival outcomes.