SBIR-STTR Award

Iron overload conditions such as thalassemia and hemochromatosis result from the increased intestinal absorption of iron from inorganic iron and heme iron. Chelation therapy has been used with limited success, phlebotomy is usually required for severe iron overload. This can become problematic in patients whose iron overload is accompanied by anemia. In Northern European and the U.S., the majority of iron (2/3) that is utilized by the body is derived from heme iron in the diet, and not inorganic iron. Inhibition of iron uptake from heme would be critical to any attempt to prevent iron absorption. We have developed a model for iron absorption from heme in both tissue culture cells and in the rat. The heme is solubilized in a bile salt micelle. Both tissue culture cells and in vivo iron is absorbed and incorporated into cellular proteins. Certain soluble porphyrin analogs are capable of inhibiting the uptake of iron from heme. These inhibitors would be a major advance in the treatment of iron overload diseases. We propose to investigate the toxicity and effectiveness of the compounds already identified, and to explore additional analogs synthesized by Porphyrin Products. This is important since there are no inhibitors of heme absorption currently recognized. PROPOSED COMMERCIAL APPLICATIONS: Development of pharmacologic agent to treat iron overload conditions.

Thesaurus Terms:
drug screening /evaluation, gastrointestinal absorption /transport, heme, inhibitor /antagonist, iron metabolism, iron storage disorder, porphyrin laboratory rat, tissue /cell culture

Iron overload syndromes (attributable to transfusions / dietary uptake) are a significant cause of the morbidity and mortality associated with hemochromatosis, thalasemia, and sickle cell anemia. In the developed world, 2/3 of absorbed iron is derived from heme (organic iron) rather than inorganic iron. While the mechanism by which inorganic iron is absorbed is partially understood, the mechanism by which heme iron is absorbed is not understood. Present treatments for iron overload syndromes include phlebotomy (in non-anemic cases) and subcutaneous continuous infusions of deferoxamine. The latter treatment would be rendered more effective or unnecessary if intestinal iron absorption could be halted. We have developed, in a Phase I SBIR study, an inhibitor of heme-iron uptake that is effective in tissue culture cells and in the rat duodenal loop model. These models provide a good approximation of the human physiology. The inhibitor is a soluble metalloporphyrin (Cr-TMP) that inhibits the uptake of iron from heme at about 4 mu/M in tissue cultured cells and appears non-toxic to tissue culture cells. It is active in vivo at less than 200 nanomole/kg and is poorly absorbed by the intestinal mucosa. In Phase II, (A) we will develop a synthesis capable of producing large amounts of the compound, institute quality control and GMP protocols, and stabilize and appropriately formulate the drug for delivery. (B) We will further assess toxicity in tissue culture cells. (C) We will discover the optimal concentration required to inhibit the uptake of heme iron in the rat duodenum, explore the effects of food and other potential interactions on the drug's action, and conduct long-term toxicity studies in rats. (D) SRI will assess genetic and other toxicity. (E) We will explore the drug's mechanism of action. (F) We will induce iron deficiency anemia in dogs by use of the inhibitor. These studies should provide a basis for a partnership with biotechnology companies for a Phase III pursuit of an IND and appropriate studies in humans. A business plan to accomplish these goals appears in the Phase II application.

Thesaurus Terms:
drug design /synthesis /production, gastrointestinal absorption /transport, heme, inhibitor /antagonist, iron, metalloporphyrin, pharmacokinetics analog, drug adverse effect, drug screening /evaluation, gastrointestinal function dog, high performance liquid chromatography, laboratory rat, mass spectrometry, nuclear magnetic resonance spectroscopy, tissue /cell culture