Inhibition of Intestinal Heme Iron Absorption

Period of Performance: 02/01/2006 - 01/31/2007

$432K

Phase 2 SBIR

Recipient Firm

Frontier Scientific, Inc.
Logan, UT 84323
Principal Investigator

Abstract

DESCRIPTION (provided by applicant): 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.