Sickle cell disease (SCD) is a hereditary blood disorder, affecting millions of patients worldwide, leading to high medical costs and a shortened life expectancy. Although many approaches to prevent the symptoms of sickle cell disease (SCD) have been and currently are being explored, no method is approved for clinical use except administration of hydroxyurea, which is frequently toxic due to undesirable side effects, for sustained use by many patients. Thus, new methods for treatment of sickle cell disease are sorely needed. A safe and effective antisickling agent can reduce the effects of SCD, reduce medical costs and increase the life expectancies of sufferers of the disease. This SBIR phase I application is a drug development plan for preclinical studies of 5-hydroxymethyl-2-furaldehyde (5HMF). 5HMF has been studied extensively, both in vitro and in vivo in a battery of preliminary tests by NHLBI SCD Reference Laboratory. It binds to HbS within RBCs and prevents sickling, both in vitro and in vivo. Preliminary in vivo studies with Tg sickle mice show that 5HMF is orally active with high bioavailability and has high red cell membrane permeability. 5HMF prolongs the life of severe hypoxic transgenic sickle cell (Tg) mice significantly and inhibits hypoxia induced sickling. Thus, 5HMF possesses a unique feature of antisickling action and clearly warrants further pre-clinical and toxicological investigation. Therefore, our specific aims include: (1) Comparison of the effect of 5HMF on the position of the oxygen equilibrium curves of human blood samples and those obtained from Sprague-Dawley rats and Beagle dogs that are treated with various doses of 5HMF, by multipoint tonometry, (2) Determination of the single dose acute toxicity, pharmacokinetics and pharmacodynamics of 5HMF in Sprague-Dawley rats and Beagle dogs, following oral/intravenous administration of 5HMF, and (3) Determination of the repeat-dose toxicity and pharmacokinetics of 5HMF in Sprague-Dawley rats and Beagle dogs, following oral/intravenous administration of 5HMF for 14 consecutive days. The toxicological response and tissue distribution will be assessed in proposed animal models. Our long term ultimate goal is to develop a safe and effective antisickling agent as either an oral or IV-delivered therapeutic for SCD. The Phase I SBIR preclinical, in vivo animal efficacy and toxicology studies should clearly identify 5HMF as the new antisickling agent. The goals of phase II SBIR proposal will be to initiate Phase I study of 5HMF to establish the safety, tolerance and efficacy of 5HMF, by the most favored mode of delivery, in healthy human volunteers and sickle cell patients. ? ? ?
