The Sickle Cell Disease (SCD) Reference Laboratory (SCD-RL) was established to perform efficient, accurate and cost-effective evaluation of candidate agents for the treatment of SCD. Since its inception in 1997, the SCD-RL has validated seven new potential therapeutic agents including three agents that prolong the survival time of transgenic sickle mice under hypoxic conditions and four agents that promote the production of fetal hemoglobin (Hb F) in K562 cells. These promising results validate the approach taken by the SCD-RL, which is based on a comprehensive approach to the characterization of potential antisickling agents. The SCD-RL utilizes a standard in vitro protocol including more than 10 procedures to determine whether a candidate agent has beneficial and/or adverse effects. In addition to assessing anti-sickling effects in vitro, other parameters such as prolongation of the delay time prior to the polymerization of deoxygenated sickle hemoglobin, shift of the oxygen equilibrium curve to the left, induction of Hb F synthesis, hydration or reduction of dehydration of red blood cells (RBCs), and adhesiveness of RBCs to endothelial cells, are examined. The SCD-RL also studies the adverse effects of potential drugs such as formation of methemoglobin, hemolysis, and/or increase in the amount of denatured hemoglobin inside RBCs. Results of the in vitro evaluation of candidate drugs are then presented to the Ad Hoc Committee. This Committee reviews results and recommends which drugs should be evaluated by in vivo evaluation protocols utilizing transgenic mice. The SCD-RL found a particular transgenic mouse line that exclusively develops acute chest syndrome (ACS) upon exposure to hypoxia. The availability of a NIH-funded Reference Laboratory has facilitated and promoted the interest of outside commercial and academic entities. We received a much higher volume of requests for drug evaluation than originally expected. Based on the experience of the last 3 years, we believe that the SCD-RL plays a major role in assessing compounds which have already received an initial screen by other investigators. This enhances the likelihood of finding potentially clinically useful compounds.
