SBIR-STTR Award

Our company will develop an in vitro tissue culture system which will permit studies of drugs' capability to enhance production of fetal hemoglobin. The Investigator stated that increased fetal hemoglobin in cells of patients with beta-hemoglobinopathy ameliorates the clinical symptoms of the underlying disease. Several pharmacologic agents have been used to stimulate HbF synthesis during recent years. Treatment of patients with 5-azacytidine and hydroxyurea has resulted in higher fetal hemoglobin levels. Despite this, the clinical benefit has not been clearly established. Most agents which have been employed are either toxic or have been implicated in carcinogenesis. Therefore there is considerable interest in identifying less toxic agents which have potential to increase fetal hemoglobin. Thus far, only a handful of these agents have been tested, mainly due to the lack of an appropriate exDerimental system that allows a rapid and accurate determination of the effect on hematologic cells. The Investlgator indicates he has recently developed a novel, two-phase liquid culture system for growing erythroid progenitors derived from the peripheral blood of normal individuals and patients with hemoglobinopathies. He states that this system has proved to recapitulate in vitro many of the hematologic effects of hydroxyurea in vivo, including the stimulation of fetal hemoglobin production. The purpose of this research is to utilize this methodology for measuring total and fetal hemoglobin. He would employ the method for mass screening of agents to determine their fetal hemogrobin stimulating notential. The ultimate goal of these studies is to identify drugs with little toxicity which have a significant potential for stimulation of fetal hemoglobin. He intends to optimize the conditions of their culture system for stimulation of hemoglobin production and then screen various agents to determine their effects. Subsequently, he will use the methodology to study the modes of action of agents which appear successful istimulating fetal hemoglobin production. Awardee's statement of the potential commercial applications of the research:Our new methods after fully developed, can be used for mass screening of agents for their abilities to stimulate HbF growth, thus, producing an efficient therapy with low toxicity for patients with Beta-hemoglobinopathies, such as sickle cell anemia. Furthermore, we will develop an assay to evaluate individual patient's response to a certain drug or drug combination in vitro, thus eliminating expensive and risky experiments on the patients. These methods and products will be useful for all patients with similar diseases worldwide.National Heart, Lung, and Blood Institute (NHLBI)

Increased fetal hemoglobin (HbF) in cells of patients with beta-hemoglobinopathies (beta-thalassemia and sickle cell anemia) ameliorates clinical symptoms of the underlined disease. Recently, several pharmacological agents have been used to stimulate HbF synthesis: treatment of patients with 5-azacytidine or hydroxyurea resulted in higher HbF levels; yet, the clinical benefit is still unclear. Since these agents are either toxic and/or have been implicated in carcinogenesis, there is considerable interest in other, less toxic, agents with the potential to increase HbF. So far only a handful of agents have been tested, mainly due to the lack of an appropriate experimental system that allows a rapid and accurate determination of the effect on relevant cells.We have recently developed a novel, 2-phase liquid culture system for growing erythroid progenitors derived from the peripheral blood of normal individuals and patients with hemoglobinopathies. This system has proved to recapitulate in vitro many hematological effects of hydroxyurea in vivo, including stimulation of HbF production.The purpose of our research is to utilize this and modified methods for measuring Hb production developed in Phase I, for mass screening of agents for their HbF stimulating potential and subsequently studying their modes (S) of action to produce an efficient, low toxicity therapy. The latter studies will provide the rationale for further screening of additional agents and their chemical modification in order to increase efficacy. Classification of the drugs according to functional and mechanistic considerations will enhance experiments with combinations of drugs belonging to different groups and, thus, expected to act synergistically. In addition, we will attempt to develop, based on the cell culture system, an assay for evaluating an individual patient's response to a particular drug or drug combination. This will prevent both expensive and potentially risky treatment of patients that do not respond and suggest an alternative treatment (e.g., by other agents).National Heart, Lung, and Blood Institute (NHLBI)