Thalassemia and B and D Globin Gene Expression

Period of Performance: 09/01/1995 - 05/31/1996


Phase 1 SBIR

Recipient Firm

OSI Pharmaceuticals, Inc.
Uniondale, NY 11553
Principal Investigator


The approach of Oncogene Science for the treatment of beta-thalassemia is to identify chemical compounds which modulate transcription of the adult beta-globin gene and/or induce expression of the delta-globin gene. The process of drug selection is considerably facilitated by the use of highly sophisticated automated facility which permits the high throughput screening of about 120,000 compounds per year against a single therapeutic target. A large body of data support the hypothesis that the globin genes compete for a limited number of activating transcription factors. Thus a reduction in beta-globin promoter activity has been shown to correlate with increased transcription of the delta and gamma genes. For treatment of severe beta-thalassemia involving homozygous structural alteration of the beta-globin gene, attenuation of the beta-globin promoter activity is predicted to result in increased gamma and delta-globin synthesis and HbF and HbA/2 production, and alleviate the otherwise fatal symptoms of beta- thalassemia. The delta and beta promoters, linked to the LCR HS-II element, will be fused to the luciferase reporter gene. In addition, the luciferase gene will be inserted at the translational initiation codon (ATG) of the two respective genes, within the context of a plasmid harboring the entire delta beta locus. In Phase II, these stable cell lines will be employed in high throughput robotic drug screening for compounds which modulate expression of the beta and delta globin genes, in subsequent assays of selectivity and potency, and to define mechanism of drug action. PROPOSED COMMERCIAL APPLICATION: The medical need for improved treatments of beta and alpha thalassemias is largely unmet. The cost of treating thalassemia in the US has been estimated to about $100,000 per year. The number of beta and alpha thalassemia patients in emerging economies world wide is large.