The long-term objective of this research is to develop genetic therapies for non-Hodgkin's lymphoma (NHL). The initial target is the most common chromosomal translocation in NHL, t(14;18), which fuses the BCL-2 gene with the JH and constant regions of immunoglobulin (Ig) genes. The resultant BCL-2/Ig fusion mRNA leads to dysregulated BCL-2 expression that inhibits cell death, or apoptosis. BCL-2 overexpression also reduces sensitivity to chemotherapy-induced apoptosis. In the WSU-FSCCL NHL cell line antisense oligonucleotides (AS-ODN) targeted not only to the BCL-2 gene, but also to Ig sequences present in all t(14;18) fusion genes, decrease BCL-2 expression and induce apoptosis. While AS-ODN that target BCL-2 would be toxic to many normal cells, AS-ODN targeted to Ig sequences are predicted to be specifically cytotoxic to NHL cells. Because they target Ig constant regions, Ig AS-ODN need not be individually designed.
The specific aims of this application are: 1) to optimize Ig AS-ODN cytotoxicity in vitro and to test whether Ig AS-ODN sensitize cells to chemo- and/or radio-therapy; 2) to test the efficacy and toxicity of Ig AS-ODN in a SCID mouse/WSU-FSCCL model of in vivo therapy with Ig AS-ODN; and 3) to determine the frequency of expression of different Ig constant regions, e.g., C mu vs C gamma in t(14;18) positive fresh NHL samples to define which Ig AS-ODN sequences need to be developed clinically. Ig AS-ODN with therapeutic efficacy and acceptable toxicity will be candidates for development of clinical trials in NHL.
