SBIR-STTR Award

Our goals are to develop novel methods which rapidly identify genes in living cells and lead pharmaceutical compounds in the area of immunomodulation. We will develop a functional read-out for tagged genes that uses a highly sensitive beta-lactamase (bla) gene reporter system to rapidly 1) screen for novel genes responsive to immunomodulatory agents in living cells and 2) identify drug candidates with different specificity from existing drugs. We hypothesis that this gene tagging strategy can be used to create a set of stably transfected T cell lines expressing immunomodulatory genes and to rapidly screen for novel immunosuppressive agents that prevent expression of those genes. PROPOSED COMMERCIAL APPLICATION: Over $1 billion worth of immunosuppressants are used annually in attempts to prevent graft rejection and graft virsus host reactions. However, immunosuppressant therapy carries serious risk of nephrotoxicity and hypertension, along with substantial related cost for ongoing monitoring of renal function. Thus there is a need for improved immunosuppressive agents or combinations of agents which exhibit more desirable pharmacokinetics.

Aurora has developed a gene-tagging method which uses a highly sensitive beta-lactamase (bla) reporter system to rapidly a) screen for novel genes which respond to immune activators, and b) identify drug candidates which inhibit this immune activation. Phase I activities demonstrated feasibility by isolating immunoresponsive clones and using one to identify three structurally novel potential immunosuppressors. Phase II activities will generate improved retroviral gene traps to a) allow isolation of immunoresponsive genes from all three reading frames; and b) facilitate identification of the trapped genes. Clones containing appropriate trapped genes will be used to screen chemical libraries to identify three classes of immunosuppressors: a) those which inhibit the PKC pathway (non cyclosporin-like); b) those which inhibit the IP3/Ca++ pathway (cyclosporin-like); and c) those which inhibit pathways other than these two. Products will include: 1) clones to be used as cell-based screens for immunosuppressors; 2) clones to be used as counterscreens to qualify candidate compounds as validated immunosuppressor leads; 3) validated immunosuppressor leads obtained from Aurora's proprietary chemical libraries using these cell-based screens; and 4) services to perform screening of chemical libraries using clones selected by the corporate partner. PROPOSED COMMERCIAL APPLICATIONS: Over $1 billion worth of cyclosporin is used annually in attempts to prevent graft rejection and graft versus host reactions. However, cyclosporin therapy carries serious risk of nephrotoxicity and hypertension, along with substantial related costs for ongoing monitoring of renal function. Thus there is a need for improved immunosuppressive agents or combinations of agents which exhibit less toxicity. The novel structural leads and cellular screens being developed by Aurora are expected attract a commercial partner for continued development of such agents.