Transforming growth factors-b (TGF-bs) are complex cytokines with a wide range of biological functions. Overproduction of TGF-bs leads to pathogenic manifestations and is associated with immunosuppression in cancer, autoimmunity, HIV-associated neuropathy, promotion of virus replication in HIV patients, excessive scar formation during wound healing, and several other disorders. Present techniques for in vivo inactivation of excessive TGF-b by antisense molecules, neutralizing antibodies or decorin are very expensive and pharmacokinetically inefficient. In this Phase I grant application, these investigators propose to select single-stranded DNAs (ssDNA) that bind TGF-b1 or TGF-b2 and block their signal transduction by inhibiting TGF-b-receptor complex formation. Nucleic acid inhibitors of TGF-b signaling pathway have not been generated until now. These inhibitors are anticipated to have high commercialization potentials, and may be used in treating many human diseases that are associated with TGF-b overproduction. The PI has obtained some preliminary results that demonstrate this is an achievable goal. The PI provides two new procedures for in vitro and in vivo selection of DNA inhibitors of TGF-b signaling pathway. The protocols employed are universal and usable for screening of large combinatorial libraries to detect different inhibitors of TGF-b signaling pathway. The isolated ssDNA inhibitors are inexpensive to produce, can be easily administered, and are pharmacokinetically controllable.
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