This proposal is based on the finding that structures that are recognized by RNAse P can be introduced into any foreign RNA (e. g. mRNA) via hybridization to a small oligoribonucleotide resulting in cleavage of the targeted mRNA. Thus, such small RNAs or external guide sequences can be used in the development of novel approaches toward treatment of human genetic disorders and infectious diseases. The proposed goals are: (i) to optimize the EGS efficiency via determining the optimal structure for cleavage and targeting efficiency and (ii) to develop an EGS-based therapeutic approach to the treatment of HIV infection by targeting CCR5 mRNA.