Targeted Inactivation of the CCR5 HIV Coreceptor with Peptide Nucleic Acids

DESCRIPTION (provided by applicant): Over 34 million people are currently living with HIV/AIDS. Combination antiviral therapies have significantly reduced the morbidity and mortality of the disease; however, there is currently no cure for the disease. Discovery that a naturally occurring variant of CCR5, the delta32 mutation, renders cells resistant to HIV infection has led to efforts by several academic laboratories and biotech companies to find gene therapy approaches to mimic the delta32 mutation. This project will demonstrate the feasibility of using peptide nucleic acids (PNAs) as a therapeutic to genetically truncate the CCR5 protein in CD34+ stem cells and block HIV cell entry. Preliminary experiments that modified the CCR5 gene used a targeting PNA with a donor DNA sequence to induce a stop codon near the delta32 mutation. In this Phase I project, we will develop a novel strategy for PNA-induced CCR5 gene modification to increase the CD34+ mutation frequency to clinically useful levels. Specific