COMPOSTIONS AND METHODS FOR TARGETED GENE THERAPY

摘要

Compositions containing molecules that bind to duplex DNA in a sequence-specific manner to form a triple-stranded structure are disclosed. Triplex-forming molecules facilitate strand displacement and triplex formation, referred to as a "clamp," in which one molecule binds to the target strand by Hoogsteen binding and the other molecule binds to the target strand by Watson-Crick binding in a sequence specific manner. A Watson- Crick binding "tail" added to the end of the Watson-Crick binding portion of the clamp increases the stringency of binding to the target duplex, improves the frequency of modification at the target site, and reduces the requirement for a polypurine:polypyrimidine stretch compared to triplex forming oligonucleotides (TFOs) or peptide nucleic acids (PNAs). When administered in combination with a donor oligonucleotide, triplex-forming molecules can enhance recombination of a donor oligonucleotide at the target site. Ex vivo and in vivo methods of gene correction in patients using the disclosed compositions are also disclosed.