New classes of small, cell permeable genome regulators to expand the age of genomic medicine

Project Summary/Abstract Pyrrole-imidazole polyamides are a class of synthetic DNA-binding ligands that can be programmed to target specific DNA sequences, including repetitive DNA, in the human genome. The major scientific problem this proposal addresses is the development of two new classes of small, cell-permeable genome regulators to extend the capabilities of these molecules. This project aims to fill the critical gap in genome targeting by creating first-in-class small, cell-permeable genome editors that can be relationally designed to edit genomes for a variety of downstream functions. This objective will be pursued through 3 Projects: The expected outcomes include (1) the development of bifunctional polyamides capable of editing a tandem repeat of interest in cell and animal models, (2) the creation of polyamides to recognize 15–20 base pair motifs occurring only once in the human genome, and (3) the democratization of these molecules to place them in the hands of biologists. If successful, this project could lead to novel therapeutic strategies for not only repeat expansion disorders but genetic diseases broadly, providing new tools to researchers and advancing the field of precision genomic medicine.