Stimulation of Targeted Homologous Recombination for Gene Therapy – STaHR

Genome editing (GE) is a promising strategy for gene therapy. Engineered nucleases such as TALE and CRISPR-Cas9 can now be used to target a double strand break (DSB) at any DNA sequence of interest in the genome in order to stimulate GE. For gene therapy and several important applications, it is important to favour DSB repair by homologous recombination in order to perform highly controlled and precise GE. The program partners have longstanding experience in programmable nucleases, studies of DSB repair and gene therapy approaches. Partner 2 has proposed a two step model of DSB repair pathway choice. The research programme consists in taking advantage of current knowledge of DSB repair pathways to test original strategies for increasing the efficiency of GE by HR. A second task will consist in identifying new positive regulators to stimulate HR. Importantly, the most promising strategies will be tested, including one strategy already validated in the experimental systems used by Partners 1 & 2, and optimized in 2 different models of human genetic disease in which better, more efficacious therapeutic options are needed.