Advancing Hematopoietic Engineering by Enhancing HSC Gene Editing and Engraftment while Alleviating Genotoxicity

Targeted gene editing of human hematopoietic stem cells holds great therapeutic promise for the treatment of several inherited blood and storage diseases. Hematopoietic stem cells derived from patients are engineered in culture by means of programmed DNA “scissors” (e.g., CRISPR/Cas9), which allow site-specific correction of the genetic defect at the root of the disease. Genetically engineered and corrected hematopoietic stem cells are infused back in the patient, reconstituting a functional hematopoietic system. To allow the engraftment of engineered cells and make space in the bone marrow niche, pharmacological treatments must be administered to patients prior to cell infusion.  We recently developed novel procedures reaching more efficient targeted gene editing in human hematopoietic stem cells. However, these efficiencies remain still insufficient to effectively treat some genetic diseases. Furthermore, the gene editing procedure may have an undesired detrimental impact on modified cells. Finally, the pharmacological treatments used to enable engraftment of engineered cells in the patient may cause short- and long-term severe adverse events. The goal of our studies is to develop innovative and alternative procedures enhancing the efficiency and efficacy of targeted gene editing, dampening the toxicity on the engineered cells and on the patient. These improvements will allow to broaden the number of diseases that may benefit from these approaches, ultimately offering a safe and effective therapeutic treatment to more patients.