Traceless delivery of ‘genome editors’ for treatment of severe genetic diseases

Genome editing has enormous potential to transform the future of genetic medicines. Many technologies have been developed, but further refinement is needed to improve safety and efficacy. The main obstacle is efficient delivery of the genome editor. To help achieve this, I have pioneered the development of a new platform for delivery of genome editors. Lentivirus-derived nanoparticles (LVNPs) incorporate ribonucleoprotein (RNP) complexes and show potent genome editing both ex vivo and in vivo. LVNP-delivery addresses key limitations of current delivery modalities: (i) it overcomes limited packaging capacity, (ii) it reduces unwanted genomic integration, and (iii) it reduces exposure to the therapeutic payload which has multiple benefits. To inform clinical development this project will generate preclinical evidence for LVNP-directed correction of genetic disorders in hematopoietic stem cells, induced human pluripotent stem cells, and in respiratory stem cells in the lung. Furthermore, to address potential complications of host immune responses, I aim to replace the HIV-1 derived components with biologically active homologues rescued from the human genome. To engineer a fully endogenous system, I will also incorporate human fusogens to provide cellular tropism. This project aims to fulfil the vision of widespread use of genome editing to correcting genetic defects in patients.