CRISPR-based gene editing for Choroideremia

Most clinical trials for retinal gene therapies have centered on gene supplementation mediated by adeno-associated viruses (AAVs), including our pioneering trial targeting Choroideremia. While this approach has demonstrated therapeutic potential, it comes with notable limitations. Gene supplementation is applicable only to recessive genetic disorders, and its long-term efficacy remains controversial, with some follow-up studies documenting relapses in visual function after treatment. Furthermore, AAV vectors face critical challenges such as packaging constraints, high production costs, and immunogenicity.

CRISPR-based genome editing technologies offer a transformative approach for the permanent correction of virtually any disease-causing mutation in the genome. Among these tools, prime editing stands out for its exceptional precision and versatility, enabling the targeted introduction of small insertions, small deletions, and all 12 possible base-to-base conversions. 

In this project, we investigated the use of prime editing to correct the LETT variant in the CHM gene, employing both cellular and zebrafish models of Choroideremia. To address the limitations associated with AAVs, we additionally explored the potential of lipid nanoparticles for delivering mRNA encoding the prime editing components. 

Period: Jan 2023 - Jun 2024

Funding: Throssel and Hillier Families Research Award

Collaborators: Moosajee Lab (UCL Institute of Ophthalmology)