Therapeutics

adRP is a progressive degenerative eye disease that leads to severe vision loss, significantly impacting quality of life. There are currently no effective curative treatments, highlighting the urgent need for gene-editing-based therapeutic solutions.

1. Mutant Allele-Specific Targeting

We have devised mutant allele-specific targeting for adRP mutations, ensuring selective elimination of pathogenic alleles while preserving functional wild-type alleles.

- We utilise a range of Cas nucleases, including SpCas9, eSpCas9(1.1), SpCas9-VQR, SaCas9, and SpCas9-NG, to achieve highly specific gene editing.

- sgRNA Screening – Through an extensive screening process in cell lines carrying heterozygous adRP mutations, we identified multiple highly selective gRNA candidates capable of eliminating mutant alleles while sparing wild-type alleles.

- Our optimised approach successfully removed almost all mutant alleles, ensuring minimal disruption to normal gene function and preserving retinal integrity.

2. Prime Chop-or-Change (PCOC) Strategy

Our PCOC (Prime Chop-or-Change) approach represents a next-generation gene editing solution designed to maximise therapeutic efficiency for adRP.

- Dual-Action Mechanism: PCOC combines the precision of prime editing with the robust activity of Cas9 nucleases, allowing either correction of the mutant allele or knockout of unedited mutant alleles, ensuring a therapeutically favorable outcome regardless of editing efficiency.

- Versatility and Efficiency: We applied PCOC to cell lines carrying common adRP mutations (RHO P23H, RHO T17M, and NR2E3 G56R), utilising an optimised combination of prime editing with Cas9 nucleases (SpCas9, SaCas9, eSpCas9(1.1), SpCas9-NG, SpRY-Cas9, and SpCas9-VQR).

- Breakthrough  Results: Our PCOC candidates demonstrated superior efficacy in selectively eliminating mutant alleles while increasing the proportion of functional alleles, significantly outperforming conventional Cas9 knockout approaches.

With high efficiency, precision, and therapeutic versatility, PCOC holds strong promise as a groundbreaking gene-editing therapy for adRP, offering a potential curative solution for patients suffering from this debilitating condition.