Harvard researchers find improved efficacy against retinal disease in mice

Researchers from Harvard University and the Broad Institute, led by Dr. David Liu, founder of Prime Medicine, have made significant strides in restoring vision in blind mice using prime editors delivered through a novel particle system. The findings showcase the successful use of prime editor-engineered virus-like particles, or PE-eVLPs, as a delivery mechanism for prime editors to the eyes of mouse models with genetic retinal diseases. This innovative approach enhances the efficiency of prime editing and addresses safety concerns associated with the process.

The study marks a groundbreaking achievement as it represents the first instance of therapeutic prime editing being achieved in animals by delivering protein-RNA complexes. Prime editing, positioned as a more precise and potentially safer alternative to CRISPR, facilitates the modification of base pairs without disrupting both DNA strands or necessitating DNA templates, unlike the conventional CRISPR method. Dr. Liu, a prime editing pioneer, emphasized the significance of this research in utilizing protein-RNA complexes for therapeutic prime editing.

Despite recent successes in prime editing technology, challenges in delivery persist. While lipid nanoparticles have been effective for liver conditions due to their tendency to accumulate in the liver, they are less proficient in delivering therapies to other tissue types. Viral delivery methods have shown promise in this context, with virus-like particles (VLPs) emerging as a notable candidate. VLPs, coated with virus proteins but lacking genetic material, have been utilized in vaccines such as the Gardasil series.

The researchers initially attempted to adapt engineered VLPs from base editing for prime editing but encountered limited efficacy. Following modifications, the prime editing efficacy improved significantly. Further redesigning of the VLPs addressed mechanistic bottlenecks, leading to substantial increases in prime editing efficiencies compared to the original base editing version. The improved particles also enhanced base editing effectiveness.

To validate the precision and delivery capability of PE-eVLPs, the researchers conducted experiments on mice with genetic retinal diseases where it achieved success without complications. In a more challenging mouse model with a severe retinal disease, PE-eVLPs not only corrected the mutation at a higher efficacy rate than previous viral delivery methods but also significantly improved visual function.

The results demonstrate the potential of optimized PE-eVLPs for in vivo correction of pathogenic mutations and partial rescue of disease phenotypes in animals. Dr. Liu’s team intends to further refine the particles for targeting different tissue types, indicating a promising trajectory for the application of prime editing in therapeutic interventions.

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