Researchers engineer in vivo delivery system for prime editing, partially restoring vision in mice

UC Irvine School of Medicine researchers are part of a collaborative team with the Broad Institute of MIT and Harvard that has developed a new and highly efficient delivery system for therapeutic CRISPR/Cas9 prime editor (PE) constructs called PE-engineered virus-like particles (eVLPs). These eVLP constructs enable the efficient and safe delivery of CRISPR components, which can address the vast majority of inherited genetic diseases. Specifically, the Broad Institute researchers collaborated with UCI to demonstrate therapeutic prime editing in vivo at two therapeutically relevant genes.

“This therapeutic strategy has the potential to treat many different ophthalmological diseases,” said Samuel Du, MD/PhD candidate and National Eye Institute research fellow. “In particular, prime editing broadens the scope of gene editing because it is able to correct DNA mutations that are inaccessible to another advanced CRISPR/Cas9 technology called base editing.”

This is a significant finding because many current delivery systems for CRISPR/Cas9, and prime editors in particular, are limited by cargo capacity and safety concerns. The use of eVLPs promises to circumvent both of these hurdles and greatly improve the safety and efficiency of gene editing in vivo. Delivery of CRISPR/Cas9 editing constructs is proving to be the biggest challenge in moving gene editing into the clinic where it is needed to treat previously untreatable diseases, and the gold standard virus vectors have many limitations.

"We are particularly excited about the potential of PE in treating ophthalmological inherited diseases,” said Krzysztof Palczewski, PhD, Donald Bren Professor, UCI School of Medicine and Irving H. Leopold Chair of Ophthalmology at the Gavin Herbert Eye Institute. “As there are over 200 mutated genes responsible for inherited blinding diseases, and multiple potential causative mutations in each gene, the challenge of applying classical pharmacology to each mutated gene and each mutation is prohibitive, and prime editing could be the answer to quickly develop treatments for these diseases.”