Prime Medicine reports new preclinical data demonstrating the ability of prime editors to efficiently and precisely correct the predominant mutations that cause rhodopsin-associated autosomal dominant retinitis pigmentosa (RHO adRP). The data, which showed correction of pathogenic mutations causing RHO adRP at efficiencies above the levels believed to have the potential to halt disease progression, were presented at the International Symposium on Retinal Degeneration 2023 Congress (RD2023) in Costa del Sol, Spain.

“The data presented today are the first proof-of-concept data for Prime Editing’s application in treating ophthalmological indications, and highlight the ability of Prime’s novel, dual AAV delivery platform to efficiently deliver Prime Editors to the eye,” said Jeremy Duffield, MD, PhD, CSO of Prime Medicine.

RHO adRP is a rare inherited retinal disease that causes progressive vision loss in early adolescence, leading to eventual blindness in adulthood due to photoreceptor degeneration. It results from mutations in the gene RHOwhich encodes rhodopsin, the light-sensitive G protein-coupled receptor involved in phototransduction in rods. This leads to the progressive loss of rods and, subsequently, cones in the retina. 

“Specifically,” added Duffield, “today’s data highlight the ability of two Prime Editors to correct the predominant mutations causing RHO adRP—one to correct p.P23H, the most common disease-causing mutation in RHO in the U.S., and one to correct 18 different mutations at a mutational hotspot in RHO, including p.V345L and p.P347L, which are the most prevalent mutations in Europe. With no detected off-target edits in human photoreceptors and no AAV integrations observed in these studies, today’s results are a positive step forward for those living with RHO adRP, for whom there are currently no approved treatment options.”

To address the predominant mutations causing RHO adRP, Prime Medicine conducted comprehensive high-throughput screening of more than 1,000 prime editor guide RNAs (pegRNAs). Two potent prime editors were identified—one that precisely corrected RHO p.P23H located near the N-terminus of rhodopsin, and one that precisely corrected the mutational hotspot located near the C-terminus, which includes 18 pathogenic mutations including RHO p.V345L and p.P347L. The company then developed and optimized a proprietary dual AAV system to deliver the prime editors via subretinal injection in humanized mouse models. Prime editor performance was assessed in a suite of in vitro assays and demonstrated up to 45% correction at RHO p.P23H, and more than 70% correction at RHO p.V345L and p.P347L. According to scientific literature and Prime Medicine research, 25% correction at both RHO p.P23H and the C-terminal mutational hotspot may be sufficient to halt progression of RHO adRP, and correcting these mutations has the potential to benefit approximately 60% of patients living with this disease. 

The meeting presentation included the following, more specific, findings: 1) up to 70% precise correction in photoreceptors at RHO p.P23H and up to 65% at RHO p.V345L or p.P347L at a mutational hotspot using prime editors delivered by a dual AAV system via subretinal injection with less than 0.5% on-target unintended edits detected; 2) Efficient delivery of prime editors by dual AAV to human (retinal explants) and murine (in vivo) photoreceptors; 3) RHO correction well tolerated with no detectable changes in retinal thickness or glial fibrillary acidic protein (GFAP) gene expression; 4) No measurable integration of the AAV vector at the edit site, as measured by one-sided polymerase chain reaction (PCR); 5) No detectable off-target edits observed in human photoreceptors following a genome-wide off-target screening analysis.


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