June 22, 2024

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Prime Medicine’s Breakthrough in Editing for Genetic Eye Diseases

Prime Medicine’s Breakthrough in Editing for Genetic Eye Diseases



Prime Medicine’s Breakthrough in Editing for Genetic Eye Diseases.

Prime Medicine Releases First In Vivo Editing Experiment Data for Treating Genetic Eye Diseases.

During the 2023 Retinal Degeneration International Symposium (RD2023) held in Spain, Prime Medicine reported its latest preclinical research data, demonstrating the effectiveness and precision of its prime editor in correcting dominant mutations causing Rhodopsin-Related Autosomal Dominant Retinitis Pigmentosa (RHO adRP). The editing efficiency achieved levels sufficient to halt the progression of the disease.

Dr. Jeremy Duffield, Chief Technology Officer of Prime Medicine, stated that the data presented at the event represents the first proof-of-concept data for prime editing in treating ophthalmic indications. This highlights the company’s novel dual-vector AAV delivery platform’s capability to efficiently deliver the prime editor to the eye.

Rhodopsin-Related Autosomal Dominant Retinitis Pigmentosa (RHO adRP) is a rare genetic retinal disease that leads to progressive vision loss in early adolescence and eventual blindness in adulthood due to the degeneration of photoreceptor cells. This disease is caused by mutations in the RHO gene, which encodes for rhodopsin, a photosensitive G protein-coupled receptor involved in phototransduction in rod cells. The gene mutations result in the gradual loss of rod and cone cells in the retina.

 

Prime Medicine's Breakthrough in Editing for Genetic Eye Diseases

 

 

The data presented by Prime Medicine indicates that the company’s two therapies have the ability to correct dominant mutations in RHO adRP, including the p.P23H mutation, the most common pathogenic mutation in American retinitis pigmentosa, and 18 different mutations in the mutation hotspot region, including p.V345L and p.P347L, the most common mutations in Europe. Furthermore, subsequent testing showed no off-target editing, and no integration of AAV vectors into the host genome.

These results represent a significant advancement for RHO adRP patients, as there are currently no approved treatments for this disease.

To address the dominant mutations causing RHO adRP, Prime Medicine’s researchers conducted comprehensive high-throughput screening of over 1,000 prime editing pegRNAs. Two effective prime editors were identified, one for precise correction of the p.P23H mutation in RHO and the other for the mutation hotspot region, which includes 18 different pathogenic mutations such as RHO p.V345L and p.P347L.

Prime Medicine subsequently developed and optimized a proprietary dual AAV vector system to deliver the prime editor via subretinal injection in a humanized mouse model. The results showed an editing efficiency of 45% in RHO p.P23H and over 70% in RHO p.V345L and p.P347L. Correcting 25% of the mutations was sufficient to halt the progression of RHO adRP, and these edited mutations represent approximately 60% of patients with the disease.

 

 

About Prime Editing

In October 2019, Professor Liu Ruqian, a pioneer in gene editing technology, published a paper in the journal Nature, introducing a new precise gene editing tool called prime editing (PE). This tool can effectively achieve free conversion of all 12 single-base changes without relying on DNA templates and can accurately insert or delete multiple bases. The tool has the potential to repair 89% of the known pathogenic human genetic variations, approximately 75,000 in total.

Prime Medicine's Breakthrough in Editing for Genetic Eye Diseases

 

Following this, Professor Liu Ruqian established Prime Medicine in 2022, which went public on Nasdaq in October.

Prime editing improves upon previous CRISPR-Cas9-based gene editing technologies, which rely on DNA double-strand breaks (DSB), and DSBs can lead to adverse outcomes such as unpredictable insertion or deletion of gene sequences, chromosomal abnormalities, and potential cancer risks. Liu Ruqian also pioneered base editing, which does not require DSB to achieve precise gene editing but can edit only single bases. Prime editing, on the other hand, does not require DSB and can achieve both base editing and precise insertion or deletion of multiple bases.

In May 2023, Professor Liu Ruqian’s team published a paper in Nature Biotechnology introducing an improved and upgraded version of prime editing called Twin Prime Editing (TwinPE). It can delete, replace, integrate, and invert large DNA segments, providing an effective tool for treating complex human genetic diseases caused by large gene mutations.

 

Prime Medicine's Breakthrough in Editing for Genetic Eye Diseases

 

Prime Medicine’s website lists 18 development projects, with the most advanced one being a therapy for treating Chronic Granulomatous Disease (CGD), which is currently in the IND application stage. CGD is an X-linked recessive genetic disease caused by mutations in the CYBB gene, which encodes for the gp91-phox subunit of the NADPH oxidase enzyme. Patients experience recurrent suppurative infections throughout their body, and severe cases can lead to sepsis and life-threatening conditions.

In May of this year, Prime Medicine’s researchers presented their latest preclinical data at the 26th Annual Meeting of the American Society of Gene and Cell Therapy (ASGCT), reporting the potential of prime editing to correct pathogenic mutations in CGD. The data showed that prime editing precisely corrected the p47phox pathogenic mutation in CD34+ long-term hematopoietic stem cells from four donors, achieving an editing level exceeding 92% and restoring the NADPH oxidase activity and myeloid cell function in their progeny.

At the ASGCT meeting, Prime Medicine highlighted its prime editing-assisted site-specific integration nuclease gene editing platform (PASSIGE™), demonstrating its potential applications in generating multi-edited CAR-T cell therapies for certain cancers and immune diseases without using viral vectors.

Additionally, there are three projects in the prime optimization stage for treating Wilson’s Disease (WD) using lipid nanoparticles (LNP) delivery, Retinitis Pigmentosa (RP) using adeno-associated virus (AAV) delivery, and Friedreich’s ataxia (FA) using AAV delivery.

 

R&D pipeline

Prime Medicine's Breakthrough in Editing for Genetic Eye Diseases

 

 

 

 

 

References:
https://www.nature.com/articles/s41586-019-1711-4
https://www.nature.com/articles/s41587-023-01758-z
https://primemedicine.com/pipeline/
https://investors.primemedicine.com/news-releases/news-release-details/prime-medicine-presents-first-vivo-proof-concept-prime-editing

Prime Medicine’s Breakthrough in Editing for Genetic Eye Diseases

(source:internet, reference only)


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