In May 2024, Peking University Third Hospital Yang Liping team Published in the journal Nature Communications“In vivo genome editing via CRISPR/Cas9- mediated homology-independent targeted integration for Bietti crystalline  corneoretinal dystrophy treatment”The research paper reported the non-clinical results of the efficient, safe and long-term stability of crystalline retinal degeneration (BCD) gene editing therapy, completed the proof of concept of BCD gene editing therapy, and once again achieved a breakthrough in the field of genetic retinal disease treatment technology, laying the technical foundation for realizing the beautiful vision of lifetime cure with one drug administration in the future. Previously, the RHO-adRP gene editing treatment pipeline ZVS203e developed by Yang Liping's team based on gene editing technology has obtained IND license in China and the United States and entered the formal clinical trial stage, the gene editing treatment results for often cryptogenic genetic variation diseases further indicate the potential application prospect of gene editing technology in ophthalmology. It also indicates that the team is further mature in gene editing therapy technology.

Crystal-like retinal degeneration is a hereditary retinal degenerative disease, patients usually 20-30 years old night blindness, with the progression of the disease center vision gradually decreased (average annual decline of 4.5 letters, about equivalent to 1 row of the visual acuity table), most patients about 40 years old due to serious visual impairment and field of vision narrowing become legally blind. The global incidence of BCD is 1 in 57,600, and the disease is more common in East Asia, with an incidence of about 1 in 25,000 in China. BCD is inherited autosomal recessive and is caused by CYP4V2 gene mutation. CYP4V2 gene encodes an ω3-polyunsaturated medium chain fatty acid hydroxylase, which is highly expressed in retinal pigment epithelial cells (RPE) and is involved in fatty acid metabolism. CYP4V2 gene mutation leads to abnormal lipid metabolism in RPE, which leads to degeneration and apoptosis of photoreceptor cells. At present, there are no commercially available treatments for BCD worldwide.

In this study, CRISPR/Cas9 technology was used to explore gene editing therapy based on HITI principle. Results in HEK293T cells, patient-derived iPSC cells, and humanized Cyp4v3 mouse models show that precise DNA repair can be achieved at the DNA level, and the repaired DNA can be efficiently transcribed and translated to effectively treat disease. GUIDE-seq and other methods did not find miss risk. This achievement has a breakthrough significance in the field of treatment of hereditary retinopathy, and provides a new idea and strategy for the treatment of hereditary retinopathy.

Yang Liping, a researcher in the Department of Ophthalmology, Peking University Third Hospital, is the corresponding author of this article. Meng Xiang, PhD student in ophthalmology at Peking University Third Hospital, is the first author of the paper.

Corresponding author: Yang Liping is a researcher of Ophthalmology at Peking University Third Hospital, doctoral supervisor, and deputy director of Beijing Key Laboratory of Reconstruction, Protection and Rehabilitation of Ocular Nerve Injury. She is also a member of the Standing Committee of Birth Defect Prevention and Molecular Genetics Branch of China Maternal and Child Health Care Association and a member of the Genetic Eye Disease Professional Committee of Chinese Medical Doctor Association Ophthalmology Branch. As the project leader, he presided over a number of projects such as the 145th major project of the Ministry of Science and Technology, the National Nature Foundation, and the key project of the North Science and Technology Committee, and published more than 30 SCI articles. With the deep integration of industry, university and research, gene therapy drugs with independent intellectual property rights are developed for the common pathogenic genes and mutation hotspots in Chinese IRDs patients. At present, more than 10 PCT patents and invention patents have been authorized, the BCD gene replacement therapy ZVS101e project has completed phase I/II clinical trials, and the RHO-RP gene editing therapy drug ZVS203e project has obtained Chinese and American IND approval documents.

Professor Yang Liping

Meng Xiang is a PhD candidate in ophthalmology at Peking University Third Hospital and a joint doctoral candidate at the National University of Singapore. He studied with Professor Yang Liping, Ophthalmology Department of Peking University Third Hospital since master degree. The co-mentor of the joint training is Professor Ching-yu Cheng, an internationally renowned expert and physician scientist in fundus diseases. Main research interests: fundus diseases, gene therapy of inherited retinal diseases, genotype and phenotype research, etc.

Dr. Meng Xiang

Original link: https://www.nature.com/articles/s41467-024-48092-9