In April 2024, Professor Wei Wenbin's team, Researcher Yang Liping's team, and Associate Researcher Wang Likun's team, in Nature Subsidiary periodical Signal Transduction and Targeted Therapy（IF=39.3）Published a paper entitled“Gene replacement therapy in Bietti crystalline corneoretinal dystrophy: an open-label, single-arm, exploratory trial”The research paper reports favorable safety and superior efficacy results due to clinical trials of the technology ZVS101e.

The study was a single-arm, open-label, exploratory clinical trial involving 12 participants, each receiving a single intraocular subretinal injection of the same dose of ZVS101e, with the primary purpose of evaluating the safety of the drug and the secondary purpose of evaluating the efficacy of the drug. Safety measures include the type, incidence and severity of adverse events and immunogenicity. Efficacy evaluation indicators mainly included best corrected visual acuity (BCVA), microfield of vision, multifocal electroretinogram (mfERG) and Visual function questionnaire (VFQ-25). After treatment, the efficacy of the drug was evaluated using the baseline of the injection eye as the control.

At present, patients have been followed up for 180-365 days, during which most adverse events were mild or moderate, and most were related to surgery or oral hormones. No drug-related serious adverse events and immunotoxic-related adverse events were observed, showing a good safety profile.

After treatment, participants showed visual improvement as early as 2 weeks after surgery and maintained it for at least 1 year. At 180 and 365 days postoperatively, the treated eye BCVA improved by an average of 9.0 and 11.0 letters from baseline. At 365 days after surgery, 80% of subjects had an improvement in BCVA from baseline, of which 40% had an improvement of ≥15 letters, which was clinically significant. The results show that ZVS101e gene therapy not only prevents visual decline in BCD patients, but even reverses the natural course of progressive deterioration of patients, which is of great significance in the field of BCD treatment. The average light sensitivity of micro visual field improved from baseline, indicating the improvement of visual field function; the comprehensive score of visual function questionnaire increased from baseline; the scores of general vision and peripheral vision significantly increased, indicating the improvement of vision-related quality of life of subjects. In addition, at 365 days after surgery, 100% of the subjects showed an increase in the amplitude density of the mfERG P1 wave, an indicator of objective visual function, from baseline, representing an improvement in the function of the subjects' retinal cells, indicating that the visual improvement in the subjects was not a placebo effect.

Figure 1 Change in BCVA from baseline after drug administration

Research team

Wei Wenbin, Professor of Ophthalmology, Beijing Tongren Hospital Affiliated to Capital Medical University, Yang Liping, Researcher of Ophthalmology, Peking University Third Hospital, and Wang Likun, Associate researcher, Peking University School of Basic Medicine are co-corresponding authors of this paper. Dr. Wang Jinyuan, PhD 2023 graduate of Beijing Tongren Hospital, Capital Medical University and postdoctoral/assistant researcher of Tsinghua University School of Clinical Medicine, is the first author of this paper. Beijing Zhongyin Technology Co., Ltd. is the partner of this study, and Professor Wei Wenbin's team jointly conducted the clinical trial, and provided drug and financial support.

ZVS101e injection

The research and development concept of ZVS101e (rAAV8-hCYP4V2) was first proposed by researcher Yang Liping, and after more than ten years of hard exploration, the first investigator-initiated clinical trial was carried out in 2021, which is the first gene therapy clinical trial for BCD disease in the international scope (NCT04722107). In the same year, it was granted orphan drug status by the US FDA. In 2022, ZVS101e injection obtained the IND approval in China and the United States, and the first subject enrolled in the phase I/II clinical trial was completed in February 2023, which is the first registered clinical trial for BCD in the world. At present, the drug has completed phase I/II clinical trials and is about to enter phase III clinical trials, which is expected to bring breakthrough treatment prospects for BCD diseases that are currently incurable, thus providing new and potential treatment options for patients.

Original link: https://www.nature.com/articles/s41392-024-01806-3#Sec30

Crystal-like retinal degeneration (BCD) 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, 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 is no effective treatment for BCD worldwide, and there is an urgent clinical need.

Beijing Zhongyin Technology Co., Ltd. cooperated with the team of Yang Liping, a researcher in the Ophthalmology Department of Peking University Third Hospital, and carried out research on the pathogenesis and gene therapy of BCD with the help of the team's more than 20 years of in-depth research in inherited retinal diseases. Research and development of the original innovative drug ZVS101e injection (rAAV8-hCYP4V2) with independent intellectual property rights, complete a series of in vivo and in vitro pharmacological and pharmacodynamic studies to solve key problems in the field of BCD treatment, non-clinical research results published in Hum Mol Genet 2023, Obtained a total of 6 national invention /PCT patents.