Zhongyin Biotech Advances Domestic Ophthalmic Gene Therapy for Inherited Retinal Diseases with Clinical Integration and Pipeline Progress

Inherited Retinal Dystrophies (IRDs), known in Chinese as hereditary retinal degenerations, are the most common and severe ophthalmic genetic disorders in clinical practice. They encompass a range of conditions, including retinitis pigmentosa and Leber congenital amaurosis, and represent the leading cause of blindness in children and the working-age population. Currently, there are no effective treatments for IRDs.

Due to the unique anatomical features of the eye, including transparent refractive media, a relatively enclosed structure, and high immune privilege, ophthalmic diseases are considered one of the most suitable areas for gene therapy, with a fairly mature industrial development. In 2017, Spark Therapeutics' RPE65 gene replacement therapy drug Luxturna became the first FDA-approved gene therapy for inherited retinal diseases (IRDs). In December 2018, the U.S. FDA approved Editas Medicine's CEP290 gene-editing therapy for clinical trials, marking the first CRISPR/Cas9-based treatment authorized for use in humans. Furthermore, major multinational pharmaceutical companies have actively entered this field. According to incomplete statistics, there are currently more than ten IRD gene replacement therapies in clinical trial stages worldwide.

Professor Yang Liping, an ophthalmology expert at Peking University Third Hospital, told VCBeat that the incidence of inherited retinal diseases (IRDs) in Western countries is approximately 1/3,784 to 1/4,000, whereas in China it is as high as around 1/1,000. “Although Luxturna is actively seeking market entry in China, its high cost significantly limits accessibility. Moreover, there are substantial differences in the spectrum of disease-causing genes and mutation hotspots between patients in China and those abroad. Therefore, directly using imported gene therapy drugs is not the optimal choice for domestic patients.”

In fact, with the approval and market launch of Luxturna, domestic capital in China has begun to enter this field, significantly driving the development of ophthalmic gene therapy drugs. However, the research and development of gene therapy drugs involves complex scientific accumulation and specialized industrialization requirements. Key aspects such as target screening in the early stages of drug development, target design, drug safety and efficacy evaluation systems, vector delivery systems, and surgical procedures all require years of experience to master. Only a few research institutions and enterprises with solid R&D foundations have the capability to drive substantial progress in the industrialization of ophthalmic gene therapy drugs.

In 1998, while pursuing her master’s degree at the Zhongshan Ophthalmic Center, Yang Liping studied under Professor Zhang Qingjiong, embarking on a long-term research career in hereditary eye diseases. During her doctoral studies, Yang Liping and Professor Cao Anmin’s team discovered that photoreceptor apoptosis is the common ultimate cause of blindness in hereditary retinal degenerations caused by various pathogenic genes. Based on this finding, the research team hypothesized that blocking the photoreceptor apoptosis pathway could provide a unified and effective therapeutic approach for these diseases.

Through extensive experiments, Yang Liping and her team identified microglia as playing a critical role in photoreceptor apoptosis associated with hereditary retinal degeneration. Inhibiting microglial activation can effectively slow the progression of retinal degeneration; however, “if the underlying genetic mutations are not corrected, this therapeutic benefit will be very limited.”

Constrained by limited technical capabilities, research progress on alleviating retinal degeneration through gene repair has been exceedingly slow. In the early stages, Yang Liping could only employ single-strand conformation polymorphism (SSCP) to detect gene mutations, and completing genetic diagnosis for a single family often required three to four months. This situation began to improve only after next-generation sequencing (NGS) technology gradually entered laboratory and clinical applications.

Subsequently, with the support of Director Ma Zhizhong, Professor Yang Liping’s team developed the “Genetic Diagnostic Chip for Hereditary Eye Diseases” based on target sequence capture technology and established a genetic diagnostic platform for hereditary eye diseases. This platform was among the first in China to conduct clinical genetic diagnosis of hereditary eye diseases. According to Professor Yang Liping, the first-generation chip could effectively capture 371 pathogenic genes associated with 36 common hereditary eye diseases. After multiple updates, “the currently used chip has been upgraded to the fifth generation, which can effectively capture 441 pathogenic genes associated with 76 common hereditary eye diseases.”

To date, Professor Yang Liping’s team has established a clinical genetic diagnostic platform for hereditary eye diseases at the Peking University Eye Center. By leveraging the “Hereditary Eye Disease Genetic Diagnostic Chip,” next-generation sequencing (NGS), and Sanger sequencing, supplemented by advanced bioinformatics analysis, the platform has provided free pathogenic gene diagnostics to over 2,000 families with hereditary eye diseases. Furthermore, in collaboration with the Reproductive Medicine Center and the Department of Obstetrics and Gynecology at Peking University Third Hospital, Professor Yang’s team has utilized prenatal diagnosis and preimplantation genetic diagnosis (PGD) to assist dozens of patients with hereditary eye diseases in having healthy offspring.

Meanwhile, Professor Yang Liping’s team has successively achieved significant milestones in their research on gene replacement therapy drugs, which began in the second half of 2011. “Preliminary real-world genetic diagnostic data helped us summarize the spectrum of gene mutations and mutation hotspots in Chinese patients with hereditary retinal degeneration.”

Professor Yang Liping candidly stated that research into gene therapy drugs is no easy task. “It took us nearly three years just to complete preliminary work, such as refining supporting instruments and equipment and exploring appropriate implementation methods.” Taking mouse models as an example, preclinical studies on gene therapy for inherited retinal degenerations rely on these models to evaluate in vivo efficacy and safety. However, the murine eye is significantly smaller than the human eye, making procedures such as subretinal injection in mice, assessment of visual function post-treatment, and histomorphological and molecular biological evaluations of ocular tissues highly technically demanding. Building on this foundational exploration, Professor Yang Liping’s team has established nearly 20 mouse models of inherited retinal degenerations. In collaboration with multiple partners, they have launched several research projects on gene replacement and gene editing therapies. Many of these studies have essentially completed their preclinical development phases, and clinical trials are being actively advanced.

In Professor Yang Liping’s view, the research and development of gene therapy drugs is akin to the growth of bamboo, requiring gradual cultivation and accumulation. However, once the technology matures, it should not remain confined to the laboratory; instead, it must be translated into tangible products for clinical application. “How to transform years of technological expertise into solutions that address patients’ needs is a question I have been contemplating,” she stated.

Following promising results in animal studies of the gene replacement and gene editing therapies developed by her team, Professor Yang Liping began exploring the possibility of collaborating with CHIGENOVO, a biotechnology company specializing in clinical genetic diagnosis, reproductive prevention, and the development of gene therapy drugs for hereditary eye diseases, to advance the commercialization of these achievements.

“In our preliminary work, we have completed a series of foundational studies and animal experiments, demonstrating the feasibility of gene therapy in vivo and observing initial therapeutic effects,” pointed out Professor Yang Liping. “Drug development requires close coordination across multiple stages, including basic research, GMP-grade AAV virus production, clinical trials, regulatory submission, and commercialization.”

CHIGENOVO, established in January 2016 and headquartered in Beijing, holds the status of a National High-Tech Enterprise. The company has received investments from several renowned equity funds, including Puhua Capital, Cowin Capital, and Shouke Kaiyang. CHIGENOVO’s gene therapy drug R&D platform features an experimental area of approximately 500 square meters, comprising a molecular biology laboratory, a stem cell laboratory, an AAV virus packaging laboratory, a biological evaluation laboratory, and an IVD product development laboratory. Additionally, the company’s genetic diagnostic platform for hereditary eye diseases is qualified as a third-party medical testing laboratory, capable of handling clinical genetic diagnostics for 500 hereditary eye disease samples per month.

Despite years of experience as ophthalmologists and researchers, Professor Yang Liping and her team are highly proficient in basic research and clinical drug trials but have limited knowledge of the mid-to-downstream stages of drug development. By collaborating with CHIGENOVO to develop gene therapy drugs, both parties can leverage their complementary strengths, with the latter addressing the research team’s shortcomings in areas such as AAV vector production and regulatory submissions. Furthermore, after validating the feasibility of gene therapy for a specific gene, significant human and material resources are required for process optimization to identify the optimal target. “Leveraging the capabilities of a corporate team can achieve twice the results with half the effort.”

In October 2019, CHIGENOVO submitted an application for exploratory clinical trials. Its two investigational products, ZVS101e (gene replacement) and ZVS203e (gene editing), were set to complete small-scale process development and foundational research, respectively, targeting various types of gene mutations including RPGR, CYP4V2, PDE6B, USH2A, and PRPF31. Among these, ZVS101e was expected to submit an Investigational New Drug (IND) application by the end of 2020.

It is reported that CHIGENOVO has initiated a new round of financing amounting to tens of millions of RMB. The funds will be primarily used to complete two exploratory clinical studies and submit the Investigational New Drug (IND) application for ZVS101e.