VYGene Therapeutics Leverages HSV-1 Vector Platform to Drive Differentiated Gene Therapy Pipeline Amid Industry Growth

In recent years, the cell and gene therapy sector has garnered significant favor from capital markets, with major transactions occurring frequently. Driven by active investment, increasingly clear regulatory frameworks, and continuous advancements and optimizations in technologies such as genetic engineering, expression vectors, and gene delivery systems, the global gene therapy industry has witnessed rapid progress.

Among these, in the field of viral vector-based gene therapy, the HSV-1 vector oncolytic virus T-VEC has been approved by the FDA for the treatment of melanoma; the adeno-associated virus (AAV) vector Luxturna has been approved by the FDA for retinal dystrophy associated with RPE65 gene mutations; and the AAV vector Zolgensma has been approved by both the FDA and the EMA for the treatment of spinal muscular atrophy.

Behind the successive approvals of related products, it is evident that the gene therapy industry is flourishing.

Vector technology is the key to the success of gene therapy.Most gene therapy companies use adeno-associated virus (AAV) vectors. AAV offers advantages such as a broad host cell range, stable expression, and the ability to achieve high titers; however, safety concerns have emerged in several recent case studies. As new gene therapy technologies advance, AAV vectors still face challenges that require breakthroughs, particularly regarding their gene cargo capacity and dosage requirements.

While continuously striving to break through existing technological limitations, an alternative approach is to forge a new path by establishing appropriate vector technologies that circumvent these issues at the source. Herpes simplex virus type 1 (HSV-1) vectors offer advantages in terms of safety and cargo capacity, making them one of the most promising viral vectors in recent years.

In terms of safety:HSV-1 is one of the most common viruses to which humans are susceptible. Clinical manifestations of HSV-1 infection in daily life include cold sores at the corners of the mouth and inflammatory symptoms in the throat, often colloquially referred to as “shanghuo” (internal heat). Under normal circumstances, no one experiences severe health issues due to such “shanghuo” symptoms. This is because, unlike other viral vectors, HSV-1 does not integrate into or disrupt the human genome, nor does it cause integrative mutations, thereby demonstrating a favorable safety profile. Upon reactivation of HSV-1 in the body, the human immune system gradually adapts to the virus, ultimately establishing a state of lifelong symbiosis.

Thus, HSV-1 vectors offer inherently controllable safety profiles compared to other viral vectors. Clinical data from T-VEC, an HSV-1 vector-based therapy approved in the United States, demonstrate that this gene therapy has not been associated with any serious adverse events, with only mild Grade 1 and Grade 2 clinical reactions, such as fever, observed.

In terms of loading capacity:HSV-1 can accommodate approximately 30 kb of exogenous genes, which is eight times the loading capacity of commonly used AAV vectors (AAV vectors can carry approximately 4 kb of exogenous genes). Due to the higher payload capacity of HSV-1 vectors, they can deliver multiple therapeutic genes, thereby addressing the limitations of AAV vectors in delivering large genes or treating polygenic diseases.

Regarding the functions of the vector:HSV-1 vectors possess a broad host cell spectrum. Engineered replication-deficient vectors can efficiently deliver target genes to various cell types, making them suitable for the treatment of multiple diseases.

Based on its unique neurotropism and non-cytotoxic nature toward neural cells, HSV-1 can establish long-term latency in neurons through the expression of latency-associated transcripts (LATs). Consequently, HSV-1-based vectors have emerged as the most efficient gene delivery systems for the nervous system, offering distinct advantages in the treatment of neurological disorders. Internationally, they are widely utilized in basic research and drug development for conditions such as Parkinson’s disease, Alzheimer’s disease, and chronic pain.

HSV-1 also exhibits strong infectivity toward epithelial cells and skeletal muscle cells, making it suitable for the treatment of dermatological conditions and other indications such as psoriasis, hemophilia A, and spinal muscular atrophy. Furthermore, given its high transfection efficiency in dendritic cells (DCs) and capacity to carry multiple antigen genes, HSV-1 vectors hold considerable promise as gene vaccines. Due to their broad tropism and high transduction efficiency, HSV-1 vectors are also playing an increasingly important role in RNA interference research.

HSV-1-based gene therapy offers numerous advantages; what are the key technical barriers associated with it?

First, the design and construction of the HSV-1 vector backbone are relatively complex.It is necessary to knock out essential genes of the herpes simplex virus type 1 (HSV-1) to prevent viral replication in normal cells and facilitate the establishment of latency. Furthermore, since the virus cannot replicate after the deletion of essential genes, corresponding engineered cell lines must be established to express these genes and support viral production. Compared with other vectors, the development of HSV-1-based vectors involves more complex procedures and higher technical barriers, requiring years of technological accumulation to establish a comprehensive and robust system.

To translate gene therapy products based on prior technical reserves, it is also necessary to establish an appropriate CMC process and a corresponding quality standard system.Gene therapy is a “new and fast-moving” sector, where many technologies require redevelopment for industrialization, and it is also an area of rapid development. Therefore, establishing Chemistry, Manufacturing, and Controls (CMC) for gene therapy products presents certain challenges, necessitating industry-wide collaboration and the accumulation of corporate expertise.

It is not uncommon for companies abroad to pursue gene therapy strategies using HSV-1 as a vector. Leveraging the unique advantage of HSV-1 vectors in more effectively entering skin cells, the U.S. gene therapy company Krystal Biotech has developed multiple gene therapies for rare skin diseases, employing gene-edited HSV-1 as the delivery vector.

Krystal’s KB105, developed for the treatment of congenital ichthyosis, and KB407, for cystic fibrosis, have been granted Orphan Drug Designation by the U.S. Food and Drug Administration (FDA). KB103, for the treatment of dystrophic epidermolysis bullosa (DEB), has received Regenerative Medicine Advanced Therapy (RMAT) Designation and Orphan Drug Designation from the FDA, as well as Priority Medicines (PRIME) designation from the European Medicines Agency (EMA) for DEB. KB103 has achieved positive results in Phase 3 clinical trials, with a New Drug Application (NDA) expected to be submitted to the FDA in 2022.

In China, although no HSV-1-based products have been approved for market launch to date, relevant companies have already made strategic moves in this area. Beijing Weiyuan Likang Biological Technology Co., Ltd. is currently the only company in China that has laid out its business in both oncolytic virus and gene therapy product directions using HSV-1 as a vector.

Beijing Weiyuan Likang Biological Technology Co., Ltd. was established in 2017. Its core team has enjoyed over a decade of seamless collaboration. The company possesses a herpes simplex virus type 1 (HSV-1) vector technology platform backed by more than 16 years of technical expertise. Its candidate drugs target major diseases, including cancer, neurological disorders, immune system diseases, hematological conditions, and genetic disorders, offering broad market prospects.

Weiyuan Likang’s HSV-1 vector technology platform utilizes a proprietary, independently isolated HSV-1 viral strain and holds independent intellectual property rights. For HSV-1 vector construction, Weiyuan Likang has developed a suite of tools employing various methods, including CRISPR-Cas9 gene editing. This platform features rapid development, stable viral seed stocks, and high-level expression of carried functional genes.

Due to the large size and susceptibility to inactivation of HSV-1 vector particles, their large-scale production poses significant challenges. Through years of research accumulation—from establishing cell lines and developing Chemistry, Manufacturing, and Controls (CMC) processes to participating in the formulation and establishment of China’s first quality standards for HSV-1 oncolytic viruses—the team has developed a stable and efficient platform for the large-scale manufacturing of gene therapy drugs. As one of the few domestic companies with independent industrialization capabilities, the company leverages its mature production processes and effective cost control to offer more affordable product pricing.

Based on the HSV-1 vector technology platform, Weiyuan Likang’s products under development include oncolytic virus products and gene therapy products for non-oncological indications.

Currently, the oncolytic virus product series developed by Weiyuan Likang that are advancing more rapidly include VT1093 and VT1092., received Clinical Trial Approval Notices issued by the National Medical Products Administration (NMPA) in 2020 and 2021, respectively. The clinical trials of VT1093 are being conducted simultaneously at Shanghai Pudong Hospital, Beijing Tongren Hospital, and other medical centers, with favorable safety outcomes already observed.

Weiyuan Likang’s gene therapy product portfolio is primarily focused on the treatment of rare diseases and other major conditions. Indications for its drug candidates include psoriasis, hemophilia A, rare skin disorders, and spinal muscular atrophy, with multiple pipelines having completed early-stage development.

Compared with the development of oncology drugs, the clinical trial process for this product line is relatively faster. Under normal circumstances, the clinical phase trials for oncology drug development typically take approximately 5 to 7 years. In contrast, the development of gene therapies for rare diseases can complete clinical phase trials within 2 to 3 years through various green channel pathways, enabling market launch at the fastest possible speed.

Currently, non-oncolytic gene therapy products with relatively rapid progress include VGC1082 and VGC1025.

VGC1082 is indicated for the treatment of hemophilia A and is administered via intramuscular injection. Hemophilia A accounts for 80% to 85% of all hemophilia patients. According to relevant statistics, the global market for hemophilia (primarily comprising treatments for hemophilia A and hemophilia B) has exceeded $10 billion, with projections indicating it will surpass $15.1 billion by 2025, reflecting a compound annual growth rate (CAGR) of 4.5% from 2017 to 2025. VGC1082 is also expected to initiate its clinical trial application process this year.

VGC1025 is indicated for the treatment of epidermolysis bullosa. Epidermolysis bullosa is classified into hereditary (congenital) and acquired forms. This disease has been included in China’s first batch of rare diseases catalog, with approximately 20,000 new cases annually in China. Currently, there are no effective therapeutic agents available, indicating strong market demand.

In addition to the aforementioned core projects, Weiyuan Likang currently has more than a dozen products in its pipeline advancing concurrently. Looking ahead, we anticipate that Weiyuan Likang will address major diseases—including cancer, neurological disorders, immune system diseases, hematological conditions, and genetic disorders—through gene therapy approaches. The company aims to gradually evolve into an integrated biopharmaceutical enterprise encompassing R&D, manufacturing, and sales of biopharmaceuticals, thereby delivering highly effective and affordable gene therapy products to a broader patient population.