World Hemophilia Day | China Approves First AAV Gene Therapy Drug: How Humanized Animal Models Enable Breakthroughs in Rare Disease Treatment

On April 10, China’s National Medical Products Administration (NMPA) officially approved Dalnacogene Pankparvovec Injection (brand name: XinJiuning, research code: BBM-H901)—an adeno-associated virus (AAV)-based gene therapy developed by Belief BioMed—for the treatment of adult patients with hemophilia B. This approval marks a historic milestone as China’s first approved gene therapy drug for a rare disease, this innovative “one-time administration, long-term efficacy” treatment not only significantly improves patients’ quality of life but signals the country's entry into a new era of commercialization for advanced therapeutics like gene therapy.

The announcement comes just ahead of World Hemophilia Day (April 17), this major breakthrough highlights a new era of transformation in hemophilia research—reminding us that even though the journey from genetically engineered animal models to clinical translation is long, progress is well underway.

Understanding Hemophilia and the Role of Gene Therapy

Hemophilia refers to a group of inherited bleeding disorders caused by deficiencies in specific coagulation factors. The main subtypes include:

• Hemophilia A – caused by F8 gene mutations & resulting factor VIII deficiency
  
• Hemophilia B – caused by F9 gene mutations & resulting factor IX deficiency
  
• Hemophilia C – less common, caused by F11 gene mutations & resulting  factor XI deficiency
  

Among these subtypes, Type A and Type B are the most prevalent. Currently, factor replacement therapy remains the mainstay treatment for hemophilia.^[1]

The newly approved injectable therapy, BBM-H901, uses a liver-targeted recombinant adeno-associated virus (rAAV) vector to deliver an optimized human Factor IX (F9) gene directly to hepatocytes. Clinical data show that BBM-H901 significantly reduces the annualized bleeding rate (ABR) and leads to rapid, sustained expression of factor IX, offering a substantial improvement over traditional prophylactic factor IX replacement therapy. It rapidly increases and sustainably maintains factor IX activity levels in patients, thereby effectively preventing bleeding episodes.

Animal Models Reshape Gene Therapy Development

The path to clinical approval for gene therapy depends heavily on the availability of reliable and predictive preclinical models. Animal models enable researchers to evaluate therapeutic efficacy, safety, and gene expression dynamics under conditions that closely mimic human physiology. However, conventional models often fall short due to interspecies differences in gene regulation.

To address this, researchers are increasingly adopting humanized gene replacement animal models—in which the mouse gene is replaced in situ with the human ortholog, including introns and regulatory regions. These models offer significantly enhanced reliability of preclinical studies and accelerated transition of gene therapies into clinical trials, particularly for liver-targeted gene therapies like those for hemophilia.

Cyagen’s HUGO-GT™ Program: Enabling Innovation in Hematological Disease Research

Cyagen has developed a suite of validated animal models of disease through its HUGO-GT™ (Humanized Genomic Ortholog for Gene Therapy) Program. To support the development of gene therapies for hematological disorders, including coagulation-related diseases, we have established various Hemophilia models such as the B6-hF9 mouse (Catalog No. C001644), as well as B6-F8 KO and F9 KO mouse models.

Additional Humanized Models for Hematological Disease Research are below:

Validation of the B6-hF9 Humanized Mouse Model

The following findings confirm the B6-hF9 model as a robust platform for studying hemophilia B and testing novel gene therapies targeting the human F9 gene.

(1) Gene Expression Analysis

Figure 1. Detection of Human and Mouse F9 Gene Expression in the Livers of Wild-Type (WT) and B6-hF9 (hF9) Mice (7 weeks old).
RT-qPCR analysis showed significant expression of the human F9 gene in the livers of male B6-hF9 mice, with no detectable expression of the mouse F9 gene. In contrast, male wild-type mice exhibited strong expression of the mouse F9 gene, with no detectable human F9 expression (n = 3, Bars represent mean ± SEM).

(2) Protein Expression Analysis

Figure 2. Detection of Human Factor IX Expression in Plasma of Wild-Type (WT) and B6-hF9 (hF9) Mice (6 weeks old).
ELISA results showed that both female and male B6-hF9 mice exhibited significantly higher levels of human Factor IX in their plasma compared to wild-type mice (n = 5, Bars represent mean ± SD).

(3) Coagulation Panel Tests

Figure 3. Comparative Analysis of Coagulation Parameters in Wild-Type (WT) and B6-hF9 (hF9) Mice (6 weeks old).
Activated partial thromboplastin time (APTT), prothrombin time (PT), thrombin time (TT), and fibrinogen (FIB) levels showed no statistically significant differences between female and male B6-hF9 mice and their wild-type counterparts (nB6-hF9 = 5, nWT = 4, Bars represent mean ± SEM).

Conclusion: Humanized Mouse Models Drive the Future of Gene Therapy for Hemophilia

The approval of China's first AAV-based gene therapy drug for hemophilia B marks a pivotal advancement in rare disease treatment and gene therapy commercialization. As the field accelerates toward more effective and durable therapeutic options, the role of animal models, particularly humanized mouse models, has never been more critical. These models bridge the gap between basic research and clinical application, providing essential data on gene expression, protein functionality, and safety profiles.

Cyagen’s HUGO-GT™ platform offers a suite of genetically humanized mouse models—such as B6-hF9 for hemophilia B—that support translational research and the development of next-generation AAV gene therapies. As we commemorate World Hemophilia Day, we recognize the profound impact of these tools in driving innovation and improving patient outcomes in hemophilia treatment and other hematological disorders.

Cyagen’s Next-Generation Humanized Mouse Models: HUGO

Cyagen has launched the HUGO (Humanized Genomic Ortholog) Project, inviting global partners to collaborate on developing novel fully humanized models to support new drug development.

HUGO-GT™ Next-Generation Humanized Models

The Humanized Genomic Ortholog for Gene Therapy (HUGO-GT™) mouse model offers a higher degree of humanization compared to traditional models to serve as an effective evaluation platform, especially for gene therapy drugs with high requirements for gene sequence integrity, such as ASO, Targeted Gene Editing, and siRNA.

Our HUGO-GT^TM fully humanized genome mice are developed based on the proprietary TurboKnockout-Pro technology to achieve in situ replacement of mouse genes, encompassing a broader range of intervention targets and providing full coverage of pathogenic gene mutation sites-all without patent or ownership disputes. The fully humanized target genes within these models are consistent with the pathogenic genes carried by humans and cover the majority of drug targets, significantly enhancing screening efficiency for various types of preclinical drug experiments.

Cyagen's AI-AAV platform

AAV is a widely used delivery vector in gene therapy, and the modification of AAV capsid proteins is beneficial for ensuring the safe and effective delivery of target genes to the human body. Cyagen's AI-AAV platform revolutionizes gene therapy by addressing industry hurdles through efficient screening for multi-target AAV mutants used in gene therapy drugs. Cyagen's established artificial intelligence (AI) model, powered by deep learning, enables targeted predictions for the brain via intravenous injection or intrathecal injection, whole-eye expression and retinal penetration via intravitreal injection. Compared to traditional directed evolution, AI-assisted screening of AAV has achieved multidimensional breakthroughs by providing high yield, high tissue targeting, and superior sequence quantity/quality in less time—overcoming current bottlenecks in gene therapy.