HUGO-GT^TM Grant Awards

“The HUGO-GT program provides valuable insights into the translation of gene therapies from bench to bedside, aiding in the development of targeted and effective treatments for various genetic diseases. I think it has the potential to reshape preclinical model selection, since these mice own the highest level of humanization that you could find from the market, which will be more accurately recapitulate the disease state you’re trying to address.”

——Dr. Marvin Ouyang, CSO of Cyagen Bioscience

Why Humanized Mice?

Compared to traditional transgenic (Tg) animal models, the humanized mouse model is a powerful tool that excels in replicating human physiological and pathological characteristics. This makes humanized mice the preferred choice for studying human diseases and assessing the safety and effectiveness of potential therapeutics. Humanized mice provide improved alignment with human biology, leading to more precise predictions of drug responses and disease mechanisms – potentially streamlining the translation from preclinical research to clinical applications.

What are the shortcomings of current humanized mouse models?

Despite their popularity, common humanized models — including transgenic (Tg) mice, coding sequence (CDS), and single-exon humanized mice — fall short in achieving full human gene integration into the mouse genome. These current-generation models come with notable limitations such as random insertion, complex genetic backgrounds, and inadequate humanized regions.

How can humanized models be improved for preclinical research?

One of the key requirements during preclinical study is selection of appropriate animal models, which help translate basic study into clinical applications. To advance our understanding of disease mechanisms and drug development, there is a pressing need for full-length genomic DNA humanized mice. These models can faithfully replicate human gene expression patterns, regulations, and functional properties in a mouse model. However, replacing the entire genomic DNA sequence poses technical challenges as introducing large exogenous sequences may impact the expression and regulation of endogenous genes, presenting a significant obstacle.

“Current commonly used humanized models can only achieve partial insertion of the human gene, which exhibit notable limitations, including random insertion, complex genetic background and line establishment, as well as inadequate humanized regions. To facilitate further advancement of disease mechanistic study and related drug development, full-length genomic DNA humanized mice — that can faithfully recapitulate the expression pattern, regulation, and functional properties of human gene in a mouse model — are urgently needed to replace the existing animal models and reshape the translational research framework for drug development.”

------ Lance Han, CEO of Cyagen Biosciences

In response to these demands, Cyagen has developed novel whole genomic DNA humanized mouse models for accelerating gene therapy drug development: Humanized Genomic Ortholog for Gene Therapy HUGO-GT™ mice. The HUGO-GT™ next-generation humanized mouse models feature the following technical improvements to provide clinically relevant humanized mouse models more closely aligned with real-world biological mechanisms:

Our proprietary TurboKnockout-Pro technology is used to perform in-situ replacement of the targeted mouse endogenous gene, creating full-length genomic sequence humanized mouse models with a broader range of intervention targets.

Incorporation of our highly efficient large-fragment vector fusion technology enables our wild-type (wt) HUGO-GT™ mice to serve as a versatile template for customized targeted mutagenesis.

In addition to our mouse models, we offer Contract Research Organization (CRO) services in various fields, including ophthalmology, neuroscience, tumor immunology, and other disease areas. Our aim is to empower research on genetic diseases and facilitate the development of gene therapy drugs.

When replacing a mouse gene with the full genomic sequence of its human counterpart, the size of the DNA sequence can pose challenges for CRISPR-based approaches. In such cases, the use of homologous recombination in embryonic stem (ES) cells remains a viable and effective option.

Cyagen has leveraged the power of TurboKnockout-Pro, our proprietary high efficient ES targeting technology, to achieve in-situ replacement of the targeted mouse endogenous gene and successfully construct full-length genomic sequence humanized mouse models: HUGO-GT mice, that encompass a broader range of intervention targets.

HUGO-GT program is a comprehensive approach that combines the advantages of humanizing mouse genes through genomic replacement with the investigation of disease-causing mutations and potential gene therapy interventions.

Advantages of HUGO-GT™ Genomic DNA Humanized Model

• In Situ Gene Replacement: Full genomic sequences (UTR, exon, intron) ensure accurate human gene function within the mouse genomic context and in vivo environment.
• Minimal Gene Regulation Disruption: Maintains natural regulation and expression patterns, preserving different isoforms across tissues and cell types.
• Flexible and Efficient: Initial wild-type humanization on mouse ES cells allows rapid introduction of disease-causing mutations, facilitating drug testing and research.
• Superior Accuracy: Reduces artifacts seen in other models, providing phenotypes that closely resemble human conditions.
• Comparative Superiority: Outperforms models with simple point mutations, CDS-only replacements, and BAC transgenes with random integration.