Specializing in advanced preclinical research for rare gastrointestinal disorders, Protheragen offers comprehensive and fully tailored development services of animal models for drug discovery and development. With a dedicated focus on tyrosinemia type I, we provide end-to-end solutions, from model generation and validation to preclinical trial support, ensuring a robust foundation for the assessment of novel therapeutic candidates.

Introduction to Tyrosinemia Type I Animal Models

Tyrosinemia Type I is a severe disorder caused by a deficiency in the enzyme fumarylacetoacetate hydrolase (FAH). It causes the accumulation of toxic metabolites like succinylacetone, resulting in progressive hepatic and renal damage. Animal models for this condition are critical for understanding the pathogenesis of the disease to assess therapeutics, like enzyme replacement, gene therapy, and small molecules. They reproduce important characteristics of the disease, like liver cell injury, renal tubule dysfunction, and the potential development of liver cancer, thereby creating a valuable biologically relevant system for preclinical evaluation.

Fig.1 An engineered E. coli Nissle strain averts lethal liver injury in a tyrosinemia type 1 mouse model. (Gu, P., et al., 2023)

Methods of Tyrosinemia Type I Animal Model Development

Constructing high-fidelity tyrosinemia type I animal models is driven by advanced methodologies aimed at accurately imitating the human FAH enzyme deficits and subsequent pathological outcomes for dependable preclinical studies.

The most pathophysiologically relevant genetically engineered model entails precisely replicating the human genetic defect via targeted disruption of the Fah gene. This is efficiently and frequently achieved in mice using gene editing and classical homologous recombination in embryonic stem cells, leading to the formation of constitutive or conditional knockout strains.

Our Services

Protheragen provides an integrated, client-centered tyrosinemia type I animal model development service because of our unique combination of professional capabilities in rare diseases and our advanced genetic and phenotyping technology. With the experience of creating highly predictive and reproducible animal models, we facilitate a scientifically sound and dependable translational pathway from drug candidate selection to application studies by validating models against key biomarkers and histopathological characteristics.

Animal Models of Tyrosinemia Type I

Protheragen provides a comprehensive portfolio of validated and customizable animal models for tyrosinemia type I research, each designed to meet specific experimental requirements in preclinical drug development.

Genetically Engineered Models

Utilizing advanced gene-editing technologies, we offer constitutive and conditional knockout models that faithfully recapitulate the human FAH gene defect.

• Fah-KO Mouse Model
• Fah-KO Rabbit Model

• Fah-KO Rat Model
• Others

Fah-KO Mouse for Tyrosinemia Type I Research

Case Study: Fah KO Mouse Model

Model Introduction

Utilizing a C57BL/6 mouse strain, this model employs a Fah gene knockout (Fah KO) design to replicate human hereditary tyrosinemia type I. The Fah gene, which is homologous to the human FAH gene, is knocked out via advanced gene editing technology. Without intervention, this results in a lethal phenotype shortly after birth, characterized by acute hepatic and renal dysfunction, hypoglycemia, and dysregulated metabolism. Therefore, the sustained survival of homozygous Fah KO mice requires continuous administration of nitisinone (NTBC).

Methodology

• Animal Model: Gene editing was used to knock out the Fah gene to simulate acute tyrosinemia type I. NTBC was added to the drinking water of the pregnant female mice in the late stage of pregnancy at a concentration of 7.5 mg/L. NTBC treatment was continued for the pups from birth until they reached 6 weeks of age. Subsequently, NTBC was withdrawn to induce acute disease onset, and the mice were monitored for phenotypic progression over a 14-day period.
• Phenotypic Analysis Methods: Comprehensive phenotypic evaluation includes body weight tracking and plasma tyrosine level measurement to assess metabolic disruption. Histopathological examination of liver tissue is performed using hematoxylin and eosin (H&E) staining, enabling detailed observation of structural abnormalities.

Phenotypic Analysis & Results

Upon termination of NTBC treatment, Fah-KO mice exhibited a significant reduction in body weight and a marked elevation in plasma tyrosine levels compared to WT mice (Fig.2). Histological assessment of the liver by H&E staining revealed severe damage in Fah-KO mice, characterized by extensive hepatocyte hyaline degeneration, increased cytoplasmic vacuolization, and loss of distinct cellular boundaries. In contrast, liver tissue from the control group showed no obvious pathological abnormalities.

Fig.2 Body weight changes (A) and plasma tyrosine concentration analysis (B) of Fah KO and WT mice after the termination of NTBC treatment. Data are presented as mean ± SEM (n=5).

Conclusion

The Fah KO mouse model reliably mirrors the pathophysiology of human tyrosinemia type I, demonstrating key disease features such as progressive weight loss, tyrosine accumulation, and severe liver damage following NTBC cessation. This robust model provides a validated, reproducible tool for evaluating novel therapeutics and exploring disease mechanisms in a controlled preclinical setting.

Contact Us

A robust and well-characterized tyrosinemia type I animal model is indispensable for advancing therapeutic candidates through rigorous preclinical evaluation, encompassing detailed pharmacodynamics, pharmacokinetics, and toxicology profiles. Protheragen can provide the dependable and high-fidelity preclinical models that your company needs for therapeutic discovery and de-risk your research and development. For project consultations and detailed service proposals, please contact our scientific team to discuss how we can support your specific research program.

Reference

• Gu, Peng et al. "An engineered Escherichia coli Nissle strain prevents lethal liver injury in a mouse model of tyrosinemia type 1." Journal of hepatology 80.3 (2024): 454-466.

All of our services and products are intended for preclinical research use only and cannot be used to diagnose, treat or manage patients.