Noonan Syndrome Animal Model Service

Noonan syndrome animal model service provides researchers with a comprehensive, genetically precise, and physiologically relevant platform to accelerate the discovery and development of novel therapeutics. Protheragen offers a fully customized suite of services, from initial model generation and phenotypic validation to in-depth efficacy and safety studies, tailored to meet the specific objectives of your drug discovery program for this complex RASopathy.

Introduction to Noonan Syndrome Animal Models

Noonan syndrome is a genetically heterogeneous disorder primarily caused by mutations in genes belonging to the RAS/MAPK signaling pathway, such as PTPN11, SOS1, RAF1, and KRAS. It is accompanied by multiple development issues and facial dysmorphia, cardiac anomalies, especially with pulmonic stenosis and hypertrophic cardiomyopathy, short stature, and possible cognitive issues. To faithfully recapitulate the human condition and enable meaningful preclinical research, genetically engineered animal models are indispensable. Our services are built on a foundation of creating and utilizing these sophisticated models that accurately mirror the genotypic and phenotypic hallmarks of Noonan syndrome, providing a critical bridge between in vitro findings and further trials.

Fig.1 Trametinib significantly reduced established cardiac hypertrophy in Lztr1^R409C/+ mice. (Abe, T., et al., 2024)

Our Services

Leveraging our deep expertise in cardiovascular rare diseases and advanced genetic engineering capabilities, Protheragen delivers an integrated, end-to-end service that de-risks and streamlines your drug development pipeline. Our team of scientists provides more than just animal models; we offer a collaborative partnership, combining robust model systems with state-of-the-art phenotyping, histopathology, and molecular analysis to deliver high-quality data that meets regulatory standards.

Animal Models of Noonan Syndrome

Genetically Engineered Models

Utilizing advanced gene editing technologies, we specialize in creating genetically engineered models that accurately replicate pathogenic germline variants within the RAS/MAPK signaling pathway. All models undergo comprehensive multi-level validation to confirm accurate genotype, recapitulation of hallmark phenotypic traits, and relevant functional deficits, ensuring relevance for Noonan syndrome research.

• Shoc2-flox model
• Ptpn11-flox model
• Lztr1-flox model

• K-Ras^V14I model
• Raf1^L613V model
• Others

Ptpn11-Flox Mouse Model for Noonan Syndrome Research

Case Study-Raf1^L613V knock-in Mouse Model Development

Model Introduction

Engineered to recapitulate the pathogenic L613V mutation in the RAF1 gene, this mouse model accurately reflects the cardinal features of Noonan syndrome. Characterized by significant postnatal growth retardation, distinct craniofacial dysmorphology, and cardiac hypertrophy, the model serves as a genetically precise and phenotypically robust platform for investigating disease mechanisms and evaluating novel therapeutic strategies.

Methodology

• Animal Model: Utilizing a targeted knock-in strategy, mice heterozygous for the Raf1^L613V/+ mutation were generated. For therapeutic assessment, a MEK inhibitor was administered via daily intraperitoneal injections at 5 mg/kg. Dosing was initiated at four weeks of age and maintained consistently over six weeks, with control animals receiving empty vehicle-only injections on the same schedule.
• Phenotypic Analysis Methods: Comprehensive phenotyping was conducted to quantify multisystemic disease manifestations. Body size analysis involved weekly measurements of body weight and anal-nasal length. Cardiac evaluation included histological assessment of myocardial architecture, wall thickness, and cardiomyocyte cross-sectional area, complemented by echocardiographic and hemodynamic functional analyses.

Phenotypic Analysis & Results

The model group demonstrated significantly reduced body size compared to wild-type littermates throughout the study period. Evidence of cardiac hypertrophy emerged as early as two weeks postpartum, marked by a significant increase in the heart weight to body weight (HW/BW) ratio. Therapy with the MEK inhibitor resulted in a remarkable reversal of the major disease phenotypes. After therapy, the cardiac phenotype was similarly responsive, with the elevated HW/BW ratio returning to the normal range. Echocardiographic and hemodynamic parameters confirmed significant improvements in cardiac structure and function, while histological assessment confirmed a normalization of cardiomyocyte size following the treatment course.

Fig.2 Phenotypic characterization and therapeutic reversal. Analysis confirmed significant growth impairment in the Raf1^L613V/+ model group relative to wild-type controls (A). Mutants developed cardiac hypertrophy with chamber dilation, which was effectively rescued by MEK inhibition, as demonstrated by restored HW/BW ratios (B) and normalized cardiomyocyte size (C). Data are presented as mean ± SEM (n=6; ***p < 0.001, **p < 0.01).

Conclusion

Representing a high-fidelity and translatable research tool, the Raf1^L613V/+ mouse model accurately recapitulates the growth, morphological, and cardiac abnormalities characteristic of Noonan syndrome. The efficacy of MEK inhibition in reversing established phenotypes underscores the model's critical utility for preclinical efficacy testing, providing compelling evidence to derisk and accelerate the development of targeted therapeutics for this RASopathy.

Contact Us

From model creation to final data analysis, Protheragen offers a one-stop solution. We conduct detailed pharmacokinetics and pharmacodynamics studies to understand your compound's absorption, distribution, and biological effects within the disease context. Furthermore, our end-to-end capabilities include comprehensive drug safety and toxicology evaluations, ensuring that potential therapeutics are thoroughly assessed for efficacy and safety. Contact us today to discuss how we can customize a research program to advance your Noonan syndrome therapeutic candidate.

Reference

• Abe, Taiki et al. "Dysregulation of RAS proteostasis by autosomal-dominant LZTR1 mutation induces Noonan syndrome-like phenotypes in mice." JCI insight 9.22 (2024): e182382.