To effectively study achalasia, a rare and debilitating disorder of esophageal motility, reliable and highly specialized preclinical models are crucial. Protheragen, specialized in advanced preclinical research tools, offers the pioneering platform that develops highly specialized preclinical animal models specifically for rare gastrointestinal disorders. Fully tailored as a comprehensive research solution, we enable researchers and scientists to accelerate their therapeutic discovery. Our service includes all aspects of the development of achalasia animal models, which replicate the human condition's complex pathophysiology, thereby bridging a critical gap in rare disease investigation.

Introduction to Achalasia Animal Models

Achalasia is classified as a rare esophageal motility disorder, a disorder characterized by impaired relaxation of the lower esophageal sphincter (LES) and a lack of peristalsis, primarily due to the degeneration of inhibitory myenteric plexus neurons. Animal models for this condition are important for understanding the inflammatory, autoimmune, and neurodegenerative factors for the development of the disorder, as well as for testing new therapy options. These models try to simulate important aspects of the human disease, such as the selective loss of nitric oxide synthase (NOS)-positive neurons, and the increase of resting pressure in the LES, thus offering a biologically relevant system for preclinical testing.

Fig.1 A spectrum of morphological alterations in the rat model of achalasia. (Pang, J., et al., 2014)

Methods of Achalasia Animal Model Development

Achalasia animal models are typically established using diverse methods to recapitulate the critical pathology of myenteric plexus impairment. These approaches can be broadly categorized as follows:

Our Services

Protheragen's end-to-end achalasia animal model development service's core advantage is due to a deeply customized approach in which we design the experimentation to the primary research goals, be it the early-stage pathogenesis or later-stage therapeutic efficacy. Our collaborative partnership model ensures clients receive not just data, but critical insights, significantly de-risk and accelerate their research programs on rare diseases, from target identification to application studies.

Animal Models of Achalasia

Nos1-KO Mouse for Achalasia Research

Case Study: Nos1-KO Mouse Model

Model Introduction

The genetically engineered neuronal nitric oxide synthase-deficient (Nos1-KO) mouse recapitulates key pathophysiological features of human achalasia, including impaired LES relaxation and disordered peristalsis. By targeting the loss of nNOS, a critical regulator of inhibitory neuromuscular signaling, this model provides a robust tool for investigating disease mechanisms and evaluating novel therapeutics.

Methodology

• Animal Model: The model employs C57BL/6J mice, and this study was divided into three experimental groups: wild-type (WT) controls, WT mice treated with Nω-nitro-L-arginine methyl ester (L-NAME; 90 mg/kg), and Nos1-knockout (Nos1-KO) mice.
• Phenotypic Analysis Methods: Esophageal function was assessed in anesthetized mice using intraluminal manometry with a custom micro-catheter assembly. Basal LES pressure was recorded, and LES relaxations evoked by swallowing and vagal nerve stimulation were quantified across three experimental groups.

Phenotypic Analysis & Results

Evaluations revealed that Nos1-KO mice developed a significantly elevated basal LES pressure (LES hypertensive) with profoundly impaired relaxation, a phenotype closely resembling human achalasia (Fig.2). In contrast, wild-type (WT) controls maintained normal basal LES pressure and exhibited prompt relaxation in response to swallowing and vagal stimulation. Crucially, pretreatment of WT animals with L-NAME significantly attenuated LES relaxation following these stimuli, confirming the specific role of nNOS-derived nitric oxide.

Fig.2 Basal LES tone was evaluated in WT and Nos1-KO mice (A). Swallow-induced LES relaxation was measured in the same groups, as shown in (B). Data are presented as mean ± SEM (n=5; *p < 0.05).

Conclusion

The Nos1-KO mouse model faithfully mirrors the core abnormalities of human achalasia, offering a physiologically relevant and reproducible system for preclinical research. Its ability to recapitulate both the impaired LES relaxation and LES hypertension phenotype enables high-quality mechanistic studies and therapeutic screening, particularly for agents targeting nitric oxide signaling or neuromuscular coordination.

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Access to a reliable and pathophysiologically accurate animal model is a cornerstone for advancing achalasia research, facilitating the critical preclinical studies in pharmacodynamics, pharmacokinetics, and toxicology for new therapies. By providing these sophisticated tools, Protheragen empowers the scientific community to translate foundational discoveries into tangible solutions for this challenging motility disorder. For project inquiries, collaborative discussions, or to request a detailed service portfolio, please contact us.

Reference

• Pang, J et al. "Megaesophagus in a line of transgenic rats: a model of achalasia." Veterinary pathology 51.6 (2014): 1187-200.

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