Hits and misses with animal models of narcolepsy and the implications for drug discovery

ABSTRACT

Introduction

Narcolepsy is a chronic and rare neurological disorder characterized by disordered sleep. Based on animal models and further research in humans, the dysfunctional orexin system was identified as a contributing factor to the pathophysiology of narcolepsy. Animal models played a larger role in the discovery of some of the pharmacological agents with established benefit/risk profiles.

Areas covered

In this review, the authors examine the phenotypes observed in animal models of narcolepsy and the characteristics of clinically used pharmacological agents in these animal models. Additionally, the authors compare the effects of clinically used pharmacological agents on the phenotypes in animal models with those observed in narcolepsy patients.

Expert opinion

Research in canine and mouse models have linked narcolepsy to the O×R2mutation and orexin deficiency, leading to new diagnostic criteria and a drug development focus. Advancements in pharmacological therapies have significantly improved narcolepsy management, with insights from both clinical experience and from animal models having led to new treatments such as low sodium oxybate and solriamfetol. However, challenges persist in addressing symptoms beyond excessive daytime sleepiness and cataplexy, highlighting the need for further research, including the development of diurnal animal models to enhance understanding and treatment options for narcolepsy.

KEYWORDS:

• Narcolepsy
• animal models
• pharmacological agents
• rat model
• mouse model
• dog model

Article highlights

• Animal models of narcolepsy provided valuable insights into the disease, particularly highlighting the involvement of the hypocretin/orexin system.

• Research in canine and mouse models led to the discovery of orexin deficiencies in narcolepsy patients, shaping diagnostic criteria and drug development focus.

• Differences in etiology, pharmacokinetics, and circadian systems between animals and humans contribute to inconsistencies.

• Challenges persist in addressing symptoms beyond excessive daytime sleepiness and cataplexy.

• Opportunities for improvement lie in exploring new drug targets and developing diurnal animal models.

Declaration of interest

The authors are all employees of Suven Life Sciences. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

One referee is an employee of the Biotech Company Ceremedy ApS. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper was not funded.