Research program on CCHS

Understanding CCHS

In people with CCHS, increased CO₂ or reduced oxygen does not trigger an adequate ventilatory response. Most patients require assisted ventilation during sleep, and the most severe forms can also affect breathing while awake. Additional manifestations reflect dysfunction of the autonomic nervous system.

More than 90% of patients carry a polyalanine expansion in PHOX2B, a gene essential for the development of respiratory and autonomic neurons. Severity generally increases with expansion length but also varies among patients with the same genotype. Some forms are diagnosed after the neonatal period. No pharmacological treatment for CCHS is currently available.

A new step: the PHOX2B +5 model

Our preprint, posted on bioRxiv* in September 2026, describes a mouse model carrying a five-alanine expansion in Phox2b (+5), corresponding to the human 20/25 genotype. This study was conducted with Muriel Thoby-Brisson’s team in Bordeaux, with major contributions from Nelina Ramanantsoa, Charline Riaud and Amelia Madani.

Global activation of the mutation causes hypoventilation, increased time spent in apnea, markedly blunted CO₂ responsiveness, high neonatal mortality and impaired growth among survivors. Even before birth, isolated brainstem preparations show a slower respiratory rhythm and an impaired response to acidification, together with abnormal development of the retrotrapezoid nucleus (RTN), an important structure for CO₂-dependent respiratory drive.

Activation of the same mutation in the MafB lineage, which includes populations derived from rhombomeres 5 and 6 of the hindbrain, also causes severe respiratory dysfunction and neonatal mortality. However, weight gain remains preserved among survivors during the first postnatal week, and the reduction in gastric milk content is attenuated.

These findings suggest partially separable developmental contributions to respiratory dysfunction and growth impairment. They provide a window for investigating early postnatal disease mechanisms and, in future studies, evaluating interventions. They do not yet identify the specific neuronal populations responsible for these differences.

*This work is a preprint and has not yet undergone peer review.

Linking circuits, function and therapeutic approaches

We study mouse models carrying mutations identified in patients, including +5 and +7 expansions. Activating mutations in different developmental lineages helps determine which populations contribute to CO₂ responsiveness, respiratory rhythm stability and upper airway control.

Our work combines non-invasive respiratory measurements in newborn mice, recordings of respiratory-network activity and brainstem anatomy. The programme is expanding to include lineage tracing, three-dimensional imaging, multiplex immunofluorescence and regional transcriptomics, linking cellular abnormalities to functional deficits and guiding compound selection.

Two complementary approaches are being explored: stimulating residual circuits, notably through noradrenergic and serotonergic pathways, and targeting disease-associated molecular pathways. Atomoxetine, etonogestrel and vorinostat (SAHA) are among the candidates investigated by the partner teams. Their efficacy and tolerability in CCHS remain to be established; this research does not constitute a treatment recommendation.

From experimental advances to clinical questions

Our research has shown that loss of the neonatal ventilatory response to CO₂ can remain compatible with survival in some Phox2b models. Populations beyond the RTN must therefore be considered when investigating neonatal lethality.

We also demonstrated obstructive apneas and impaired upper airway control in a mouse model of CCHS. The clinical relevance of this observation was corroborated by cases reported in 2023 in which obstructive sleep apnea was the initial presentation.

The programme draws on the rare alveolar hypoventilation reference centre at Robert-Debré Hospital, with Profs Christophe Delclaux and Plamen Bokov. Assessments of ventilatory control, CO₂ responsiveness and autonomic function connect experimental observations with patient phenotypes. European CCHS Consortium data, including the survival study published in Thorax in 2026, complement this approach.

Collaborations

Our network brings together complementary expertise:

– Muriel Thoby-Brisson, INCIA, Université de Bordeaux–CNRS: respiratory-network development, brainstem electrophysiology, neuroanatomy and ex vivo pharmacology.
– Laurence Bodineau, Inserm–Sorbonne Université, with Florence Cayetanot and Alexis Casciato: respiratory neuroanatomy, serotonergic modulation and progestin pharmacology. Prof. Maxime Patout contributes the adult clinical perspective.
– Luis R. Hernandez-Miranda, Ulm University, Germany: development and characterisation of Lbx1/Phox2b-lineage dB2 neurons and rhombomeric organisation of respiratory circuits.

Exchanges with patients and families, notably through the French association for CCHS (AFSO), and with the RespiFIL rare respiratory disease network are an important part of the programme.

Funding

The Air Liquide Foundation supports PHARMONDINE, led by Christophe Delclaux, to investigate pharmacological approaches for CCHS.

The Fondation pour la Recherche Médicale (FRM) supports Charline Riaud’s doctoral research on the effects of PHOX2B mutations on the development and function of central respiratory circuits (2025–2028; FDM202501050158).

Over the years, the research has received support from the French association for CCHS (AFSO), the Fonds de Recherche en Santé Respiratoire, the Fondation du Souffle, the French Society for Sleep Research and Sleep Medicine, the Air Liquide Foundation, the Île-de-France Region, the Legs Poix, the Fondation Maladies Rares and the CCHS Foundation in the United States.

Publications and scientific background