Thèse

Mercredi 15 Octobre 2025 à 9h00.

Développement d'un hydrogel à gélification in situ pour l'administration contrôlée d'un peptide thérapeutique pour le traitement de pathologies neurodégénératives

Elise ROSSON

Salle de conférence de la bibliothèque universitaire de la Doua

Invité(e) par
TILLEMENT Olivier

présentera en 2 heures :

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Directeur de thèse / thesis director :
TILLEMENT Olivier

Membres du jury / jury members :
Mme. MIGNET Nathalie, Professeure des Universités, Université de Paris : rapportrice
Mme. BEGIN Sylvie, Professeure des Universités, Université de Strasbourg : rapportrice,
M. SCHATZ Christophe, Professeur associé, Université de Bordeaux : examinateur,
Mme. BRIANCON Stéphanie, Professeure des Universités, Université de Lyon : examinatrice

Résumé / Abstract :
Therapeutic peptides represent a class of bioactive biomolecules that bridge the gap between small organic molecules and large biologics such as proteins or antibodies. They offer a promising balance between specificity, safety, and bioavailability. They are currently used in various therapeutic areas such as metabolic diseases, cancer, microbial infections, inflammatory conditions, and neurodegenerative disorders.
Neurodegenerative diseases represent a major global public health challenge, exacerbated by an aging population and the lack of curative treatments for most of these conditions. In this context, the company Axoltis Pharma has developed an innovative therapeutic peptide composed of twelve amino acids, named NX210c, with demonstrated neuroprotective and regenerative properties in both degenerative and traumatic neural pathologies. However, its clinical translation is hindered by a very short plasma half-life (~15 minutes) following intravenous administration, necessitating repeated dosing.
To address this limitation, in situ gelling hydrogels have emerged as promising platforms for sustained peptide delivery. These injectable systems remain liquid prior to administration and undergo a rapid sol-gel transition upon exposure to physiological conditions, such as temperature (37.5 °C), pH (7.4), or ionic strength (osmolarity 280 mOsm.L-1), forming a localized depot at the injection site. Their biocompatibility injectability, and ability to protect and stabilize fragile biomolecules like peptides make them particularly well-suited for subcutaneous delivery applications.
This thesis aim to optimize NX210c administration through the development of a novel chitosan-based in situ gelling hydrogel that is responsive to both pH and ionic strength. The objective is to extend the peptide’s lifespan in the body to improve its therapeutic efficacy and patients’ quality of life. To achieve this, the work was structured in two complementary phases: first, the development of a controlled release system and the study of interactions between the polymer and the peptide; and second, the evaluation of the peptide release kinetics, validated by in vitro and in vivo proof-of-concept studies.
The resulting formulation is a fully injectable hydrogel based on functionalized chitosan-DOTAGA, that undergoes rapid in situ gelation under physiological conditions. It exhibited excellent biocompatibility and biodegradability over a 21-day period, while achieving sustained peptide release for 10 to 15 days post-injection. Notably, the system provides a dual protective effect—shielding the peptide from enzymatic degradation and mitigating local tissue toxicity associated with high peptide concentrations.
This innovative delivery platform not only enhances NX210c’s pharmacokinetic profile and therapeutic potential but also opens new perspectives for the administration of other bioactive peptides or fragile therapeutic agents requiring localized and prolonged release.''