Data Offres d'emploi - Tours (37)

Topic description

La sclérose latérale amyotrophique (SLA) est une maladie neurodégénérative aujourd'hui en impasse thérapeutique. Dans la majorité des cas, elle s'accompagne d'une accumulation anormale de la protéine TDP-43 dans les cellules notamment du cerveau, ce qui contribue à sa toxicité.
Ce projet vise à développer une nouvelle stratégie thérapeutique ciblant directement cette protéine. Nous avons conçu de petits fragments d'anticorps intracellulaires capables de se lier à TDP-43 afin de limiter ses effets toxiques. Ces fragments sont délivrés dans les cellules grâce à des vecteurs de thérapie génique permettant une production durable.
Des résultats préliminaires obtenus dans un modèle murin de SLA montrent déjà une amélioration des performances motrices et de certains biomarqueurs biologiques après traitement.
Des travaux récents suggèrent également un rôle de l'axe intestin-cerveau dans la maladie, avec une implication possible de TDP-43 dans l'intestin. Le projet évaluera donc si une intervention précoce ciblant à la fois le cerveau et l'intestin peut renforcer l'efficacité thérapeutique.
Les effets seront analysés sur la progression de la maladie, les biomarqueurs circulants et les altérations métaboliques, puis confirmés dans un second modèle animal. L'objectif est d'identifier une stratégie innovante capable de ralentir la progression de la SLA en ciblant les sites clés du cerveau et de l'intestin.
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Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by the progressive loss of motor neurons, leading to paralysis and death. In the vast majority of ALS cases, pathological aggregation and mislocalization of the protein TDP-43 are observed in affected neurons. TDP-43 pathology is therefore considered a central molecular driver of disease progression and represents a highly attractive therapeutic target. However, despite intense research efforts, effective strategies to directly neutralize TDP-43 toxicity remain limited.
The present project aims to develop and evaluate an innovative therapeutic strategy based on intracellular antibodies (intrabodies) targeting TDP-43. We have generated specific single-chain antibody fragments (scFv) capable of binding TDP-43 and interfering with its pathological aggregation. These intrabodies are delivered using adeno-associated viral (AAV) vectors, enabling long-term expression within target cells. Preliminary data obtained in a TDP-43 ALS mouse model already demonstrated encouraging therapeutic effects, including improvements in motor performance and biological biomarkers following treatment. Building on these results, the proposed project will investigate whether early therapeutic intervention at the onset of first symptoms and optimized delivery strategies can further enhance treatment efficacy. In particular, we will compare the effects of targeting TDP-43 in the central nervous system, the intestine, or both simultaneously. Recent evidence suggests that the gut–brain axis may contribute to ALS pathophysiology, and emerging data indicate that TDP-43 pathology may also affect intestinal tissues. Targeting both compartments may therefore represent a novel and potentially more effective therapeutic approach.
To address these questions, we will first conduct a comprehensive preclinical evaluation of AAV-mediated anti–TDP-43 intrabody therapy in an ALS mouse model. Therapeutic efficacy will be assessed through longitudinal behavioral analyses, circulating biomarker measurements, immunological analyses and detailed molecular characterization. In addition to conventional endpoints, the project will integrate multi-omics approaches including metabolomics, proteomics and microbiome analyses to identify biomarkers of therapeutic response and to better understand the systemic consequences of TDP-43 modulation.
To ensure the robustness and reproducibility of the findings, the therapeutic strategy will also be validated in a second and independent ALS mouse model.
Beyond the evaluation of a single therapeutic candidate, the project aims to establish a robust preclinical pipeline for the development of future anti-TDP-43 therapies. This includes well-characterized animal models, optimized treatment paradigms, and clearly defined functional and molecular endpoints. The integration of omics-based biomarkers as indicators of treatment response represents a particularly innovative aspect that could improve the monitoring and stratification of therapeutic interventions. This project is built on a robust collaboration between the research teams in Tours and Montpellier, with a focus on validating the promising findings initially generated in Tours through complementary expertise and resources available in Montpellier. This collaborative framework will ensure rigorous experimental design, independent validation of results and comprehensive biological characterization of treatment effects.
Overall, this project aims to generate critical preclinical data supporting the development of intrabody-based strategies targeting TDP-43 pathology. By combining innovative therapeutic approaches with integrative molecular analyses and exploration of the gut–brain axis, the study has the potential to open new perspectives for the treatment of ALS and to contribute to the development of more effective disease-modifying therapies.
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Début de la thèse : 01/10/

Funding category

Funding further details

Financement d'une fondation pour la recherche française