Descrizione del progetto
Tecnologia di terapia genica con cellule staminali ematopoietiche migliorata per il trattamento di disturbi neurometabolici
Negli ultimi dieci anni la terapia genica, inclusa la terapia genica con cellule staminali ematopoietiche, ha dimostrato un potenziale terapeutico senza precedenti, grazie alle innovazioni nella progettazione dei vettori, nella manipolazione delle cellule staminali e nella somministrazione. Recentemente si è registrato un forte interesse per lo sviluppo di approcci di terapia genica delle cellule staminali ematopoietiche per i disturbi neurometabolici (NMD, neurometabolic disorder), malattie monogenetiche che colpiscono l’attività metabolica lisosomiale o perossisomiale. In tali patologie, i difetti del sistema nervoso portano alla morte neuronale, all’attivazione microgliale, alla demielinizzazione e alla degenerazione assonale. Il progetto TARGETNMDs, finanziato dall’UE, intende sviluppare un trattamento efficace per i disturbi neurometabolici basato su un approccio di aggiunta di geni mirati alle cellule staminali ematopoietiche in un locus della microglia recentemente identificato. La correzione del difetto in questo locus di cellule staminali ematopoietiche potrebbe generare una progenie simile alla microglia con un potenziale terapeutico senza precedenti.
Obiettivo
Hematopoietic stem cell (HSC) gene therapy based on self-inactivating integrating vectors has proven unprecedented therapeutic potential in inherited neurometabolic diseases (NMDs). However, phenotypic effects are delayed after treatment likely due to the slow replacement of resident microglia by transplant-derived cells that hampers the broad application of this approach. Moreover, unregulated gene expression driven by the in-use promoters could in the long term cause unwanted effects. Finally, recent events suggest that the treated patients might be at risk of developing side effects related to vector integration. Therefore, novel strategies anticipating therapeutic benefit and reducing these potential safety concerns are desirable to address the still unmet medical need of NMD patients.
Our long-term goal is to develop a novel, broadly effective and safe treatment platform for NMDs based on a newly empowered HSC targeted gene addition approach at a newly identified microglia locus. Our central hypothesis is that correcting the gene defect by targeted addition at this locus in HSCs of patients affected by NMDs could generate in a timely manner a microglia-like progeny endowed with unprecedented therapeutic potential. Indeed, based on our recent findings, gene editing and targeted integration at this locus are expected to uniquely favor the timely engraftment and efficient, rapid myeloid/microglia differentiation of transplanted, edited HSCs in the recipients’ brain, and to induce robust and regulated expression of the integrated transcript in transplant-derived microglia-like cells. Based on this hypothesis, we aim at developing a targeted gene addition approach at the newly selected microglia locus for correcting the underlying genetic defect in HSCs and obtaining proof of concept of its therapeutic potential in NMDs animal models. Thus, the proposed work could generate the basis for a novel treatment platform for these devastating conditions.
Campo scientifico
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Programma(i)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Argomento(i)
Meccanismo di finanziamento
ERC - Support for frontier research (ERC)Istituzione ospitante
35122 Padova
Italia