Projektbeschreibung
Gentherapie für Adenosin-Desaminase-Defizienz
Die Adenosin-Deaminase-2-Defizienz ist eine seltene, erbliche Krankheit, die anormale Entzündungen verschiedener Gewebe und Immunschwäche auslöst. Sie wird durch Mutationen des ADA2-Gens verursacht, sodass sie ein idealer Kandidat für die Gentherapie ist. Das EU-finanzierte Projekt DADA2GT erforscht eine Gentherapiestrategie zur Korrektur der ADA2-Mutationen in homologen hämatopoetischen Stammzellen. Dabei kommen Technologien zur Genomeditierung oder die Zugabe von Genen mittels lentiviraler Vektoren zum Einsatz. Diese genkorrigierenden Zellen werden der behandelten Person in einer klinischen Umgebung wieder zugeführt. DADA2GT dient dem Konzeptnachweis mit dem zentralen Ziel, die Wirksamkeit der Genkorrektur auf vorklinischer Ebene mit patienteneigenen Zellen zu bewerten.
Ziel
Deficiency of adenosine deaminase type 2 (DADA2) caused by loss-of-function mutations in the ADDeficiency of adenosine deaminase type 2 (DADA2) caused by loss-of-function mutations in the ADA2 gene is a Primary immunodeficiency (PID) diseases characterized by vasculopathy, stroke, intracranial haemorrhages, systemic inflammation, immunodeficiency, and cytopenia. Without proper treatment, DADA2 patients are at high risk of severe disability or death. Targeted pharmacological therapies are not available, and generic immunosuppressive drugs are commonly used with unsatisfactory effectiveness. Haematopoietic stem cell transplantation (HSCT) has proven effective in patients with severe manifestations, but morbidity and mortality are high and hardly acceptable in less severe cases. Thus, safer and targeted therapeutic options for these patients need to be rapidly developed. Based on the observation that HSCT can be successful, it is reasonable to presume that strategies based on ADA2 correction in autologous haematopoietic stem/progenitor cells (HSPCs) may provide new targeted therapeutic approaches for DADA2. The main goal of this project is to establish gene therapy as a new therapeutic option for DADA2. We propose: i) to develop a pre-clinical approach of gene addition mediated by lentiviral vectors targeting ADA2 expression in patient HSPCs; ii) to exploit gene-editing technologies to prove their efficiency for correction of ADA2 mutations. Gene correction efficacy will be assessed as ADA2 expression and activity in vitro in HSPCs and iPSCs isolated from patients, and in mice humanized with patients’ HSPCs. Collectively, this proof-of-concept study will provide new and robust pre-clinical data for the application of lentiviral-mediated HSPC gene therapy in DADA2. This innovative research project is built upon the world-class research expertise developed by the researcher and the host institution in the areas of PIDs, autoinflammatory disorders, and genome engineering.
Wissenschaftliches Gebiet
- medical and health sciencesmedical biotechnologygenetic engineeringgene therapy
- medical and health sciencesmedical biotechnologycells technologiesstem cells
- natural sciencesbiological sciencesgeneticsmutation
- medical and health sciencesbasic medicineneurologystroke
- medical and health sciencesclinical medicinetransplantation
Programm/Programme
Thema/Themen
Aufforderung zur Vorschlagseinreichung
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MSCA-IF-EF-SE - Society and Enterprise panelKoordinator
20132 Milano
Italien