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Development of gene therapy and genome editing strategies to treat adenosine deaminase 2 deficiency

Objective

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.

Field of science

  • /medical and health sciences/medical biotechnology/cells technologies/stem cells
  • /medical and health sciences/basic medicine/neurology/stroke
  • /medical and health sciences/clinical medicine/transplantation
  • /natural sciences/biological sciences/genetics and heredity/mutation
  • /medical and health sciences/medical biotechnology/genetic engineering/gene therapy
  • /social sciences/sociology/demography/mortality
  • /natural sciences/biological sciences/genetics and heredity/genome

Call for proposal

H2020-MSCA-IF-2018
See other projects for this call

Funding Scheme

MSCA-IF-EF-SE - Society and Enterprise panel

Coordinator

OSPEDALE SAN RAFFAELE SRL
Address
Via Olgettina 60
20132 Milano
Italy
Activity type
Private for-profit entities (excluding Higher or Secondary Education Establishments)
EU contribution
€ 183 473,28