DADA2GT · Development of gene therapy and genome editing strategies to treat adenosine deaminase 2 deficiency
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2019-06-01 → 2021-05-31
- EU contribution
- €183,473
- Participants
- 1
- Scheme
- MSCA-IF-EF-SE
Lines connect the coordinator with its partners.
Results in brief
Development of gene therapy and genome editing strategies to treat adenosine deaminase 2 deficiency
Adenosine deaminase 2 deficiency (DADA2) is a rare inherited disorder caused by autosomal recessive mutations in the ADA2 gene. Clinical manifestations include early-onset lacunar strokes, vasculitis/vasculopathy, systemic inflammation, immunodeficiency, and hematologic defects. Conventional therapies do not offer a definitive treatment modality and often carry a high burden on social costs and quality of life. Anti-TNF therapy reduces strokes and systemic inflammation but does not correct hematopoietic alterations. Allogeneic hematopoietic stem-progenitor cell (HSPC) transplantation can ameliorate most disease manifestations, but patients are at risk for severe complications, including graft versus host disease, veno-occlusive disease, organ toxicity, and infections. Therefore, the development of targeted therapeutical approaches for DADA2 is urgently needed. Being DADA2 a recessive monogenic disease, we envisioned a gene transfer approach mediated by lentiviral vectors (LV) in patients’ HSPCs as a curative option for the future. The overall objective of the DADA2GT project was to develop an LV-mediated HSPC-based gene therapy approach for DADA2. Our results support the implementation of HSPC gene therapy for DADA2.
Data: CORDIS, © European Union
Project 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.
Original text from CORDIS.
Participants
- OSPEDALE SAN RAFFAELE SRL · MilanoCoordinatorItaly
Links
- View on CORDIS
- DOI: 10.3030/841780
- https://research.hsr.it/en/institutes/san-raffaele-telethon-institute-for-gene-therapy/mechanisms-of-inflammation-in-health-and-disease.html
Data: CORDIS, © European Union