Lentiviral correction of enzymatic activity restrains macrophage inflammation in adenosine deaminase 2 deficiency
Creators
- Zoccolillo Matteo1
- Brigida Immacolata1
- Barzaghi Federica2
- Scala Serena1
- Jofra Hernandez Raisa1
- Basso-Ricci Luca1
- Colantuoni Mariasilvia1
- Pettinato Emanuela1
- Sergi Sergi Lucia1
- Milardi Giulia1
- Capasso Paola1
- Lombardo Angelo1
- Gregori Silvia1
- Sanvito Francesca3
- Schena Francesca4
- Cesaro Simone5
- Conti Francesca6
- Pession Andrea6
- Benedetti Fabio7
- Gattorno Marco4
- Lee Pui Y8
- Naldini Luigi1
- Cicalese Maria Pia2
- Aiuti Alessandro1
-
Mortellaro Alessandra1
- 1. San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute
- 2. Pediatric Immunohematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele Scientific Institute
- 3. Pathology Unit, Department of Experimental Oncology, IRCCS San Raffaele Scientific Institute
- 4. Centro Malattie Autoinfiammatorie e Immunodeficienze, IRCCS Istituto Giannina Gaslini
- 5. Pediatric Hematology-Oncology,Ospedale della Donna e del Bambino
- 6. Pediatric Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna
- 7. CTMO Ematologia Azienda Ospedaliera Universitaria Integrate
- 8. Boston Children's Hospital
Description
Adenosine deaminase 2 deficiency (DADA2) is a rare inherited disorder that is caused by autosomal recessive mutations in the ADA2 gene. Clinical manifestations include earlyonset lacunar strokes, vasculitis/vasculopathy, systemic inflammation, immunodeficiency, and hematologic defects. Anti–tumor necrosis factor therapy reduces strokes and systemic inflammation. Allogeneic hematopoietic stem/progenitor cell (HSPC) transplantation can ameliorate most disease manifestations, but patients are at risk for complications. Autologous HSPC gene therapy may be an alternative curative option for patients with DADA2. We designed a lentiviral vector encoding ADA2 (LV-ADA2) to genetically correct HSPCs. Lentiviral transduction allowed efficient delivery of the functional ADA2 enzyme into HSPCs from healthy donors. Supranormal ADA2 expression in human and mouse HSPCs did not affect their multipotency and engraftment potential in vivo. The LV-ADA2 induced stable ADA2 expression and corrected the enzymatic defect in HSPCs derived from DADA2 patients. Patients’ HSPCs re-expressing ADA2 retained their potential to differentiate into erythroid and myeloid cells. Delivery of ADA2 enzymatic activity in patients’ macrophages led to a complete rescue of the exaggerated inflammatory cytokine production. Our data indicate that HSPCs ectopically expressing ADA2 retain their multipotent differentiation ability, leading to functional correction of macrophage defects. Altogether, these findings support the implementation of HSPC gene therapy for DADA2.
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Zoccolillo M published.pdf
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