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.

Zoccolillo, M., Brigida, I., Barzaghi, F., Scala, S., Hernandez, R.J., Basso-Ricci, L., et al. (2021). Lentiviral correction of enzymatic activity restrains macrophage inflammation in adenosine deaminase 2 deficiency. BLOOD ADVANCES, 5(16), 3174-3187 [10.1182/bloodadvances.2020003811].

Lentiviral correction of enzymatic activity restrains macrophage inflammation in adenosine deaminase 2 deficiency

Conti F.;Pession A.;
2021

Abstract

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.
2021
Zoccolillo, M., Brigida, I., Barzaghi, F., Scala, S., Hernandez, R.J., Basso-Ricci, L., et al. (2021). Lentiviral correction of enzymatic activity restrains macrophage inflammation in adenosine deaminase 2 deficiency. BLOOD ADVANCES, 5(16), 3174-3187 [10.1182/bloodadvances.2020003811].
Zoccolillo, M.; Brigida, I.; Barzaghi, F.; Scala, S.; Hernandez, R. J.; Basso-Ricci, L.; Colantuoni, M.; Pettinato, E.; Sergi, L. S.; Milardi, G.; Cap...espandi
File in questo prodotto:
File Dimensione Formato  
ADV-2020-003811R2_Merged_PDF-2.pdf

accesso aperto

Tipo: Postprint
Licenza: Licenza per Accesso Aperto. Creative Commons Attribuzione - Non commerciale - Non opere derivate (CCBYNCND)
Dimensione 4.87 MB
Formato Adobe PDF
4.87 MB Adobe PDF Visualizza/Apri

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11585/871012
Citazioni
  • ???jsp.display-item.citation.pmc??? 15
  • Scopus 22
  • ???jsp.display-item.citation.isi??? 20
social impact