Update on the safety and efficacy of retroviral gene therapy for immunodeficiency due to adenosine deaminase deficiency

Abstract

Key Points Survival was 100% for 18 patients with ADA-SCID treated with genetically modified CD34+ cells (2.3-13.4 years follow up; median, 6.9 years). Long-term engraftment, immune reconstitution, and fewer severe infections were observed in 15 out of 18 patients without leukemic transformation.

Evolving Gene Therapy in Primary Immunodeficiency

“…[21][22][23][24] Subsequent studies (again using LTR-intact gammaretroviral vectors) introduced some key changes, including the withdrawal of PEG-ADA to enhance the selective advantage of corrected cells, and most importantly the use of low-and/or reduced-intensity conditioning with alkylating agents (usually busulphan, but in a few patients melphalan) to promote engraftment of HSC/Ps. [25][26][27][28][29][30][31][32] The combined overall survival rate of around 50 patients treated in these studies was 100%, with a disease-free survival rate (not requiring re-introduction of PEG-ADA or HSCT) of more than 70%. Immunological reconstitution has in general been robust, with high-level gene marking in lymphocytes and, for the first time, albeit at lower levels in myeloid cells, which is an effective surrogate for HSC/P marking in bone marrow.…”

Rapid immune reconstitution of SCID-X1 canines after G-CSF/AMD3100 mobilization and in vivo gene therapy

“…3,4,59 Of note, data from SCID-X1 4 and adenosine deaminase SCID patients 60 indicate that low-dose conditioning with busulfan is well tolerated in patients undergoing retroviral-based gene therapy and is emerging as standard of care for the treatment of these primary immunodeficiencies.…”

Mini Review: Screening and Management of Late Effects in Patients with Severe Combined Immunodeficiency after Allogeneic Hematopoietic Cell Transplantation

“…Rapid identification of ADA deficiency allows prompt initiation of enzyme replacement therapy and consideration for gene therapy [34][35][36] . Gene therapy may also be offered as a treatment option for X-linked SCID [37][38] . Finally, having a molecular diagnosis allows for risk stratification with regard to late effects following transplantation.…”