Phase I/II Safety and Efficacy Study of Gene Transfer for Artemis-Deficient Severe Combined Immunodeficiency (ART-SCID) in Newly Diagnosed Patients Using Self-Inactivating Lentiviral Vector (AProArt) to Transduce Autologous CD34 Hematopoietic Cells
University of California, San Francisco
Summary
This study aims to determine if a new method can be used to treat Artemis-deficient Severe Combined Immunodeficiency (ART-SCID), a severe form of primary immunodeficiency caused by mutations in the DCLRE1C gene. This method involves transferring a normal copy of the DCLRE1C gene into stem cells of an affected patient. Participants will receive an infusion of stem cells transduced with a self-inactivating lentiviral vector that contains a normal copy of the DCLRE1C gene. Prior to the infusion they will receive sub-ablative, dose-targeted busulfan conditioning. The study will investigate if the procedure is safe, whether it can be done according to the methods described in the protocol, and whether the procedure will provide a normal immune system for the patient. A total of 24 newly diagnosed patients will be enrolled at the University of California San Francisco in this single-site trial and will be followed for 15 years post-infusion. It is hoped that this type of gene transfer may offer improved outcomes for ART-SCID patients who lack a brother or sister who can be used as a donor for stem cell transplantation or who have failed to develop a functioning immune system after a previous stem cell transplant.
Description
Children with SCID generally do not survive beyond the first year of life without definitive treatment. The most effective current cure is hematopoietic stem cell transplant (HCT) with a human leukocyte antigen (HLA) matched sibling. While a matched sibling HCT can successfully treat ART-SCID, fewer than 20% of affected children have such a donor, and even when a matched sibling donor is available there is often incomplete T and B cell immune reconstitution. ART-SCID is the most difficult type of SCID to cure by hematopoietic stem cell transplant using alternative donors. Engraftment typically…
Eligibility
- Age range
- 0+ years
- Sex
- All
- Healthy volunteers
- No
Inclusion Criteria: * ≥2.0 months of age at initiation of busulfan conditioning * New diagnosis of typical or minimally leaky ART-SCID, as defined by the criteria below: * Artemis deficiency with bi-allelic pathogenic or likely pathogenic mutations in DCLRE1C; AND * CD3 count \< 50 autologous cells/µL (typical ART-SCID) OR spontaneous maternal chimerism, OR CD3 count \>50/µL and \<300/uL and with restricted T cell receptor Vb diversity; AND * CD45 cell response to mitogens (PHA) \< 50% of the lower limit of normal range for the lab (leaky ART-SCID). * No medically eligible HLA-identical sibli…
Interventions
- DrugAProArt-CD34
Participants will undergo infusion with autologous hematopoietic cells transduced with a lentiviral vector, AProArt, which contains the correct form of DCLRE1C complementary deoxyribonucleic acid DNA, after receiving sub-ablative, exposure-targeted busulfan conditioning.
- DeviceCliniMACS® CD34 Reagent System cell sorter device
Processing of hematopoietic progenitor cells to select CD34 cells, using the CliniMACS® CD34 Reagent System, prior to infusion.
- DrugBusulfan
Busulfan is a cell cycle non-specific alkylating antineoplastic agent, in the class of alkyl sulfonates. Patients will receive low-dose busulfan conditioning targeted over 2 days to achieve a cumulative area under the curve (AUC) of 20 mg\*hr/L.
Location
- University of California, San Francisco (UCSF) Children's HospitalSan Francisco, California