Adenosine deaminase (ADA)-deficient Severe Combined Immune Deficiency (SCID) accounts for 10-15% of human SCID. Our group and others have demonstrated that gene therapy using ?-retroviral (?-RV) vectors to transfer a normal human ADA cDNA to CD34+ hematopoietic stem cells (HSC) can substantially restore immune function in the majority of ADA SCID infants undergoing an autologous hematopoietic stem cell transplant (HSCT) after reduced intensity cytoreductive conditioning. Lentiviral vectors (LV) transduce human HSC with greater efficiency than do ?-RV and can do so with significantly shorter ex vivo culture time which may provide better survival of gene-corrected HSC to support more rapid and robust immune reconstitution. Pre-clinical studies suggest that LVs with enhancer-deleted (SIN) log-terminal repeats (LTRs) and an internal promoter with minimal trans-activating enhancer activity may be safer than the LTR-intact ?-RV used previously. Based on these facts, we are currently performing a Phase I/II clinical trial of autologous HSCT of CD34+ cells transduced with the EFS-ADA LV to assess safety and efficacy (IND 15440; NCT01852071; UO1 AI100801). There has been 100% survival with no vector-related adverse events in the nine subjects enrolled and treated to date (2-19 months follow-up as of Feb. 2015). A parallel trial at University College London (UCL) in London, UK has treated 10 subjects with the same EFS-ADA LV by a similar protocol with all subjects alive and with excellent biochemical, molecular and immunological outcomes. The EFS-ADA LV has been granted Orphan Designation by FDA and EMA. The central hypothesis of this study is that overall survival at 24 months for the ADA-deficient subjects receiving autologous HSCT/gene therapy will be superior to that of recipients of allogeneic HSCT from MUD or haplo-identical donors. We also hypothesize that autologous HSCT/gene therapy with the EFS-ADA LV will provide sufficient immune reconstitution to allow vaccination and development of protective immune responses. To test these hypotheses, we will perform the following Aims: 1) Perform a Phase II/III clinical trial to define the 24 month survival after autologous transplant with EFS-ADA LV transduced CD34+ cells for ADA-SCID; 2) Establish historical control data set; and 3) Assess the immunological reconstitution achieved under this treatment including responses to vaccination. This project will lead to advancement of this promising autologous stem cell gene therapy approach to provide an improved treatment for patients ADA-deficient SCID.
The goal of this proposal is to perform a Phase II/III clinical trial of autologous hematopoietic stem cell transplantation (HSCT) with EFS-ADA lentiviral vector transduced CD34+ stem/progenitor cells (gene therapy) for ADA-deficient SCID, determine the immunologic reconstitution conferred, and compare the outcome to historical controls undergoing allogeneic HSCT. If successful, EFS-ADA would provide an improved treatment for patients with ADA- deficient SCID and may be one of the first gene therapy drugs to reach market.