Stem Cell Gene Therapy to Treat X-Linked Severe Combined Immunodeficiency (XSCID)

This is a Phase I/II clinical trial of ex vivo hematopoietic stem cell (HSC) gene therapy for X-linked severe combined immunodeficiency (XSCID). XSCID results from defects in the IL2RG gene encoding the common gamma chain (gc) shared by receptors for Interleukin 2 (IL-2), IL-4, IL-7, IL-9, IL-15 and IL-21. XSCID patients generally lack T-lymphocytes and NK cells, and their B-lymphocytes fail to make essential antibodies. XSCID is fatal in infancy without immune reconstitution, such as by allogeneic bone marrow transplantation (BMT). However, many transplanted patients achieve only partial immune reconstitution, and consequently have recurrent infections, autoimmunity and/or poor growth. Recent successful retroviral gene therapy instead of BMT for infants with XSCID indicates that ex vivo gene therapy can provide clinical benefit to XSCID patients. We will enroll eight older XSCID patients (1.5-20 years-old; greater than or equal to 12 kg body weight), who have had attempted BMT, but who have persistent T-lymphocyte and B-lymphocyte impairments that compromise their quality of life. Prior to enrollment, these subjects will have had autologous CD34+ HSC mobilized by treatment with granulocyte colony stimulating factor (G-CSF), collected from peripheral blood by apheresis, immune selected and cryopreserved in sufficient numbers to achieve entry criteria (greater than or equal to 1.0 x 10(6) CD34+ HSC/kg body weight). HSC procurement will be conducted under a separate, approved and active NIH protocol, 94-I-0073, 'Recruitment of peripheral blood hematopoietic progenitors by granulocyte colony stimulating factor \[G-CSF\]'. Autologous CD34+ HSC will be transduced ex vivo with the gibbon ape leukemia virus (GALV) envelope-pseudotyped, replication-defective, murine onco-retrovirus vector, MFGS-gc that encodes the common gamma chain. Transductions will occur in flexible gas-permeable plastic containers using serum-free medium supplemented with 1% human serum albumin and five recombinant growth factors (50 ng/mL Flt3-L, 50 ng/mL SCF, 50 ng/mL TPO, 25 ng/mL IL-6, and 5 ng/mL IL-3). Subjects who are older than the age of 3 will be given a conditioning regimen consisting of Fludarabine and Busulfan then they will receive a single infusion of transduced HSC. Prior to the chemotherapy, and following the infusion of the cells, the same patients will also be given Keratinocyte growth factor (KGF), also known as palifermin. Subjects will be monitored for safety and efficacy; the latter evidenced by new development of autologous transduced lymphocytes with functional gc. Study endpoints are (1) efficient and safe clinical-scale transduction of HSC from post-BMT XSCID subjects; (2) administration of a nonmyeloablative conditioning regimen to improve engraftment; (3) administration of transduced HSC to eight subjects; (4) administration of KGF to improve thymic function post transplant to improve T cell development; and (5) appropriate follow up of treated subjects to monitor vector sequence distribution, gc expression in hematopoietic lineages, and lymphocyte numbers and function; as well as general health and immune status.