Eliminating SCID row: new approaches to SCID Donald B. Kohn 1,2,3 1 Departments of Microbiology, Immunology, and Molecular Genetics and Pediatrics; 2 David Geffen School of Medicine, Mattel Children’s Hospital; and 3 Eli & Edythe Broad Center for Regenerative Medicine and Stem Cells, University of California, Los Angeles, CA Treatments for patients with SCID by hematopoietic stem cell transplantation (HSCT) have changed this otherwise lethal primary immune deficiency disorder into one with an increasingly good prognosis. SCID has been the paradigm disorder supporting many key advances in the field of HSCT, with first-in-human successes with matched sibling, haploidentical, and matched unrelated donor allogeneic transplantations. Nevertheless, the optimal approaches for HSCT are still being defined, including determining the optimal stem cell sources, the use and types of pretransplanta- tion conditioning, and applications for SCID subtypes associated with radiosensitivity, for patients with active viral infections and for neonates. Alternatively, autologous transplantation after ex vivo gene correction (gene therapy) has been applied successfully to the treatment of adenosine deaminase– deficient SCID and X-linked SCID by vector-mediated gene addition. Gene therapy holds the prospect of avoiding risks of GVHD and would allow each patient to be their own donor. New approaches to gene therapy by gene correction in autologous HSCs using site-specific endonuclease-mediated homology-driven gene repair are under development. With newborn screening becoming more widely adopted to detect SCID patients before they develop complications, the prognosis for SCID is expected to improve further. This chapter reviews recent advances and ongoing controversies in allogeneic and autologous HSCT for SCID. Learning Objective ● To understand current approaches to the treatment of infants with SCID, including issues related to genetic etiology, donor choice, conditioning regimen, and the use of gene therapy SCID SCID is the most severe primary immune deficiency, with absent T- and B-cell function (and sometimes NK, depending on the respon- sible affected gene; Table 1). All forms of SCID have in common high early mortality from infections without treatment. Allogeneic BM transplantation can be curative, with 90% successful out- comes with HLA-matched sibling donors, but lower survival and variable immune reconstitution with alternative donors (mis- matched family member or unrelated adult or cord blood). SCID has been a guiding disorder for the fields of hematopoietic stem cell transplantation (HSCT) and gene therapy as the initial setting for allogeneic human BM transplantation (1968), use of matched unrelated donor BM (1974), and transplantation with haploidentical (parent) BM (1976), and was the first disease approached by gene therapy (1990) and, arguably, the first “cure” by gene therapy (1999). Role of pretransplantation conditioning in HSCT for SCID Despite the successes that have been achieved in the treatment of SCID patients, there remain many areas of ongoing controversy concerning optimal approaches. Perhaps most contentious is the use and type of pretransplantation conditioning. 1 HSCT products [BM, umbilical cord blood (UCB), peripheral blood stem cells) are heterogeneous, with long-lived stem cells present at low frequencies and lineage-restricted progenitor cells of multiple stages and activity at higher frequencies. Immune reconstitution may result from combined effects of short-term lymphoid progenitor cells producing large numbers of T, B, and NK cells early, and rarer long-term stem cells serving as a sustained source of lymphocytes, especially B and NK cells. Without conditioning, only the former effect may be achieved from T-lymphoid progenitors, supporting T-cell function reconstitution, but with minimal B and NK function reconstitution due to absence of stem cells. In fact, a recent study reported that BM from SCID infants [X-linked SCID (XSCID), Jak3-deficient, and adenosine deaminase (ADA)-deficient] con- tained essentially normal levels of early lymphoid committed progenitors, and these may be among the donor (or autologous gene-modified) cells that re-engraft to support T-lymphoid reconsti- tution in these nonconditioned SCID patients. 2 With conditioning, both the effects on early T-cell recovery from progenitors and the sustained support of B and NK activity from engrafted multipotent, long-term HSCs may be achieved. The optimal conditioning regimen, if one is to be used, remains to be determined. Transplantations for SCIDs have been done using full-intensity conditioning [eg, busulfan/cyclophosphamide, busulfan/ fludarabine  antithymocyte globulin (ATG), alemtuzumab, mel- phalan], reduced-intensity conditioning (eg, fludarabine/ATG, “little Bu,” treosulfan), or just serotherapy (eg, ATG, alemtuzumab). As in other transplantations, reduced intensity often equates to reduced toxicity, but may also be associated with reduced efficacy. Other confounding variables that may affect success include the presence of recipient NK function (which may mediate graft rejection), infants with engraftment of maternal T cells, or with autologous auto-reactive T cells as in Omenn’s syndrome, and SCID-related radiosensitivity (Artemis, DNA PKcs defects); in these cases, standard conditioning can have devastating late effects. 3 To a large STEMWARE:STEM CELL THERAPY FOR CONGENITAL BLOOD DISORDERS Hematology 2014 475 Downloaded from https://ashpublications.org/hematology/article-pdf/2014/1/475/1250958/bep00114000475.pdf by guest on 15 July 2020