PIDTC Project 6907 SCID ? Abstract Severe Combined Immunodeficiency Disease (SCID) is a genetically heterogeneous group of disorders leading to defects in T and B cell numbers or function. Our combined prospective (Protocol 6901) and retrospective (Protocol 6902) studies implemented during the 1st two grant cycles now include >750 surviving SCID patients, which will be further augmented with additional newly diagnosed patients from 44 US and Canadian PIDTC Centers during this grant cycle (Protocol 6907). Newborn screened (NBS) patients represent a high percentage of the SCID cohort, and now predominate in the USA and parts of Canada. Our prior studies have shown that: 1) ~7% of SCID cases have no identified genotype; 2) infection remains a major issue even in SCID diagnosed via NBS; 3) there are major gaps in our knowledge of hematopoietic cell transplant (HCT)- related late effects and health-related quality of life (HR-QoL); 4) while genotype strongly impacts overall survival (OS) and immune reconstitution, genotypic-specific approaches to optimize outcomes have not been defined; 5) CD4+ and nave CD4+ T cell counts as early as 6 months post HCT predict long-term OS and immune reconstitution. These results have fueled the design and implementation of a prospective randomized trial exploring intensity of conditioning infants with SCID (NCT03619551). We propose that prospective enrollment of new cases plus extended follow-up of those previously enrolled will create an unparalleled resource for robust analysis of the SCID management and diagnosis approaches. While HCT treatment approaches are selected by individual centers, comprehensive, longitudinal data from this large PIDTC cohort will permit comparative assessment of outcomes beyond OS that will generate questions we will address in multicenter prospective SCID treatment trials. The objective of this proposal is to advance the understanding, diagnosis, management, and treatment of SCID in order to define how best to optimize survival and achieve full immune reconstitution after allogeneic HCT or autologous gene therapy (GT). With our large cohort we will: 1) identify unknown genes and functional defects in T cell development; 2) associate genotype and chemotherapy exposure in infancy with post-HCT late effects; 3) assess long-term outcomes of patients with SCID diagnosed by NBS and treated at a very young age (<6 months); 4) assess HR-QoL and patient reported outcomes (PROs); 5) further characterize the incidence and clinical associations of T cell exhaustion post- HCT, further defining early post HCT biomarkers to predict OS and immune reconstitution so that interventions can be designed to avoid rejection and/or enhance immune recovery; 6) determine which patients should receive GT with autologous modified hematopoietic cells, and 7) explore the incidence and reasons for pre- HCT viral infections in NBS SCID infants to propose clinical trials for prevention. The additional impact of the proposed research is that the longitudinal natural history and mechanistic studies we perform will generate hypotheses that translate into practice-changing clinical trials for SCID patients.
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