The ultimate goal of this project is to prospectively study newly diagnosed infants and children born in North America with Severe Combined Immunodeficiency (SCID), a very rare disorder that requires hematopoietic cell transplantafion (HCT), gene therapy (GT) or enzyme replacement therapy (ERT) for survival. We are addressing quesfions that can only be answered prospectively, and are studying an increasingly interesfing group of """"""""atypical"""""""" SCID patients who are """"""""leaky"""""""" and/or who have Omenn syndrome. Finally, we will make every effort to identify a genotype for all eligible SCID patients using state-of-the-art methods to define the molecular defects and we will serially characterize key parameters of immunological reconstitution and lineage-specific chimerism. We began enrolling pafients into this study in 2010 and have accrued -40% of our goal which should be reached in 2017.
The specific aims of this study are:
Specific Aim 1) To determine the effects of patient-related factors on early survival, time to and extent of immune reconstitution and early clinical outcome after HCT for SCID or Atypical SCID.
Specific Aim 2) To determine the effects of donorand transplant-related factors on early survival, fime to immune reconstitufion and early clinical outcome after HCT for SCID or """"""""atypical"""""""" SCID. This project will help accomplish the proposal's overall objective of improving definitive therapy for SCID by comparing relafively short term outcomes ofthe different treatment approaches currenfiy being employed for HCT for SCID in a uniformly and comprehensively evaluated cohort of pafients. Uniquely, the cohort will contain a significant number of pafients with 1) SCID diagnosed by newborn screening, and 2) pafients with """"""""atypical"""""""" SCID. It will define early biomarkers that predict survival, the kinefics of immune reconstitufion, and the risk for graft versus host disease (GVHD) and/or post- HCT autoimmune disease. The results of this prospective study will address questions that cannot be answered by retrospective or cross-sectional studies and will provide the basis for clinical trials aimed at defining strategies to optimize survival and long-term immune reconstitufion while reducing complicafions after HCT for SCID.

Public Health Relevance

Primary immune deficiencies (PIDs) are rare, life-threatening inherited defects in the immune system. This prospective study of children with severe combined immunodeficiency (SCID) will help accomplish the Primary Immune Deficiency Treatment Consortium (PIDTC)'s overall objecfive of identifying pre-HCT and early post HCT biologic factors that best predict successful engraftment, immune reconstitution, and outcome with minimal toxicity.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Specialized Center--Cooperative Agreements (U54)
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Special Emphasis Panel (ZTR1)
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University of California San Francisco
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Chinen, Javier; Cowan, Morton J (2018) Advances and highlights in primary immunodeficiencies in 2017. J Allergy Clin Immunol 142:1041-1051
Miggelbrink, Alexandra M; Logan, Brent R; Buckley, Rebecca H et al. (2018) B-cell differentiation and IL-21 response in IL2RG/JAK3 SCID patients after hematopoietic stem cell transplantation. Blood 131:2967-2977
Slack, James; Albert, Michael H; Balashov, Dmitry et al. (2018) Outcome of hematopoietic cell transplantation for DNA double-strand break repair disorders. J Allergy Clin Immunol 141:322-328.e10
Langelier, Charles; Zinter, Matt S; Kalantar, Katrina et al. (2018) Metagenomic Sequencing Detects Respiratory Pathogens in Hematopoietic Cellular Transplant Patients. Am J Respir Crit Care Med 197:524-528
Haddad, Elie; Logan, Brent R; Griffith, Linda M et al. (2018) SCID genotype and 6-month posttransplant CD4 count predict survival and immune recovery. Blood 132:1737-1749
Barzaghi, Federica; Amaya Hernandez, Laura Cristina; Neven, Benedicte et al. (2018) Long-term follow-up of IPEX syndrome patients after different therapeutic strategies: An international multicenter retrospective study. J Allergy Clin Immunol 141:1036-1049.e5
Kuo, Caroline Y; Long, Joseph D; Campo-Fernandez, Beatriz et al. (2018) Site-Specific Gene Editing of Human Hematopoietic Stem Cells for X-Linked Hyper-IgM Syndrome. Cell Rep 23:2606-2616
Belderbos, Mirjam E; Gennery, Andrew R; Dvorak, Christopher C et al. (2018) Outcome of domino hematopoietic stem cell transplantation in human subjects: An international case series. J Allergy Clin Immunol 142:1628-1631.e4
Buchbinder, David; Smith, Matthew J; Kawahara, Misako et al. (2018) Application of a radiosensitivity flow assay in a patient with DNA ligase 4 deficiency. Blood Adv 2:1828-1832
Kohn, Donald B; Hershfield, Michael S; Puck, Jennifer M et al. (2018) Consensus approach for the management of severe combined immune deficiency caused by adenosine deaminase deficiency. J Allergy Clin Immunol :

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