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.

Agency
National Institute of Health (NIH)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
2U54AI082973-06
Application #
8890279
Study Section
Special Emphasis Panel (ZTR1)
Project Start
Project End
Budget Start
Budget End
Support Year
6
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Type
DUNS #
City
San Francisco
State
CA
Country
United States
Zip Code
94143
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Haddad, Elie; Allakhverdi, Zoulfia; Griffith, Linda M et al. (2014) Survey on retransplantation criteria for patients with severe combined immunodeficiency. J Allergy Clin Immunol 133:597-9
Shearer, William T; Dunn, Elizabeth; Notarangelo, Luigi D et al. (2014) Establishing diagnostic criteria for severe combined immunodeficiency disease (SCID), leaky SCID, and Omenn syndrome: the Primary Immune Deficiency Treatment Consortium experience. J Allergy Clin Immunol 133:1092-8
Dvorak, Christopher C; Hassan, Amel; Slatter, Mary A et al. (2014) Comparison of outcomes of hematopoietic stem cell transplantation without chemotherapy conditioning by using matched sibling and unrelated donors for treatment of severe combined immunodeficiency. J Allergy Clin Immunol 134:935-943.e15
Lee, Yu Nee; Frugoni, Francesco; Dobbs, Kerry et al. (2014) A systematic analysis of recombination activity and genotype-phenotype correlation in human recombination-activating gene 1 deficiency. J Allergy Clin Immunol 133:1099-108
Pai, Sung-Yun; Cowan, Morton J (2014) Stem cell transplantation for primary immunodeficiency diseases: the North American experience. Curr Opin Allergy Clin Immunol 14:521-6
Griffith, Linda M; Cowan, Morton J; Notarangelo, Luigi D et al. (2014) Primary Immune Deficiency Treatment Consortium (PIDTC) report. J Allergy Clin Immunol 133:335-47
Medical Advisory Committee of the Immune Deficiency Foundation; Shearer, William T; Fleisher, Thomas A et al. (2014) Recommendations for live viral and bacterial vaccines in immunodeficient patients and their close contacts. J Allergy Clin Immunol 133:961-6
Chinen, Javier; Notarangelo, Luigi D; Shearer, William T (2014) Advances in basic and clinical immunology in 2013. J Allergy Clin Immunol 133:967-76
Pai, Sung-Yun; Logan, Brent R; Griffith, Linda M et al. (2014) Transplantation outcomes for severe combined immunodeficiency, 2000-2009. N Engl J Med 371:434-46

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