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)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
2U54AI082973-06
Application #
8890279
Study Section
Special Emphasis Panel (ZTR1)
Project Start
Project End
Budget Start
2014-09-01
Budget End
2015-08-31
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
Burbank, Allison J; Shah, Shaili N; Montgomery, Maureen et al. (2016) Clinically focused exome sequencing identifies an homozygous mutation that confers DOCK8 deficiency. Pediatr Allergy Immunol 27:96-8
Cowan, Morton J (2016) The Primary Immune Deficiency Treatment Consortium: how can it improve definitive therapy for PID? Expert Rev Clin Immunol 12:1007-9
Griffith, Linda M; Cowan, Morton J; Notarangelo, Luigi D et al. (2016) Primary Immune Deficiency Treatment Consortium (PIDTC) update. J Allergy Clin Immunol 138:375-85
Chan, Alice Y; Punwani, Divya; Kadlecek, Theresa A et al. (2016) A novel human autoimmune syndrome caused by combined hypomorphic and activating mutations in ZAP-70. J Exp Med 213:155-65
De Ravin, Suk See; Wu, Xiaolin; Moir, Susan et al. (2016) Lentiviral hematopoietic stem cell gene therapy for X-linked severe combined immunodeficiency. Sci Transl Med 8:335ra57
Jackson, Shaun W; Scharping, Nicole E; Jacobs, Holly M et al. (2016) Cutting Edge: BAFF Overexpression Reduces Atherosclerosis via TACI-Dependent B Cell Activation. J Immunol 197:4529-4534
Punwani, Divya; Kawahara, Misako; Yu, Jason et al. (2016) Lentivirus Mediated Correction of Artemis-deficient Severe Combined Immunodeficiency. Hum Gene Ther :
Punwani, Divya; Zhang, Yong; Yu, Jason et al. (2016) Multisystem Anomalies in Severe Combined Immunodeficiency with Mutant BCL11B. N Engl J Med 375:2165-2176
Merkel, Peter A; Manion, Michele; Gopal-Srivastava, Rashmi et al. (2016) The partnership of patient advocacy groups and clinical investigators in the rare diseases clinical research network. Orphanet J Rare Dis 11:66
Chinen, Javier; Notarangelo, Luigi D; Shearer, William T (2016) Advances in clinical immunology in 2015. J Allergy Clin Immunol 138:1531-1540

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