Pre-clinical Modeling of Foamy Viral gene Therapy for Murine and Human SCID-X1
Pre-clinical Modeling of Foamy Viral gene Therapy for Murine and Human SCID-X1
批准号:
8278864
负责人:
David J Rawlings
金额:
$25.01万
依托单位国家:
美国
项目类别:
财政年份:
2012
资助国家:
美国
项目状态:
已结题
起止时间:
2012-08-07 至 2017-07-31
关键词:
Adverse eventAllogenicAnimal ModelAnimalsBiological AssayCD34 geneCellsClinical ResearchCytokine ReceptorsDataDiseaseElementsEnhancersExhibitsFamilyGene DeliveryGenerationsGenesGrantHematopoietic stem cellsHumanImmunologic Deficiency SyndromesIn VitroInterleukin 2 Receptor GammaLeadLeftLifeLinkMolecular AnalysisMultipotent Stem CellsMusMutationNatural Killer CellsOutcomePatientsPatternPre-Clinical ModelRecombinantsSCID MiceSafetySiblingsSignal TransductionSourceSpumavirusStem cell transplantStem cellsT-LymphocyteTestingTherapeuticTransactivationViralViral GenesViral Vectorbasedesigngene replacementgene therapygenotoxicityimprovedin vivoleukemogenesispre-clinicalprogramstransgene expressionvector
中文摘要
SCID-Xl是由常见γ链突变引起的灾难性免疫缺陷疾病
英文摘要
SCID-Xl is catastrophic immunodeficiency disorder caused by mutations within the common gamma chain
(yc) gene. While stem cell transplantation using a matched sibling donor can be curative, most patients lack
optimal donors leading to poorer outcomes. Gene replacement has many theoretical advantages as an
alternative therapeutic approach for SCID-Xl; and pioneering clinical studies using gammaretroviral yc
delivery lead to both significant benefit as well as unanticipated adverse events due to viral enhancer
triggered leukemogenesis. The overarching hypothesis of this PPG is that both the efficacy and safety of yc
gene delivery can be significantly improved using recombinant foamy virus (FV) based vectors. Studies in
Project 1 are designed to test the hypotheses that yc FV vectors devoid of viral enhancers (with or without
additional enhancer blocking elements flanking the transcriptional cassette) will exhibit levels of transgene
expression sufficient for functional rescue in vivo while concurrently showing reduced genotoxicity. The aims
of Project 1 are designed to test these hypotheses via detailed phenotypic, functional, and molecular
analysis in both: 1) a small animal model of SCID-Xl and 2) hematopoietic stem cells (HSC) derived from
SCID-Xl patients. Our specific studies will include efficacy and safety assessment of 1) EFIa-hu-yc FV
vectors in vivo in myeloablated vs. non-myeloablated murine SCID-Xl recipients; and in alternative in vitro
transactivation assays; 2) Preclinical and GMP-grade 1^' generation yc FV in transduced SCID-Xl patient
CD34* BM cells; and 3) Candidate insulated 2
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会议论文
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