In utero hematopoietic stem cell transplantation (IUHSCTx) is a promising approach for the treatment of a varlet)'of hematologic disorders including the hemoglobinopathies. However, in the absence of a selective advantage fornormal cells, clinical and experimental efforts at IUHSCTx have generally resulted in limited or no detectableengraftment, suggesting the existence of major barriers to engraftment in the hematopoietically competitiverecipient. The long-term objective of this project is to overcome these barriers and develop clinically applicablestrategies to increase engraftment to therapeutic levels to allow clinical expansion of IUHSCTx to the treatment ofSickle Cell Disease(SCD). We have developed three approaches in the mouse model based on IUHSCTxinduced donor specific tolerance to create high level mixed hematopoietic chimerism, across full MHC barriers,without the use of myeloablation or immunosuppression. In this application we plan to exploit donor specifictolerance to create high level chimerism, using established and new strategies, in mufine models of !hemoglobinopathy and to determine what levels of chimerism is required to cure SCD.
The specific aims of thisproposal are: 1) To establish high level mixed chimerism after IUHSCTx by the prenatal cotransplantationof donor derived HSC and immanomodnlatory cell populations. Specific donor cellpopulations will be cotransplanted with HSC prenatally to create a competitive advantage for donor cells. 2) Toestablish high level mixed ehimerism after IUHSCTx in the hemoglobinopathy recipient by strategiesbased on prenatal tolerance induction to facilitate postnatal enhancement of chimerism using nonmyeloablativeapproaches. Limited mixed chimerismachieved by IUHSCTx in routine SCD will be convertedto high level or co,_lplete donor chimerism after birth by non-toxic regimens. 3) To establish in a nonmyeloablatedmurine model of SCD, what level of mixed chimerism is sufficient to prevent sicklingcrises and organ d_mage associated with SCD. The ability to create various levels of mixed chimerism in themurine SCD model combined with phenotypic and functional assays of SCD should allow the question of whatlevel of chimerism is necessary to completely treat SCD to be addressed. The studies in this proposal aredesigned to test strategies to improve engraftment after IUHSCTx for SCD and will direct subsequent studies in alarge animal model.
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