Our long term goal is to develop novel preclinical approaches to the prenatal correction of immunodeficiency (ID) disorders that will serve as a platform for human clinical trials. To date, most studies have focused upon post-natal or pre-natal allogeneic cellular therapy which has been only partially successful. An alternative approach is to genetically correct the host. We will focus upon 2 newly developed non-viral approaches to repair genetic defects. The first is designed toward gene replacement and utilizes a transposon system to obtain stable DNA integration. Transposons are mobile genetic elements that are capable of moving DNA into the genome using a """"""""cut-paste"""""""" mechanism. Our data indicate that transposon mediated delivery in utero results in stable long-term multi-organ expression of a reporter gene.
In Aim 1, we will use the transposon system to deliver a normal copy of a defective gene into the genome prenatally as a means of correcting ID disorders. For this proposal, we have chosen 3 distinct prototypic ID disorders affecting either lymphohematopoietic or thymic epithelial cells. The second system is designed to achieve gene repair. We will use a strategy in which wild-type (wt) base pairs (bp), provided exogenously, can accomplish base exchange, substituting the wt bp for the single mutant bp that is responsible for the genetic disorder. Our preliminary date provide evidence that in vivo oligonucleotides can correct defective cell population in vivo.
In Aim 2, we will use this approach in utero to target point mutations that cause these same prototypic ID disorders. We will hypothesize, and our preliminary data suggest that the in utero environment may be particularly permissive for such studies. Because the adaptive immune system would not have developed by the time of gene therapy, gene correction would be preventative rather than therapeutic resulting in a normal immune system by birth. We are uniquely positioned to perform these studies, having assembled a team of investigators recognized as experts in ID disorders, prenatal therapy, transposon delivery, and modified chimeric structures for treating genetic disorders.
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