Use of murine models to test novel gene transfer strategies for the treatment of Fanconi anemia

dc.contributor.advisorClapp, D. Wade
dc.contributor.authorLeath, Anna C.
dc.contributor.otherBroxmeyer, Hal E.
dc.contributor.otherCornetta, Kenneth G.
dc.contributor.otherSrour, Edward F.
dc.date.accessioned2011-03-09T16:29:55Z
dc.date.available2011-03-09T16:29:55Z
dc.date.issued2011-03-09
dc.degree.date2010en_US
dc.degree.disciplineDepartment of Microbiology and Immunologyen
dc.degree.grantorIndiana Universityen_US
dc.degree.levelPh.D.en_US
dc.descriptionIndiana University-Purdue University Indianapolis (IUPUI)en_US
dc.description.abstractThe dawn of the genetic era has allowed for investigation of gene transfer therapy as a treatment for certain diseases. Fanconi anemia (FA) is a rare genetic disorder in which the majority of patients develops progressive bone marrow failure (BMF) and require bone marrow transplantation. A possible alternative treatment is autologous gene therapy; however, original clinical trials involving gene transfer for FA were unsuccessful. This has led to re-evaluation of the gene transfer protocols, the vectors and also a deeper investigation of the FA pathway itself. My work has focused on illuminating these areas to further advance gene transfer therapy for FA. Many gene transfer protocols require the hematopoietic stem and progenitor cells (HSC/HPC) to be collected and then transduced ex vivo. The most common collection method is mobilization of the HSC/HPC to the peripheral blood (PB) using granulocyte colony-stimulating factor (G-CSF) and collection via apheresis. In FA patients G-CSF fails to mobilize a sufficient number of HSC/HPC. This has led to research into agents such as AMD3100, a CXCR4 antagonist, which may replace or augment G-CSF mobilization. These data show in two FA murine models that AMD3100 synergizes with G-CSF resulting in a significant increase in mobilization as compared to G-CSF alone. Previous work in our lab has shown that prototype foamy virus (FV) is an efficient gene transfer vector. Here a modified FV vector is used to transduce mobilized FA cells. The data indicate that long-term repopulating cells mobilized with both G-CSF and AMD3100 can be efficiently transduced by our FV vector. Clinically, FA is characterized mainly by BMF, but also by myelodysplasia (MDS) and acute myeloid leukemia (AML). However, current FA murine models do not display these disease phenotypes. These data show that double-mutant Fancc-/-;Fancg-/- mice spontaneously develop BMF, MDS and complex random chromosomal abnormalities that the single-mutant mice do not. Importantly, this model closely recapitulates the phenotypes found in FA patients and may be useful as a preclinical platform to evaluate the molecular pathogenesis of spontaneous BMF and MDS in FA and novel gene transfer protocols for FA.en_US
dc.identifier.urihttps://hdl.handle.net/1805/2468
dc.identifier.urihttp://dx.doi.org/10.7912/C2/1702
dc.language.isoen_USen_US
dc.subjectFanconi anemia, Foamy virus, Gene therapy, mobilization, hematopoiesisen_US
dc.subject.lcshFanconi's anemia -- Gene therapyen_US
dc.subject.lcshGenetic transformationen_US
dc.subject.lcshHematopoiesisen_US
dc.titleUse of murine models to test novel gene transfer strategies for the treatment of Fanconi anemiaen_US
dc.typeThesisen
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