Genetic Therapy for Fanconi Anemia

  • Yang, Feng-Chun (CoPI)

Project: Research project

Project Details


DESCRIPTION (provided by applicant): Fanconi anemia (FA) is a complex genetic disorder characterized by a progressive bone marrow aplasia, genomic instability, and the acquisition of both myeloid malignancies and squamous cell carcinoma. Previous work by our group identified for the first time, major limitations in the use of murine oncoretroviruses to correct FA hematopoietic stem cells (HSCs). These disease-specific challenges include: the increased predisposition of FA cells to undergo apoptosis and clonal evolution to MDS/AML in non-corrected cells following prolonged ex vivo culture. Consequently, in recent work, we developed foamyviral (FV) and lentiviral (LV) self-inactivating vectors and demonstrated that these constructs can correct the repopulating ability of murine FA HSCs in a short 10-14 hour transduction period without pre-stimulation. We also generated separate plasmids for the FV gag, pol, and env genes and adapted the codons of the three FV genes for improved expression in human cells. This has allowed us to dramatically increase the number of infectious recombinant particles (titers) and reduce the potential for syncytial formation and subsequent toxicity especially in human CD34+ cells. Finally, modifications of the FV envelope protein enabled us to utilize the same envelope for both FV as well as LV vectors. Work proposed in this application will build on these observations. Specifically, we will generate the constructs that will provide optimized expression in human FANCC-/- stem and progenitor cells. We will test the expression of these constructs in vitro and in vivo in a series of studies in FANCC-/- cell lines, primary murine Fancc-/- progenitor and stem cells and human FANCC-/- hematopoietic progenitors and SCID- repopulating cells (SRC) in NOD/LtSz-scidIL2R gammanull (NSG) mice. We will also test the transduction efficiency of a novel FV envelope on both normal human and FANCC-/- progenitor and primary human SRCs. Finally, a major limitation in testing non-genotoxic engraftment protocols in FA has been the lack of a murine model that accurately recapitulates the spontaneous progression of bone marrow failure observed in patients. We have now developed a murine model with these characteristics and we will use it to test engraftment protocols. PUBLIC HEALTH RELEVANCE: Achievement of these goals will permit the translation of this basic work to the development of clinical protocols for effective viral mediated gene correction of Fanconi anemia. On a broader basis, these studies should provide insight into the biological behavior of hematopoietic stem cells and the ability to manipulate them ex vivo prior to transplantation and engraftment.
Effective start/end date2/1/1112/31/15


  • National Institutes of Health: $300,377.00
  • National Institutes of Health: $319,550.00
  • National Institutes of Health: $319,550.00
  • National Institutes of Health: $309,964.00


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