Supplying clotting factors from hematopoietic stem cell-derived erythroid and megakaryocytic lineage cells Journal Article


Authors: Sadelain, M.; Chang, A.; Lisowski, L.
Article Title: Supplying clotting factors from hematopoietic stem cell-derived erythroid and megakaryocytic lineage cells
Abstract: Systemically distributed proteins such as clotting factors have been traditionally expressed from muscle or liver to achieve therapeutic, long-term expression. As long-lived cell capable of generating an abundant progeny, hematopoietic stem cells (HSCs) also merit consideration for this purpose. To be clinically relevant, this approach would require that hematopoietic cells be capable of expressing high levels of functional, secreted proteins, that the risk of insertional oncogenesis be minimized, and that sufficient stem cell engraftment be achieved following minimally invasive conditioning. Recent reports demonstrate the feasibility of expressing either factor IX (FIX) or factor VIII (FVIII) in erythroblasts and platelets using lineage-restricted vectors, resulting in effective treatments in mouse models of hemophilia. The erythroid system is especially powerful in providing high protein output, yielding FIX levels approaching 1 μ g/ml per vector copy in the plasma of long-term hematopoietic chimeras, a secretion level that vastly outperforms any other current mammalian constitutive or long-terminal repeat (LTR)-driven vector system. These early but promising studies raise the prospect of further developing these strategies for clinical investigation. © The American Society of Gene & Cell Therapy.
Keywords: protein expression; promoter region; busulfan; review; angiogenesis inhibitor; cancer risk; nonhuman; protein domain; mammalia; animals; mice; cell function; thrombocyte; gene expression; erythropoietin; erythroblast; protein targeting; bleeding; protein; transcription factor; carmustine; cell lineage; viral gene delivery system; chimera; engraftment; nonmyeloablative conditioning; transcription regulation; genetic engineering; mammal; globin; erythroid cell; progeny; hematopoietic stem cells; protein secretion; malignant neoplastic disease; pluripotent stem cell; hematopoietic stem cell; gene silencing; gene insertion; malignant transformation; growth factor; parathyroid hormone; megakaryocyte; antibody; mutagenesis; protein derivative; blood clotting factor 9; thymocyte antibody; genotoxicity; lysosome storage disease; 6 o benzylguanine; blood clotting factor 8; glycoprotein iib; virus vector; blood clotting factor deficiency; enzyme deficiency; expression vector; hemophilia; hemophilia a; hemophilia b; hyperlipoproteinemia type 3; immunotoxicity; long terminal repeat; nonviral gene delivery system; nonviral gene therapy; erythroid cells; factor ix; factor viii; megakaryocytes
Journal Title: Molecular Therapy
Volume: 17
Issue: 12
ISSN: 1525-0016
Publisher: Nature Publishing Group  
Date Published: 2009-12-01
Start Page: 1994
End Page: 1999
Language: English
DOI: 10.1038/mt.2009.238
PUBMED: 19844194
PROVIDER: scopus
PMCID: PMC2814379
DOI/URL:
Notes: --- - "Cited By (since 1996): 1" - "Export Date: 30 November 2010" - "CODEN: MTOHC" - "Source: Scopus"
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  1. Alex Hongsheng Chang
    9 Chang
  2. Michel W J Sadelain
    492 Sadelain