Journal
GENE THERAPY
Volume 13, Issue 2, Pages 117-126Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.gt.3302638
Keywords
phenotypic correction; hematopoietic stem cells; factor IX; lentiviral vectors; tolerance; hemophilia B
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Funding
- Medical Research Council [G9900991B] Funding Source: researchfish
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Immune responses against an introduced transgenic protein are a potential risk in many gene replacement strategies to treat genetic disease. We have developed a gene delivery approach for hemophilia B based on lentiviral expression of human factor IX in purified hematopoietic stem cells. In both normal C57BI/6J and hemophilic 129/Sv recipient mice, we observed the production of therapeutic levels of human factor IX, persisting for at least a year with tolerance to human factor IX antigen. Secondary and tertiary recipients also demonstrate long-term production of therapeutic levels of human factor IX and tolerance, even at very low levels of donor chimerism. Furthermore, in hemophilic mice, partial functional correction of treated mice and phenotypic rescue is achieved. These data show the potential of a stem cell approach to gene delivery to tolerize recipients to a secreted foreign transgenic protein and, with appropriate modification, may be of use in developing treatments for other genetic disorders.
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