Gene- and Immunotherapy for Hematological Diseases (Special by D. Dilloo

By D. Dilloo

Unique subject factor: Acta Haematologica 2003, Vol. one hundred ten, No. 2-3

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147 Platt FM, Jeyakumar M, Andersson U, Priestman DA, Dwek RA, Butters TD, Cox TM, Lachmann RH, Hollak C, Aerts JM, Van Weely S, Hrebicek M, Moyses C, Gow I, Elstein D, Zimran A: Inhibition of substrate synthesis as a strategy for glycolipid lysosomal storage disease therapy. J Inherit Metab Dis 2001;24:275–290. 148 Cox T, Lachmann R, Hollak C, Aerts J, van Weely S, Hrebicek M, Platt F, Butters T, Dwek R, Moyses C, Gow I, Elstein D, Zimran A: Novel oral treatment of Gaucher’s disease with N-butyldeoxynojirimycin (OGT 918) to decrease substrate biosynthesis.

The lentivirustransduced stem cells, however, produced greater levels of gene-corrected neutrophils than the retrovirus-transduced stem cells when transplanted into immunodeficient NOD/SCID mice (20 vs. 4%), suggesting that lentiviral vectors may transduce the primitive stem cells capable of repopulating NOD/SCID mice better than retroviral vectors. Preclinical Studies in Murine CGD Retroviral-mediated gene transfer into bone marrow cells can correct respiratory burst oxidase activity in phagocytes in vivo and improve the defect in host defense against bacterial and fungal pathogens in murine models of CGD [15, 56, 57].

Table 1 comprises only those genes, whose expression has been shown to result in increased resistance in cells of the hematopoietic compartment. They can roughly be divided into 3 subgroups according to the mechanism that is responsible for the drug resistance: (i) genes encoding Hematoprotection by Transfer of Drug-Resistance Genes Acta Haematol 2003;110:93–106 95 membrane-bound proteins functioning as efflux pumps for cytotoxic drugs, such as the multidrug-resistance gene 1 (MDR1); (ii) genes encoding cytoplasmatic proteins that are involved in the intracellular activity or metabolism of cytotoxic drugs, such as mutant forms of dihydrofolate reductase (DHFR) or cytidine deaminase (CDD), and (iii) genes encoding nuclear proteins with the ability to repair the DNA damage caused by cytotoxic drugs, such as O6methylguanine DNA methyltransferase (MGMT).

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