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**20** 

*Russian Federation* 

**Gene Therapy of Hematopoietic and Immune** 

Hematopoietic stem cells (HSCs) present arguably the best entry point for gene therapy of hematopoietic and immune systems since genetically modified HSCs are long-lived and would eventually transfer the therapeutic constructs to all their descendants. However, gene therapy via HSCs, although conceptually simple, has proven to be a technically formidable problem that has yet to be solved successfully. Despite overtly positive results obtained in gene therapy experiments performed with mouse and larger animal models, these achievements did not translate into clinically acceptable outcomes for non-human primates and human patients, with exception of a few specific disease instances where a therapeutic gene brought about significant survival advantages to transduced cells (Cavazzana-Calvo et al., 2000, Schmidt et al, 2003). Major differences between outcomes of conceptually similar experiments in mice and primates underscore the notion that the fundamental principles governing functioning of hematopoietic system in small short-lived vs. larger long-lived animals differ significantly. Low degree of chimerism obtained in experiments with primates and humans is likely a result of intrinsically low efficiency of viral transduction of long-term repopulating (LTR) HSCs coupled with subsequent massive silencing of integrated constructs (Ellis, 2005; Horn et al, 2002). One may hypothesize that this situation reflects a better protection of hematopoietic system from external

influences, in particular invasion of foreign genetic material, in longer-living animals.

of the efficient gene therapy via HSCs; some of these strategies are discussed below.

**2. Improvements of vectors and ex vivo HSC transduction protocols** 

However, our deepening knowledge of molecular mechanisms underlying functioning of HSCs within the organism provides hints as to what strategies may lead to the development

Numerous studies indicate that lentiviral vectors that are capable of transducing nondividing cells may represent a more promising tool for introduction of genetic material into HSCs compared to retroviral vectors (Uchida et al, 1998, Case et al., 1999). This may be attributed to a largely quiescent nature of LTR HSCs, especially in larger animals (Cheshier et al., 1999, Shepherd et al., 2007). Since even lentiviral vectors transduce more efficiently dividing cells than quiescent ones (Trobridge et al., 2004), the current transduction protocols relied until recently on the use of culture conditions that induced entry of HSCs into cell

**1. Introduction** 

**Systems: Current State and Perspectives** 

Maria Savvateeva1, Fedor Rozov1,2 and Alexander Belyavsky1 *1Engelhardt Institute of Molecular Biology, Russian Academy of Sciences* 

*2University of Oslo, Centre for Medical Studies Russia, Moscow* 

