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Abstract I Investigator I Publications

Epigenetic of Vector-Chromatin Interactions

The potential of gene therapy as alternative therapeutic treatment for congenital disorders has been convincingly demonstrated in several clinical trials. In our own trial, aimed at the correction of Chronic Granulomatous Disease (CGD), a significant improvement in the health conditions of the patients was achieved. However two major adverse effects were observed during the trial: (i) DNA-methylation at the vector promoter leading to silencing of transgene expression and (ii) development of monosomy 7 as a consequence of MDS1/EVI1 activation. We and others have shown that the inclusion of chromatin opening elements in the transfer vector precludes vector inactivation and allows for a vector copy number dependent expression of the therapeutic gene. The epigenetic effects of such elements on chromatin remodeling at the vector integration sites are yet unknown. Therefore the aim of this proposal is to define the genotoxicity and epigenetics of vectors containing chromatin opening elements and to develop strategies to neutralize side effects if they exist.

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Manuel Grez, Ph.D.
Georg-Speyer-Haus
Paul-Ehrlich-Strasse 42
60596 Frankfurt
e-mail: grez[at]em.uni-frankfurt.de
www.georg-speyer-haus.de

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5 selected Publications related to the project (* Supported by DFG SPP1230)

*Stein S., Ott MG., Schultze-Strasser S., Jauch A., Burwinkel B., Kinner A., Schmidt M., Krämer A., Schwäble J., Glimm H., Koehl U., Preiss C., Ball C., Martin H., Göhring G., Schwarzwaelder K., Hofmann WK., Karakaya K., Tchatchou S., Yang R, Reinecke P., Kühlcke K., Schlegelberger B., Thrasher AJ., Hoelzer D., Seger R., von Kalle C., Grez M. Genomic Instability and Myelodysplasia with Monosomy 7 caused by EVI1 Activation after Gene Therapy for Chronic Granulomatous Disease. Nat Med, 2010, 16:198-204.

*Loew R, Meyer Y, Kuehlcke K, Gama-Norton L, Wirth D, Hauser H, Stein S, Grez M, Thornhill S, Thrasher AJ, Baum C , Schambach A. A new PG13-based packaging cell line for stable production of clinical grade self inactivating -retroviral vectors using targeted integration Gene Therapy 2009, 17:272-280.

*Moreno-Carranza B., Gentsch M., Stein S., Schambach A., Santilli G., Rudolf E., Ryser M.F., Haria S., Thrasher AJ., Baum C., Brenner S., Grez M. Transgene optimization significantly improves SIN vector titers, gp91(phox) expression and reconstitution of superoxide production in X-CGD cells. Gene Therapy 2009, 16:111-118.

Ott MG, Schmidt M, Schwarzwaelder K, Stein S, Siler U, Koehl U, Glimm H, Kühlcke K, Schilz A, Kunkel H, Naundorf S, Brinkmann A, Deichmann A, Fischer M, Ball C, Pilz I, Dunbar C, Du Y, Jenkins NA, Copeland NG, Lüthi U, Hassan M, Thrasher AJ, Hoelzer D, von Kalle C, Seger R, Grez M. Correction of X-linked Chronic Granulomatous Disease by gene therapy, augmented by insertional activation of MDS/EVI1, PRDM16 or SETBP1., Nat Med. 2006, 12:401-409.

Stein S, Siler U, Ott MG, Seger R, Grez M. Gene therapy for Chronic Granulomatous Disease. Curr Opin Mol Ther. 2006, 8:415-422. Review

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