Thierry VandenDriessche & Marinee K.L. Chuah
Gene Therapy for Bleeding Disorders and Vector Development
VIB Vesalius Research Center, K.U.Leuven

Thierry VandenDriessche PhD: Free Univ. of Brussels, Brussels, Belgium, '92 Postdoc: NIH, Bethesda, USA, '92-'95 VIB Group leader since 1995 Marinee K.L. Chuah PhD: Free Univ. of Brussels, Brussels, Belgium, '92 Postdoc: NIH, Bethesda, USA, '92-'95 VIB Group leader since 1995

e-mail phone +32 16 34 57 75 ADDRESS e-mail phone +32 16 34 57 75 ADDRESS

Current team members
Group leaders: Marinee Chuah, Thierry VandenDriessche
Postdoctoral scientist: Janka Matrai
Ph.D. Students: Eyayu Belay, Inge Petrus, Mariana Loperfido, Mario di Matteo, Melvin Rincon
Support personnel: Abel Acosta Sanchez, Ermira Samara

Keywords
gene therapy - viral gene transfer - nanoparticles - hemophilia - vector development

Science

The first successful gene therapy trials underscore the potential of gene therapy to combat disease and alleviate human suffering. This research group has been focussing  on the development and characterization of  a broad platform state of the art gene delivery technologies including viral (retroviral, lentiviral, adenoviral, AAV ) and non-viral vectors (hepatocyte-specific nanoparticles). These gene therapy approaches are being evaluated in terms of efficacy and safety in preclinical animal models that mimic the cognate human diseases. In particular, the main target diseases are (i) severe bleeding disorders due to either clotting factor deficiencies (hemophilia A and B) or abnormal platelet differentiation (GATA-1 deficiency) and (ii) ischemic disease. The ultimate objective is to obtain sufficient basic and preclinical research results  to justify a gene therapy clinical trial and to gain a better understanding of the vector-host interaction at the cellular and molecular level. The group was  the first to demonstrate that hemophilia  could be cured by gene therapy using retroviral vectors in factor VIII-deficient mice. They also showed  that long-term  therapeutic clotting factor levels could be obtained using either lentiviral or high-capacity adenoviral (HC-Ad) vectors. In particular, unprecedented clotting factor levels approaching 100-fold the normal levels (i.e., 10,000-fold the minimal therapeutic threshold), were obtained following HC-Ad vector-mediated factor VIII delivery in hemophilic mice. Based on these encouraging results, it was essential to extend these studies in larger animal models. The group showed that a significant therapeutic effect could be obtained in a large animal  model (hemophilia "A" dog) without toxicity, which had not been shown previously.  These results contribute to a better understanding of the safety and efficacy of HC-Ad vectors. However, the studies also indicated that the innate immune system represents a significant obstacle that would need to be overcome prior to evaluating these gene therapy approaches in clinical trials. This could possibly be achieved by generating cell-type specific "targetable" vectors which can target hepatocytes with high efficiencies. This was recently accomplished using nanoparticle technology. Current research efforts are geared towards the development of improved, targetable non-viral and viral vectors, including AAV-vectors derived from alternative primate serotypes. Ongoing investigations on the use of adult human stem/progenitor cells (mesenchymal,  myoblastic) as targets for gene transfer, pave the way towards  the convergence of gene therapy with tissue engineering and advances our understanding of the underlying biological processes. Finally, we are exploring the use of various  ex vivo and in vivo gene therapy approaches as a means to deliver angiogenic factors (VEGF, PLGF and other novel factors) into ischemic tissues (myocardial and peripheral limb ischemia)  and for the treament of neurodegenerative disease (amyotrophic lateral sclerosis).

Go to the  Department's own website for more details.

Press Release
See also press release (12/07/2007): VIB scientist receives major research grant
See also press release (03/05/2009): Moving gene therapy forward with mobile DNA - based on a publication in Nature Genetics (Mátés et al., Nature Genetics, 2009)

Mátés L, Chuah L, Belay E, Jerchow B, Manoj N, Acosta-Sanchez A, Grzela D, Schmitt A, Becker K, Matrai J, Ma L, Samara-Kuko E, Gysemans C, Pryputniewicz D, Miskey C, Fletcher B, VandenDriessche T, Ivics Z, Izsvák Z
Molecular evolution of a novel hyperactive Sleeping Beauty transposase enables robust stable gene transfer in vertebrates
NAT GENET 41, 753-61, 2009



VandenDriessche T, Ivics Z, Izsvak Z, Chuah L
Emerging potential of transposons for gene therapy and generation of induced pluripotent stem cells
BLOOD 114, 1461-8, 2009



Chuah L, Schiedner G, Thorrez L, Brown B, Johnston M, Gillijns V, Hertel S, Van Rooijen N, Lillicrap D, Collen D, VandenDriessche T, Kochanek S
Therapeutic factor VIII levels and negligible toxicity in mouse and dog models of hemophilia A following gene therapy with high-capacity adenoviral vectors
BLOOD 101, 1734-1743, 2003



Yamada T, Iwasaki Y, Tada H, Iwabuki H, Chuah k, VandenDriessche T, Fukuda H, Kondo A, Ueda M, Seno M, Tanizawa K, Kuroda S
Nanoparticles for the delivery of genes and drugs to human hepatocytes
NAT BIOTECHNOL 21, 885-890, 2003



Vandendriessche T, Thorrez L, Naldini L, Follenzi A, Moons G, Berneman Z, Collen D, Chuah L
Lentiviral vectors containing the human immunodeficiency virus type-1 central polypurine tract can efficiently transduce nondividing hepatocytes and antigen-presenting cells in vivo
BLOOD 100, 813-822, 2002

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