Forschungsdatenbank der Universitt Zrich Medizinische Fakultt by mikeholy


									Forschungsdatenbank der Universität Zürich
Medizinische Fakultät > Kinderspital Zürich: Medizinische Klinik > Immunologie, Abteilung >
Prof. Dr. Reinhard Seger

Using iPSC technology to model human CGD disease: A feasibility study

Summary / Zusammenfassung
CGD is a rare and genetically heterogeneous immunodeficiency disorder caused by mutations in
the cytosolic or membrane associated subunits of NADPH oxidase. This results in defects in the
respiratory burst that is necessary for destruction of ingested microorganisms, leading to severe
clinical manifestations that range from recurrent bacterial and fungal infections of body surfaces
and internal organs to pyoderma, granuloma formation of various sizes, pneumonia, inflammations
of the gastrointestinal tract, liver abscess and osteomyelitis. Several animal models and
immortalised cell lines have been created to mimic human CGD and to test the function of gene-
corrected haematopoietic stem cells, which are viewed as the best source for stem cell
transplantation. Both of these approaches suffer from drawbacks, in that short-lived animals do not
fully represent the clinical disease in the one case, and that human sample access is needed on
frequent basis in the other. To overcome these obstacles and create a human CGD disease model,
in this feasibility study we aim to generate induced pluripotent stem cells (iPSC) from CGD
iPSC are generated by the overexpression of several pluripotent transcription factors in fibroblasts
derived from skin biopsies. Our pilot data and that of others suggest that iPSC are similar to human
embryonic stem cells (hESC) and can be coaxed to differentiate into haematopoietic progenitor
cells and phagocytic cells. Creation of patient-specific iPSC lines coupled with future efficient
differentiation to phagocytic and haematopoietic progenitor cells will enable our groups to create a
human CGD model which can be used to ask specific questions about the biology of the disease
without recurrent need to obtain patients’ samples. In the long term, this investigation will lay the
foundation for new therapeutic regimes that will focus on correction of the gene defect at the iPSC
stage and further production of functional haematopoietic progenitors for transplantation into the
bone marrow of the patients.

Keywords / Suchbegriffe

Project Leadership and Contacts / Projektleitung und Kontakte
Prof. Reinhard Seger (Project Leader)                        
Dr. med. Janine Reichenbach (Project Leader)             

Funding Source(s) / Unterstützt durch
CGD Research Trust UK

In Collaboration with / In Zusammenarbeit mit
Dr. Lyle Armstrong und Prof. Majlinda Lako (Institute of                           United Kingdom
Human Genetics and NESCI, NewcastleUniversity)
Prof. William James, Sir William Dunn School of Pathology,                         United Kingdom
University of Oxford, South Parks Road, Oxford OX1 3RE

Project 15016                                                                                Seite 1
Duration of Project / Projektdauer
May 2010 to May 2012

Project 15016                        Seite 2

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