Researchers unravel molecular events after gene therapy trial of a hereditary immune disease
New findings from the follow-up of a clinical gene therapy trial performed in 2004 for chronic granulomatous disease (CGD), a rare form of inherited immunodeficiency characterized by recurrent, often life threatening bacterial and fungal infections.
Monosomy 7 in dominant clones of P1 and P2. Monosomy 7 was most predominant in cells isolated from bone marrow derived colonies containing integration 87429F02, while monosomy 7 was not detected in non-transduced cells.
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In 2006 a team of researchers reported on the successful engraftment of functionally corrected cells in two young adult X-CGD patients that initially led restored enzyme function and eradication of pre-existing infections in both patients. Unexpectedly, inactivation of the transgene and uncontrolled growth of gene modified cell clones occurred resulting in a lack of antimicrobial activity in the phagocytic cells and the development of myelodysplastic syndrome (MDS). Whether the therapeutic gene itself or the viral vector or other factors were responsible for these side effects became a challenging though decisive question that now could be clarified down to the molecular level. The results published by the researchers around Manuel Grez (Biomedical Research in Frankfurt), Christof von Kalle (German Cancer Research Center, Heidelberg) Dieter Hölzer (University Medical School, Frankfurt) and Reinhard Seger (University Childrens Hospital, Zurich) in this month’s edition of Nature Medicine offer new insights into the complex mechanisms that were causal for the unwanted side effects in both patients.
The viral vector bearing the therapeutic gene can be incorporated into the DNA at different sites. Ideally, many different of these gene corrected cells contribute to the cell pool restoring the long-term function of a defect gene. The present data show that in the two patients this was only the case in the first months after transplantation. Over course of time a few blood stem cell clones containing retroviral insertions in a particular gene were overrepresented because this location in the genome gave them a growth advantage. As the researchers could demonstrate, gene activation this gene, MDS1/EVI1, was also causal for chromosomal instabilities, leading to a loss of one chromosome 7 and to development of myelodysplastic syndrome, a bone marrow failure. These new findings provide a basis to dissect the order and mechanism of the molecular and cellular events leading to malignancy and are of substantial importance for assessing efficacy and biosafety of gene therapy vectors in ongoing and future clinical trials.
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. (DH, RS, CvK and MG share senior authorship). Genomic Instability and Myelodysplasia with Monosomy 7 consequnet to EVI1 Activation after Gene Therapy for Chronic Granulomatous Disease. Nature Medicine 2010 Jan 24. [Epub ahead of print] DOI:10.1038/nm.2088