Christopher Baum Laboratory Research Interests
Scientific Goals
The Baum lab's goal is the development of novel cell and gene therapeutics for inherited or acquired disorders of the hematopoietic system. They invest equal emphasis in conceptual and technological progress as well as detailed risk assessment. This includes studies addressing the biology of hematopoietic stem cell and their leukemic transformation. The lab interacts closely with colleagues in Baum's team at the Hannover Medical School, Germany.
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Vector Development
The team has a proven expertise in the design and evaluation of novel gene vectors and genetic selection systems for transplanted cells. The development of gene delivery systems focuses on safety-modified retroviral (including lentiviral) vectors. Key interests include the understanding of vector-host interactions regulating transcriptional and post-transcriptional events of transgene expression. On the basis of this work, the lab attempts to generate improved vectors that mediate long-lasting transgene expression at predictable levels after transplantation of gene-modified hematopoietic or lymphatic cells in vivo.
Side Effects of Gene Therapy
Improving the efficiency of genetic interventions goes hand in hand with exploring the kind and incidence of unwanted side effects. In hematopoietic gene therapy, side effects may originate from genetic damage following the insertion of the transgene, from interference of ectopic transgene expression with cellular signaling networks, from immune responses evoked by the transgene product, or by aberrant reading frames of the vector. Such side effects need to be explored in suitable animal models in order to develop rules for safe and predictable gene therapy.
Selectable Marker Genes
Using vectors as tools, Baum's lab is attempting to define therapeutic windows for the expression of selectable marker genes in transplanted cells. In the research at Cincinnati Children's Hospital Medical Center, the lab is developing vectors that mediate sufficient expression levels for a variety of clinically relevant target genes, and at the same time is trying to avoid side effects of unregulated transgene expression. In close collaboration with David Williams, MD, and Christof von Kalle, MD, Dr. Baum's lab focuses on vectors for the expression of cancer drug resistance genes such as O6-methylguanine-DNA-methyltransferase (MGMT). On the basis of a detailed analysis in preclinical model systems, clinical trials with these vectors may be initiated in the future.
Controlling Stem Cell Proliferation
An interesting way to introduce a competitive advantage to gene-modified hematopoietic cells is the ectopic expression of genes such as modified cytokine receptors that trigger proliferation in response to drugs (related abstract), or of transcription factors such as HOXB4 (related abstract). Dr. Baum's lab adapts these strategies with a specific interest in the issue of whether it will be possible to trigger stem cell proliferation without interfereing with differentiation and without promoting cellular autonomy. Further projects related to the use of cell surface markers, suicide genes and HIV gene therapy ar currently conducted at Hannover medical School. These shall be moved to Cincinnati Children's Hospital Medical Center as the projects mature for potential clinical use.
Alternative Delivery Systems
Many lessons learned in the context of stably integrating retroviral vectors also apply to the improvement of alternative gene delivery systems. Therefore, Dr. Baum's lab is interested in developing other viral or non-viral gene delivery systems, as well as protein transduction. The lab has recently discovered that retroviral vectors can be used for transient delivery of mRNA and proteins, given that reverse transcription is blocked.
Current projects at Cincinnati Children's Hospital Medical Center:
- Development of retroviral delivery methods to achieve optimal expression levels of selectable marker genes allowing to control hematopoietic chimerism following transplantation.
- Establishment of preclinical assay systems which allow an unbiased risk assessment of gene transfer technologies developed for clinical use with hematopoietic cells.
