Download Research Group Gene Therapy with Bacteria

Research Group Gene Therapy with Bacteria
Use of recombinant bacteria as an alternative tumor-specific cancer therapy
Failure of conventional cancer treatment coupled with the realisation that cancer is
essentially a genetic disease has led to development of treatment protocols based on
gene therapy. However, improvements in gene delivery systems are essential for
effective gene therapy to become clinically successful. In this project, we emphasize
alternative gene delivery systems based on the use of non-pathogenic bacteria.
One of the most important strains in this context is Clostridium. The specificity of
clostridia for tumors resides in its obligate requirement for hypoxic conditions.
Intravenously injected clostridial spores localise to and selectively germinate in
hypoxic regions of solid tumors. Significant advances in the genetic engineering of
clostridia allow the construction of recombinant strains that produce anti-cancer
agents. Clostridium can thus be used as a vector to deliver these proteins specifically
at the tumor site. We have data showing the feasibility of this approach.
It is the overall objective to demonstrate the validity and to evaluate the potential
and safety of the clostridial-based gene delivery approach, eventually in patients
with inoperable solid tumors. Thanks to a breakthrough in the development of a new
transformation technique by us and one of our collaborators, it has become possible
to genetically engineer Clostridium sporogenes. Compared to other strains, C.
sporogenes shows the best tumor colonizing ability resulting in a substantial increase
in therapeutic ratio. We will stably integrate a novel nitroreductase enzyme (NTR-H)
with superior CB1954 prodrug converting capacities in the chromosome of this
clostridial host. The NTR/CB1954 combination has already been successfully tested in
Clostridium by several groups and in a variety of other gene therapy approaches.
Non-invasive imaging methodologies validated by our group and available in the lab,
will be employed for preclinical in vivo validation of the system and form the basis
for stringent individualized monitoring of treatment efficacy.
The originality and innovative aspects of the project are lying within the use of
bacteria as a vector that can deliver almost any conceivable protein and that can be
combined with a plethora of other treatment modalities.