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Intellectual & Developmental Disabilities Research Center
Research Projects (Non-Federal Funding)
Project Title:
Regulated GDNF Delivery in vivo Using Neural Stem Cells
Principal Investigator:
Clive Svendsen, PhD
We have recently
shown that direct infusion of the growth factor glial derived
neurotrophic factor (GDNF) into the putamen of patients with PD can
significantly improve their symptoms. However, delivery in patients
is limited by diffusion of GDNF and complexities of refilling
mechanical pumps associated with delivery. During the first two
years of this grant we have modified human neural stem cells grown
in the culture dish to express GDNF. These cells released GDNF
both in vitro and following grafting into the brains of rats with
experimentally induced Parkinson’s disease. The GDNF was
continually released from the cells for over 10 weeks. It had
significant effects on dopamine neuron fiber sprouting at early time
points. As PD involves the death of selective neurons within the
brain (perhaps through an unknown toxic insult) this represents a
good model through which we may gain a better understanding of this
process and how to prevent it. We have begun optimizing viral
infection of human neural stem cells to achieve controlled GDNF
release - both in vitro and in vivo following transplantation into
the damaged brain. Through a number of experiments we have finally
found a single vector that is able to switch on and off the release
of GDNF efficiently in the culture dish. We are now starting
transplant studies with these cells in our models of Parkinson’s
disease. We have also established small animal PET techniques to
look at the effects of GDNF directly on the bain dopamine
chemistry. This involved modifying the current system to
accommodate four rats simultaneously and switching to a more
sensitive tracer. Our latest results show that we can monitor
changes in brain dopamine very efficiently over time and this will
be used in our current studies assessing the effects of switching on
and off GDNF expression in vivo. This study has provided "proof of
concept" for using stem cells releasing growth factors in
Parkinson’s disease under an inducible promoter. This method may
be useful clinically to prevent cell death following other
neurotoxic insults or general damage to the brain.
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