One research team looked at the ability of human neural progenitor cells (hNPCs) as a potential therapy when hNPCs were engineered to produce glial derived neurotrophic factor (GDNF) in the brain following hNPC transplants.
“Localized delivery is essential for aiming therapeutic molecules when treating neurodegenerative disorders,” said Maria Emborg, PhD, of the University of Wisconsin-Madison. “There are currently a number of clinical trials underway using direct gene therapy approaches to deliver potent trophic factors throughout the basal ganglia.”
Emborg and colleagues report that hNPCs genetically modified to over-express GDNF were able to survive transplant and produced GDNF for three months, and that functional recovery in test animals increased while no obvious negative side effects from the transplant procedure were observed.
An international team of researchers from the University of Kentucky Medical Center and the Shandong Provincial Hospital, Shangdong, PR of China, are studying the neurorestorative effects of the exogenous protein neurturin (NTN), another member of the GDNF family. They found that the protein may have beneficial effects on PD as their results showed some restorative influences after cell transplantation.
“Tissue distribution of trophic factor is a critical variable to achieve optimal effects on dopamine function and promote behavioral improvement,” said corresponding author Richard Grondin, PhD of the University of Kentucky. “The volume of GDNF distribution in the trophic factor recipients significantly correlated with motor function improvements. Tissue distribution may not have been optimal with NTN, but the overall effects of NTN on motor and dopaminergic function suggest potential therapeutic uses.”
According to Zhiming Zhang, M.D. corresponding author and colleagues from the University of Kentucky College of Medicine, the need is great for longitudinal noninvasive, highly sensitive imaging techniques to monitor treatment for PD. Their study reports on attempts at monitoring GDNF-induced functional changes in the basal ganglia using pharmacological MRI (phMRI) to measure response to dopamine. The aim is to eventually be able to visualize changes in the living brains of PD patients.
“Our hypothesis was that phMRI techniques combined with selective dopaminergic agents could monitor PD treatment,” said Zhang. “GDNF has been proven to halt or reverse progressive degeneration of the nigrostriatal DA system in models of PD. The ability to reliably monitor therapeutic effects would provide valuable information in assessing the progression of PD.”
In their study, Zhang, et al found that phMRI “showed its potential” by detecting functional changes before and after infusion with GDNF. These changes were also accompanied by improvements in motor function.
Transplantation of dopamine neurons as therapy for PD has been tested recently. Researchers sought to answer questions about where to place the transplanted neurons to gain the best environment for the optimal effect. One research team found that grafted dopamine neurons could “extend neurites toward a desired target over several millimeters through the brain in animal models…” which favors the prospect of “circuit reconstruction from grafted neurons placed at appropriate locations in the neural circuitry."
According to corresponding author John Sladek, PhD of the University of Colorado School of Medicine, there have always been questions about the regenerative capacity of mammalian neurons. One point at issue was the need to provide a “neuronal microenvironment that would be more conducive for regulated neurological control of DA production and release by the grafted neurons,” said Sladek.
Test results suggested that substantia nigra grafts could send targeted DA neurons to a location where they could survive and extend neurites over longer distances.
“Survival of the grafts and extension of the axons is of importance because it positions the DA neurites to grow in a trajectory toward the striatum, using the striatal grafts as an attractant,” concluded Sladek.
“Taking these four papers together we can see that primate studies are helping to elucidate the likelihood of favorable outcomes following stem cell transplantation with respect to route of administration, possible modes of action and the ability to track the effects.” said Jeffrey Kordower, PhD of the Rush University Medical Center, Chicago and guest editor of this special meeting issue of CELL TRANSPLANTATION.
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