Novel Cell-based Strategy for GDNF Delivery in Parkinson's Disease
Neurotrophic Factors Challenge, 2012
Glial cell line-derived neurotrophic factor (GDNF) is the most potent nerve cell growth molecule capable of protecting the dopamine neurons that are affected in Parkinsonís disease (PD). However, advanced clinical trials yielded inconclusive results, likely attributable to insufficient delivery of GDNF to the degenerating neurons due to its limited diffusion in brain tissue, as well as the large target volume of the human brain. Our novel cell-based strategy will deliver GDNF to all or most degenerating dopamine neurons, thereby slowing or reversing disease progression and improving motor function.
We propose to deliver GDNF to degenerating dopamine neurons by bone marrow-derived cells called macrophages. These cells are capable of infiltrating into the brain and homing to sites of neurodegeneration where they become microglial cells and form close connections with adjacent neurons. Through a genetic engineering strategy, macrophage-derived microglia are reprogrammed to deliver GDNF to neighboring neurons. We will test this strategy using a genetically modified strain of pre-clinical models (MP) that develops PD-like pathology of the dopamine neurons and associated movement abnormalities. Bone marrow cells (designated hematopoietic stem cells) from genetically identical donor models will be engineered with viral vectors that express high levels of GDNF or a control protein GFP selectively in macrophages. These reprogrammed cells will be transplanted into MP models preconditioned to facilitate cell engraftment in the bone marrow and the efficiency of transplantation will be confirmed after 4 weeks. Serial assessments will be made of behavior, movement, and body weight, followed by terminal collection of brain tissue for determination of dopamine content and neuron loss.
Relevance to Diagnosis/Treatment of Parkinsonís Disease:†††††††††††††††††††††
The objective of this project is to realize the full potential of GDNF treatment for protecting the integrity and function of dopamine neurons using a cell-based delivery strategy in a genetic model of PD. †In comparison with direct brain injection approaches, our technology avoids invasive procedures, delivers GDNF-secreting macrophage/microglial cells selectively to essentially all neurons within regions of dopaminergic degeneration in PD, and provides sustained GDNF release, thereby obviating the need for multiple treatments.
The expected results are that our hematopoietic stem cell-based macrophage-mediated GDNF delivery approach will mitigate degeneration of dopamine neurons in PD, providing a novel neuroprotective, disease-modifying therapy. The results of this study will form the basis for further pre-clinical work and ultimately clinical trials in PD patients.
Associate Professor at University of Texas Health Science Center at San Antonio
Location: San Antonio, Texas, United States