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Funded Studies

Novel Cell-based Strategy for GDNF Delivery in Parkinson's Disease

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 Parkinson’s 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.

Project Description:             
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 Parkinson’s 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.

Anticipated Outcome:          
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.

Final Outcome

Although available therapies for Parkinson's disease (PD) can improve symptoms, none of them are able to stop the death of dopamine-producing brain cells that cause the disease. A protein called glial cell line-derived neurotrophic factor (GDNF) can protect dopamine-producing brain cells, but this treatment cannot be given as a pill or injection because GDNF will not travel to the brain. A novel alternative would be to engineer models' own immune cells to make GDNF and carry it to the brain. Using a pre-clinical model with Parkinson's symptoms, we showed that this GDNF delivery approach not only improved movement and other symptoms of PD but also slowed the death of dopamine-producing cells, providing a novel noninvasive therapy for Parkinson's able to slow or stop disease progression. The results of this study will form the basis for further pre-clinical work, e.g. studies in more advanced pre-clinical models, and ultimately, clinical trials.

September 2014


  • Senlin Li, MD

    San Antonio, TX United States

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