Promising Outcomes of Original Grant:
The overall goal of this project is to develop V-SmartTM nanovesicles for delivering GDNF to the brain as a novel treatment of Parkinson's disease (PD). In the first stage of the project, the goal was to demonstrate delivery of GDNF to brain regions affected in PD. As proposed, Lauren Sciences demonstrated in pre-clinical models successful delivery of GDNF to the striatum and the substantia nigra following systemic administration of optimized V-SmartTM nanovesicles loaded with GDNF. Vesicles were optimized by designing and synthesizing new components to improve brain penetration and targeting to the striatum and the substantia nigra, where dopaminergic neurons degenerate in PD.
Objectives for Supplemental Investigation:
After our success in demonstrating delivery of GDNF encapsulated in our V-SmartTM nanovesicles to brain regions affected in PD, Lauren Sciences will now test the ability of such vesicles to confer beneficial effects in a PD pre-clinical model. As originally planned, we will prepare optimized, GDNF-loaded V-SmartTM nanovesicles, administer them intravenously and find the optimal dosing regimen by determining the rate of elimination of the delivered GDNF from the striatum. Then, using a treatment regimen that will produce persistent levels of GDNF in the striatum, we will test GDNF-loaded V-SmartTM nanovesicles in 6-OHDA pre-clinical models. The beneficial effects in this PD model will be evaluated by rotational behavior, striatal dopamine levels and the number of tyrosine hydroxylase expressing cells. We expect this study to demonstrate that GDNF-loaded V-SmartTM nanovesicles are effective in preventing neurodegeneration in this model.
Importance of This Research for the Development of a New PD Therapy
The demonstration of efficacy of GDNF-loaded V-SmartTM nanovesicles in a PD pre-clinical model will lead to developing scaled-up production and conducting further preclinical studies and, if successful, opening an IND with the FDA to commence clinical trials for PD patients with our GDNF-loaded V-SmartTM nanovesicles. Lauren Sciences’ ultimate goal is to have on the market a V-SmartTM therapeutic for PD.
The PD model used was obtained by injecting the toxin 6-hydroxy dopamine (6-OHDA) to the striatum on only one side of the brain. The 6-OHDA causes damage to dopaminergic neurons in the injected side, and this damage results in a drop of dopamine level (DA) and a decrease in the number of dopaminergic cells in the damaged side of the brain. Additionally, mice with a damaged striatum on one side of the brain turn around (rotate) when treated with amphetamine, and the number of rotations serves as an index for the severity of the damage to the dopaminergic neurons. Before the efficacy studies, a brief pharmacokinetic (PK) study was conducted to determine the dose and treatment regimen (frequency of dosing) for the efficacy study. Then, using the selected dose, we injected, by i.v., GDNF encapsulated in V-SmartTM vesicles into the PD models and, during the selected treatment regimen, measured how this treatment affects (improves) the rotation behavior. At the end of the treatment, we measured DA levels in the striatum of each side, and the number of dopaminergic cells in each side of the substantia nigra.
We found that treatment of PD models with encapsulated GDNF: significantly reduced the number of amphetamine-induced rotations, lowered the drop in dopamine levels in the damaged striatum and increased the number of dopaminergic cells in the substantia nigra. These beneficial effects from the encapsulated GDNF indicate the potential of our V-SmartTM vesicles, with encapsulated GDNF, to effectively treat PD. This successful outcome of our project paves the way for extensive pre-clinical studies that will lead to clinical trials in PD patients.
Presentations & Publications
Poster. Annual Conference of the American Society for Nanomedicine (ASNM) in Rockville, MD (March 2014)
Poster. Annual Meeting of the American Academy of Neurology (AAN) in Philadelphia, PA (April-May 2014).