Objective/Rationale:
This project will study the delivery and distribution of promising therapeutics for Parkinson’s disease. The explored compounds will be infused directly into the brain of npre-clinical models and will be chemically labeled to be visible on magnetic resonance images. Infusions will utilize a novel programmable pump and catheter system that can improve control of drug dosing and delivery. Improved predictability and control of direct infusions will open the door to new treatments for Parkinson’s disease.
Project Description:
A novel pump and catheter system for direct infusion to the brain, currently under development at Codman, Inc., will be refined for application in pre-clinical models. The developed pump and catheter system will be surgically inserted into the brain of the models and connected to a pump located in the abdomen. This system will be used to deliver two potential therapeutic agents for the treatment of Parkinson’s disease. Each infused compounds will be chemically modified making it visible on MR images. Sets of images will be used to estimate the distribution of the therapeutic compounds in brain tissue. The accuracy of the drug distributions derived from the MR images will be determined by comparing them to quantitative drug distributions derived by histological techniques on the necropsied brain tissue.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Many powerful anti-Parkinsonian compounds have been crippled by their inability to pass through the blood-brain barrier. Efforts to deliver these drugs through catheters implanted into the brain have shown promise but have had variable results. This study will meet a compelling need to predict and deliver precise doses of drugs to targeted sites in a reproducible and controllable manner. The project will develop a novel pump and catheter system coupled with unique imaging techniques to measure the distribution in the brain of two potential therapeutic compounds.
Anticipated Outcome:
The outcome of this project will be (i) better understanding of how drugs of different size and chemical characteristics move through the brain under convection enhanced delivery; (ii) the development of imaging techniques to measure the distribution of therapeutic compounds with the potential to treat Parkinson’s disease; and (iii) refinement of a unique programmable pump and catheter system for delivering therapeutics effectively and safely to the regions of the brain affected by Parkinson’s disease.
Progress Report
During the first year, the research team evaluated various designs of catheters in gels from both convection enhanced delivery and ease of reliable use perspectives. The group has identified a multiport-stepped catheter design for use in their in-vivo studies. An intermediate acute study will be used to refine experimental protocol/data-collection/analysis before conducting the capstone chronic infusion study.
Final Outcome
We tested the correspondence in the volume of distribution between the Parkinson’s therapeutic GDNF and two MR visible tracers Gd-DTPA (Magnevist) with a molecular weight of approximately 1 kDa and Gd labeled albumin (Galbumin) with a molecular weight of approximately 65 kDa. We developed a method and a combination chronic/acute infusion system to co-infuse small volumes of these tracer and therapeutic mixtures into the putamen. Comparing the distribution of GDNF determined from histology and tracers determined from MR images we determined that the Galbumin with a molecular weight closer to that of GDNF better defined the distribution of the therapeutic. This has implications for the selection of tracers in clinical trials to indicate patency and drug distribution.
Presentations & Publications
Published Abstract/Poster/Manuscript:
1. Tracking the distribution of GDNF with tracers of different molecular weight. PA Hardy, LH Bradley, Z Zhang, C Ross, K Kubota, P Margaraiz, R Venugopalan. Presented at the 2011 Meeting of the Society for Neuroscience, Washington DC. Poster #619.23