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Funded Studies

Blood-Brain Barrier Modification Using Heterotopic Nasal Mucosal Grafting for Enhanced Symptoms & Side Effects and Macromolecular Disease Modifying Drug Delivery in Parkinson's Disease

Objective/Rationale:
One of the most significant problems in the treatment of Parkinson’s disease is the inability to provide continuous and high molecular weight drug delivery to the central nervous system due to the presence of the blood-brain barrier. The objective of this project is to test the efficacy of a novel method of bypassing the blood-brain barrier using transplanted semi-permeable mucosal grafts thereby providing continuous access for novel Parkinson’s disease therapies directly to the brain.

Project Description:
In order to test this novel method we will establish a pre-clinical model to mimic the technique of replacing the lining of the brain with highly permeable mucosal grafts. This surgery is commonly performed clinically during cranial base reconstruction following transnasal brain tumor removal. We will determine the ability of the graft to transport drugs directly into the brain using fluorescent markers over a range of molecular weights. The extent of transmucosal drug delivery will be tested using immunohistochemical techniques and compared with direct intranasal delivery. Delivery of fluorescent markers to the striatum and substantia nigra will be considered a successful proof of concept for this promising technique.

Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Utilization of these mucosal grafts has the ability to not only eliminate the motor complications associated with pulsatile delivery of Symptoms & Side Effects Parkinson’s disease therapies, but they may also represent the first clinically feasible method of permanently bypassing the blood-brain barrier. This will provide for renewed potential of currently recognized high molecular weight disease modifying therapies as well as open possibilities for new avenues of experimental therapeutic research.

Anticipated Outcome:
We expect the use of these grafts to allow direct central nervous system access for high molecular weight fluorescent markers that are otherwise excluded by simple intranasal delivery. The degree of delivery is expected to occur in a weight dependent manner. Through this study we hope to gain an understanding regarding the impact of concentration, dosing duration, and molecular weight on the extent of drug distribution to the brain. This data will subsequently form the basis of future treatment efficacy studies.

Final Outcome

We have successfully developed and characterized a pre-clinical model to study the ability to deliver drugs directly to the brain through a mucosal graft. Using this model we have studied the impact of molecular weight and exposure time on the degree of diffusion of fluorescent markers into the brain. We have demonstrated successful delivery of markers up to 500kDa which is1000 times larger than any drug permitted through the blood-brain barrier. We have also found that the total distance and concentration of marker delivered to the whole brain and striatum depends closely on the size of the marker and the total exposure time. Using this model we have successfully demonstrated that the mucosal graft model is a feasible method for bypassing the blood-brain barrier and does so in a predictable manner. This model can be easily applied to patients and used to design future therapies for Parkinson’s disease which are currently limited by the blood-brain barrier.


Researchers

  • Benjamin S. Bleier, MD

    Boston, MA United States


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