Abstract
Utilization of neuropharmaceuticals for central nervous system(CNS) disease is highly limited due to the blood-brain barrier(BBB) which restricts molecules larger than 500Da from reaching the CNS. The development of a reliable method to bypass the BBB would represent an enormous advance in neuropharmacology enabling the use of many potential disease modifying therapies. Previous attempts such as transcranial catheter implantation have proven to be temporary and associated with multiple complications. Here we describe a novel method of creating a semipermeable window in the BBB using purely autologous tissues to allow for high molecular weight(HMW) drug delivery to the CNS. This approach is inspired by recent advances in human endoscopic transnasal skull base surgical techniques and involves engrafting semipermeable nasal mucosa within a surgical defect in the BBB. The mucosal graft thereby creates a permanent transmucosal conduit for drugs to access the CNS. The main objective of this study was to develop a murine model of this technique and use it to evaluate transmucosal permeability for the purpose of direct drug delivery to the brain. Using this model we demonstrate that mucosal grafts allow for the transport of molecules up to 500 kDa directly to the brain in both a time and molecular weight dependent fashion. Markers up to 40 kDa were found within the striatum suggesting a potential role for this technique in the treatment of Parkinson’s disease. This proof of principle study demonstrates that mucosal engrafting represents the first permanent and stable method of bypassing the BBB thereby providing a pathway for HMW therapeutics directly into the CNS.
Highlights
Neurologic disorders affect more than 20 million patients in the US alone and account for over $400 billion in annual expenditure for both their treatment and chronic care [1,2]
A mucosal graft harvested from a donor mouse septum was applied over a right parietal craniotomy 3 mm in diameter following dural reflection(Fig. 1B–D)
A reservoir was surgically implanted over the mucosal graft to form a tight seal allowing topical dosing of the graft with different fluorescent rhodamine-dextran markers ranging from 20–500 kDa
Summary
Neurologic disorders affect more than 20 million patients in the US alone and account for over $400 billion in annual expenditure for both their treatment and chronic care [1,2]. The paucity of effective neurodegenerative therapies is directly attributable to the presence of the blood-brain barrier(BBB) and blood-cerebrospinal fluid barrier(BCSFB). These barriers are composed of densely packed cells with copious intercellular tight junctions(TJ), active efflux pumps, and a trilamellar basement membrane which prevent the absorption of polar or high molecular weight(HMW) molecules larger than 500Da [3]. This results in restriction of up to 98% of all potential neuropharmaceutical agents from reaching the central nervous system(CNS) [3]. Described experimental methods such as transcranial catheter placement [4] and the use of protein conjugates [1] may be invasive or require extensive drug manipulation to optimize trans-
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