The overall goal of our current research is to develop novel treatments and drug delivery methodologies for conditions involving CNS, such as, meningeal and brain cancer, neurodegenerative diseases and enzyme deficiencies. Hypothetically, the perivascular network of liquid conduits enveloping arteries and veins in CNS may cover the entire CNS parenchyma and extend into all brain structures, spinal cord and nerve roots. The periarterial space is rapidl remixed along the arterial axes due to the pulsation of the arteries. However, the rates of remixing along the vessel, which define the rates of solute transport in the perivascular space, are unknown and can be expected to depend on the size of the artery. The extent of the periarterial envelopes along the arteries also has not been studied (it is known that they don't extend to the capillaries). Finally, although the data clearly shows that the periarterial space is "leaky" for even large molecules, the penetrability of the periartherial sheaths as well as their structure have not been characterized. The sheaths may have size- selective permeability, but the size cutoffs have not been studied. These gaps of knowledge hinder the development of the perivascular drug delivery route towards substructures of CNS (some of which may be more or less accessible through perivascular space) and thus stand in the way of development of new therapies. The objectives of this exploratory study are (i) to investigate the structure and functional capacity of the perivascular network, and (ii) to estimate the rate of solute exchange between the CSF and CNS along the perivascular route. Impact. The study is expected to result in a comprehensive structural and functional description of the perivascular network of CNS with respect to solute transport between the CSF and CNS. This will open the way to rational development of novel drugs targeted to CNS through the perivascular route.

Public Health Relevance

This study is intended to investigate how macromolecular agents administered to the cerebrospinal fluid enter into the brain along the perivascular conduits, and whether this pathway is suitable for drug delivery to the CNS. The data to be obtained is critical for developing biopharmaceuticals and drug-carrying nanoconstructs optimized for intrathecal treatment of presently incurable conditions involving CNS, such as, cancer, age-related disiases (Parkinson's, Alzheimer's) and enzyme deficiencies.

National Institute of Health (NIH)
Exploratory/Developmental Grants (R21)
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Gene and Drug Delivery Systems Study Section (GDD)
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Koenig, James I
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Massachusetts General Hospital
United States
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