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ULTRASOUND-MEDIATED BLOOD-BRAIN BARRIER PERMEABILIZATION IN PRIMATES

Award Number: R43NS054410
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: HEALTH SERVICES
PERIOD OF PERFORMANCE START DATE: 05/02/2006
PERIOD OF PERFORMANCE END DATE: 03/31/2007

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ULTRASOUND-MEDIATED BLOOD-BRAIN BARRIER PERMEABILIZATION IN PRIMATES - DESCRIPTION (provided by applicant): The blood-brain barrier (BBB) represents both a safeguard against the penetration of physiologically harmful substances into the central nervous system (CMS), and a considerable hurdle to the delivery of therapeutic agents. A technology allowing safe, targeted, reversible opening of the BBB would potentially revolutionize both the study and treatment of CNS disorders, including neurodegenerative conditions and brain and spinal cord malignancies that have proven resistant to conventional approaches. BBB disruption with hypertonic solutions enhances CNS penetration of macromolecules, but at the cost of pronounced fluid shifts and lack of regional specificity. Ultrasound-mediated BBB disruption has been another approach explored. High intensity focused ultrasound (HIFU) has been demonstrated to open the BBB at energy levels that do not result in cellular injury, but associated heating of bone and adjacent tissue prevents HIFU application without direct exposure of the brain by the creation of a bone window. A further drawback is the long duration of opening induced. More recently, low intensity directed ultrasound (LODUS) has been demonstrated to have a similar effect on the barrier properties of the cerebral microvasculature without the confounds of HIFU. Incidental discovery of the permeabilizing effect occurred when non-invasive transcranial application of LODUS to a human patient was found to result in enhanced extravasation of MRI contrast material without evidence of injury. Subsequent rodent studies demonstrated that even under non- optimized conditions LODUS induced a safe and rapidly reversible opening of the BBB to substances as large as adenovirus vectors. The goal of this Phase I study will be to conduct dose response experiments addressing the important ultrasound delivery parameters of intensity and pulse length in a preclinical validation of safety and efficacy in African green monkeys. The proposed experiments would not be possible in non-primate animal models for important anatomic considerations or in humans for cost and ethical reasons. Evans Blue, which binds serum albumin, will be employed as a marker of macromolecule BBB permeability to allow both a visual and quantitative determination of efficacy through well established fluorometric techniques. Successful completion of these primate optimization studies will allow development of robust and clinically relevant protocols for the reversible opening of the BBB for research and therapeutic applications to neurodegenerative diseases, brain cancer and other CNS conditions. Blood vessels in the brain differ from those in the rest of the body in that they prevent most drugs from passing into the surrounding tissue. While this is often beneficial, it can inhibit the range of therapies that can be employed to successfully treat diseases such as Alzheimer's and brain cancer. This research aims to develop a method to deliver drugs and other therapies to the brain in a way that is safe and easy to apply.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2006 ( Subtotal = $208,554 )
2006	2006	RX GEN INC	100 DEEPWOOD DRIVE	HAMDEN	CT	06517	SOUTH CENTRAL CT	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	5/2/2006	NEW	$208,554
														Subtotal = $208,554

Grand Total All Awards = $208,554

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ULTRASOUND-MEDIATED BLOOD-BRAIN BARRIER PERMEABILIZATION IN PRIMATES

Award Number: R43NS054410

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: HEALTH SERVICES

PERIOD OF PERFORMANCE START DATE: 05/02/2006

PERIOD OF PERFORMANCE END DATE: 03/31/2007

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