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ULTRASOUND-MEDIATED BLOOD-BRAIN BARRIER PERMEABILIZATION IN PRIMATES

Award Number: R44NS054410
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/15/2008
PERIOD OF PERFORMANCE END DATE: 05/31/2010

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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 (CNS), as well as 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 malignancies that have proven resistant to conventional approaches. In Phase I studies, a low intensity directed ultrasound (LODUS) system was built and used to effectively open the BBB in nonhuman primates. In addition, methods were developed to assess penetration of macromolecules such as IgG from blood. LODUS parameters were elucidated to safely open the BBB. These observations substantiated a prior incidental discovery that LODUS could enhance extravasation of MRI contrast material without evidence of injury in a human. Building on these proof of concept Phase I results, the goal of Phase II is to provide substantial and compelling preclinical evidence that LODUS effectively and safely, and reversibly opens the BBB in nonhuman primates. The proposed experiments would not be possible in non-primate animal models due to anatomic limitations and poor relevance to humans or in human subjects due to cost and ethical concerns. The Specific Aims are: 1) to quantify the efficacy of LODUS by examining uptake of fluorescent dextrans of different molecular weights; 2) to determine the kinetics of LODUS mediated BBB permeabilization and investigate possible mechanisms of the effect; 3) to evaluate the safety and efficacy of repeated LODUS delivery; and 4) to demonstrate that LODUS can safely deliver clinically relevant macromolecules such as trastuzumab (Herceptin) to the brain parenchyma. To ensure success in this project the expertise of scientists and engineers from four organizations are being utilized. Successful completion of these Phase II studies will facilitate development of robust and clinically relevant protocols for the reversible opening of the BBB for research and therapeutic applications to treat neurodegenerative diseases, brain cancer and other CNS conditions. This proprietary technology will also enable offering of attractive preclinical services to customers and potential partners developing CNS therapeutics and diagnostics. Blood vessels in the brain differ from those in the rest of the body in that they prevent most drugs from entering the brain. While this is often beneficial, it can prevent many potentially beneficial therapies from reaching their sites of action where they could successfully treat diseases such as Alzheimer's, Parkinson's, and brain cancer. We are developing a safe ultrasound device to allow drugs and other therapies to enter the brain and treat these and other neurological diseases.


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: 2009 ( Subtotal = $668,381 )
2009	2009	RX GEN INC	100 DEEPWOOD DRIVE	HAMDEN	CT	06517	SOUTH CENTRAL CT	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	6/10/2009	NON-COMPETING CONTINUATION	$668,381
														Subtotal = $668,381

Issue Date FY: 2008 ( Subtotal = $694,061 )
2008	2008	RX GEN INC	100 DEEPWOOD DRIVE	HAMDEN	CT	06517	SOUTH CENTRAL CT	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	6/11/2008	COMPETING CONTINUATION	$694,061
														Subtotal = $694,061

Grand Total All Awards = $1,362,442

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ULTRASOUND-MEDIATED BLOOD-BRAIN BARRIER PERMEABILIZATION IN PRIMATES

Award Number: R44NS054410

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 06/15/2008

PERIOD OF PERFORMANCE END DATE: 05/31/2010

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