After cancer and heart disease, neurodegenerative diseases, such as Alzheimer's, Parkinson's, multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS), take more lives each year than any other illness. Although some effective treatments are available, most of those diseases remain undertreated. This is mainly because the blood-brain barrier (BBB) limits the delivery of systemically-administered drugs. As a result, only 5% of the more than 7000 small-molecule drugs available can currently treat Central Nervous System (CNS) diseases. Safe and localized opening of the BBB has been proven to present a significant challenge. Focused Ultrasound (FUS), in conjunction with microbubbles, remains the sole technique that can induce localized BBB opening noninvasively and safely. Prior to our studies reported herein, the bioactivity and therapeutic potential of the trans-BBB delivery was unknown. In this renewal study, we aim at determining 1) the role of the FUS technique in the treatment of Alzheimer's disease (AD) in established mouse models (aim 1), 2) build a new FUS system with neuronavigation capabilities for demonstrating proof of concept of neuroprotection in NHP (aim 2) and 3) build a clinical system and test initial feasibility and safey in a small cohort of patients (aim 3). In this renewal, the primary objective is thus to challenge the FUS technique for demonstrating therapeutic effects in AD models, translating those in large animals and demonstrating clinical feasibility. The underlying hypothesis of the proposed study is thus that the neurotherapeutic potential demonstrated in the previous funding period translates to neurotherapeutic effects in Alzheimer's disease including initial clinical feasibilit. The multi-disciplinary team assembled encompasses all critical specialty areas involved, such as ultrasound and microbubble engineering as well as MRI, PET and fluorescence brain imaging, drug delivery, behavioral assessment and mouse model development as they pertain to neuroscience and neurology.
The specific aims are thus to: 1) Demonstrate neuroprotection and neurorestoration in the AD mouse model in vivo; 2) Build a new system for accurate targeting and demonstrate therapeutic effects in NHP in vivo; and 3) Build a new system for accurate targeting in humans in vivo.

Public Health Relevance

One of the primordial reasons why Alzheimer's remains undertreated is that current treatments of neurological and neurodegenerative diseases are limited due to the lack of a truly noninvasive, transient, and regionally selective brain drug delivery method. For the purpose of this study, we will apply FUS for the effective treatment of Alzheimer's disease and employ gene delivery due to its great promise and associated low blood-brain barrier impermeability.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG038961-09
Application #
9647400
Study Section
Biomedical Imaging Technology Study Section (BMIT)
Program Officer
Refolo, Lorenzo
Project Start
2011-08-01
Project End
2021-02-28
Budget Start
2019-03-01
Budget End
2020-02-29
Support Year
9
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Columbia University (N.Y.)
Department
Biomedical Engineering
Type
Biomed Engr/Col Engr/Engr Sta
DUNS #
049179401
City
New York
State
NY
Country
United States
Zip Code
10027
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Sierra, Carlos; Acosta, Camilo; Chen, Cherry et al. (2017) Lipid microbubbles as a vehicle for targeted drug delivery using focused ultrasound-induced blood-brain barrier opening. J Cereb Blood Flow Metab 37:1236-1250
Wang, Shutao; Karakatsani, Maria E; Fung, Christine et al. (2017) Direct brain infusion can be enhanced with focused ultrasound and microbubbles. J Cereb Blood Flow Metab 37:706-714

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