After cancer and heart disease, neurodegenerative diseases, such as Alzheimer's, Parkinson's, multiple sclerosis (MS), amythrophic lateral sclerosis (ALS), take more lives each year than any other illness. Although great progress has been made in recent years toward understanding of neurodegenerative diseases, few effective treatments and no cures are currently available. This is mainly because the blood-brain barrier (BBB) limits the delivery of the vast majority of systemically-administered drugs available to treat those diseases. The underlying hypothesis of this study is that delivery of therapeutic molecules is safe and effective through the blood-brain barrier (BBB) using Focused Ultrasound (FUS). Our preliminary results have shown that the FUS technique can induce BBB opening entirely noninvasively, selectively and be monitored with MRI at sub-millimeter resolution in vivo, both in normal mice and Alzheimer's-model mice. The primary objective of this study is thus to establish the neurotherapeutic potential of trans-BBB delivery using FUS, i.e., determine its complete safety and efficacy profiles. Once those are established, a secondary objective entails the potential for translation to the clinic, i.e., development of FUS prototypes for non-human primate and human use for future large animal and clinical assessment, respectively. The multi-disciplinary team assembled encompasses all critical specialty areas such as ultrasound engineering, Alzheimer's pathophysiology in animals and humans, histological and behavioral studies and transgenic model development as well as MR and fluorescence imaging expertise.
The specific aims of the study are therefore to: 1) assess the safety of the BBB opening in the presence or absence of disease in vivo;2) evaluate the efficacy of FUS-enhanced pharmacological therapies in vivo;and 3) build and test the FUS systems for transcranial BBB opening in non- human primates and humans. Following the proposed studies, this entirely noninvasive and highly localized BBB opening method will be tested in large animals and, ultimately, humans in conjunction with the most promising, systemically administered pharmacological agents to demonstrate its true clinical potential, for Alzheimer's or other neurodegenerative or neurological diseases.

Public Health Relevance

Due to the impermeability of the blood-brain barrier (BBB), neurological disorders and all age-related neurodegenerative diseases remain undertreated despite the thousands of pharmacological agents available. The primary objective of this study is thus to establish the neurotherapeutic potential of trans-BBB delivery using FUS. A secondary objective entails assessment of its potential for translation to clinical practice.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Medical Imaging Study Section (MEDI)
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Petanceska, Suzana
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Columbia University (N.Y.)
Biomedical Engineering
Schools of Engineering
New York
United States
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Wang, S; Olumolade, O O; Sun, T et al. (2015) Noninvasive, neuron-specific gene therapy can be facilitated by focused ultrasound and recombinant adeno-associated virus. Gene Ther 22:104-10
Chen, Hong; Chen, Cherry C; Acosta, Camilo et al. (2014) A new brain drug delivery strategy: focused ultrasound-enhanced intranasal drug delivery. PLoS One 9:e108880
Chen, Hong; Konofagou, Elisa E (2014) The size of blood-brain barrier opening induced by focused ultrasound is dictated by the acoustic pressure. J Cereb Blood Flow Metab 34:1197-204
Marquet, Fabrice; Teichert, Tobias; Wu, Shih-Ying et al. (2014) Real-time, transcranial monitoring of safe blood-brain barrier opening in non-human primates. PLoS One 9:e84310
Wang, Shutao; Samiotaki, Gesthimani; Olumolade, Oluyemi et al. (2014) Microbubble type and distribution dependence of focused ultrasound-induced blood-brain barrier opening. Ultrasound Med Biol 40:130-7
Wu, Shih-Ying; Tung, Yao-Sheng; Marquet, Fabrice et al. (2014) Transcranial cavitation detection in primates during blood-brain barrier opening--a performance assessment study. IEEE Trans Ultrason Ferroelectr Freq Control 61:966-78
Chen, Cherry C; Wu, Shih-Ying; Finan, John D et al. (2013) An experimental study on the stiffness of size-isolated microbubbles using atomic force microscopy. IEEE Trans Ultrason Ferroelectr Freq Control 60:524-34
Chen, Cherry C; Sheeran, Paul S; Wu, Shih-Ying et al. (2013) Targeted drug delivery with focused ultrasound-induced blood-brain barrier opening using acoustically-activated nanodroplets. J Control Release 172:795-804
Samiotaki, Gesthimani; Konofagou, Elisa E (2013) Dependence of the reversibility of focused- ultrasound-induced blood-brain barrier opening on pressure and pulse length in vivo. IEEE Trans Ultrason Ferroelectr Freq Control 60:2257-65