Treatment of Alzheimer’s Disease using Ultrasound-Targeted Microbubble Cavitation-Mediated Blood Brain Barrier Opening to Facilitate Drug Delivery to the Brain

使用超声靶向微泡空化介导的血脑屏障打开促进药物输送到大脑来治疗阿尔茨海默病

• 批准号: 10710373
• 负责人: Grace Conway
• 金额: $ 5.27万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-27 至 2027-07-26
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10710373
• 关键词: Address; Adherens Junction; Adverse effects; Affect; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; American; Antibodies; Area; Astrocytes; Biology; Blood - brain barrier anatomy; Blood Vessels; Blood capillaries; Brain; Calcium; Caregivers; Cells; Central Nervous System; Coculture Techniques; Combined Modality Therapy; Confocal Microscopy; Contrast Media; Cytoskeleton; Data Analyses; Deposition; Development; Dextrans; Disease; Dose; Drug Delivery Systems; Drug Design; Drug Modelings; Drug usage; Electrical Resistance; Endothelial Cells; Endothelium; Enzymes; Event; Experimental Designs; FDA approved; Failure; Family; Goals; Healthcare Systems; Image; Impaired cognition; In Vitro; Intravenous; Liver; Mediating; Mentors; Microbubbles; Microbubbles Ultrasound Contrast Medium; Microcirculation; Modeling; Molecular; Monitor; Mus; Nervous System; Neurodegenerative Disorders; Patients; Penetration; Permeability; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Phase I Clinical Trials; Phase II Clinical Trials; Physicians; Physics; Physiology; Pittsburgh Compound-B; Plasma; Positron-Emission Tomography; Proteins; Research Project Grants; Scientist; Signal Transduction; Site; Statistical Data Interpretation; Stress; Structure; Suspensions; Techniques; Testing; Therapeutic; Tight Junctions; Training; Translational Research; Ultrasonic Transducer; Umbilical vein; aging population; bench-to-bedside translation; beta-site APP cleaving enzyme 1; blood-brain barrier permeabilization; brain circulation; brain endothelial cell; career; career development; clinical translation; cognitive ability; cognitive function; design; experimental study; human old age (65+); improved; in vivo; inhibitor; insight; meetings; mouse model; multidisciplinary; nervous system disorder; novel therapeutic intervention; novel therapeutics; side effect; sonoporation; symptom management; theranostics; therapeutic candidate; ultrasound

PROJECT SUMMARY/ABSTRACT Alzheimer’s disease (AD) is a devastating, progressive, neurodegenerative disease that affects millions of Americans, yet there is no cure, and there are very limited treatment options. Failure of otherwise promising drugs for AD may be due, in part, to poor penetration into the brain and/or large systemic dose requirements to achieve therapeutic brain concentrations, resulting in off-target effects. To address blood brain barrier (BBB) impenetrability, ultrasound-targeted microbubble cavitation (UTMC) is being explored as a new treatment strategy for AD. In this approach, low intensity ultrasound is applied to intravenously injected ultrasound contrast agents (microbubbles) as they traverse the microcirculation of the brain. UTMC causes transient endothelial barrier hyperpermeability, allowing for site-specific delivery of therapeutics across the BBB. While UTMC shows promise as a technique to increase BBB permeability, its underlying mechanisms are incompletely understood, ultimately constraining clinical translation. My overarching goal is that UTMC directed to the brain offers an approach to enhance drug delivery across the BBB for treatment of AD. To facilitate clinical translation of this platform, my proposal will determine mechanisms mediating UTMC-induced BBB hyperpermeability and utilize UTMC for delivering therapeutics directed at Ab plaques in vivo in the following Aims: (1) To identify mechanisms by which UTMC causes transient BBB hyperpermeability. UTMC applied to umbilical vein endothelial cells in vitro has been shown to change cytoskeletal dynamics, leading to inter-endothelial cell gaps, which can increase paracellular permeability, and was associated with Ca2+ influx into cells in contact with, and remote from, cavitating microbubbles. Extending these findings to the BBB, I hypothesize that UTMC-mediated Ca2+ influx disrupts tight and adherens junctions between brain microvascular endothelial cells, and may also lead to Ca2+-mediated changes in adjacent astrocytes. A contact co-culture in vitro transwell model of the BBB will be used to study changes in function and structure (confocal microscopy) of endothelial cells and astrocytes after UTMC. (2) To determine whether UTMC-mediated BBB opening, in combination with drug therapy, will lower Ab plaque burden and improve the therapeutic window. I hypothesize that UTMC-mediated BBB opening will decrease the dose required for a specific drug designed to lower Ab plaque deposition, thereby minimizing off-target effects. The drug will be administered, and UTMC will be applied to the brain in a mouse model of AD. Brain Ab plaques will be quantified by serial brain PET imaging. I have assembled an exceptional multidisciplinary team of mentors and collaborators, along with specific coursework and seminars, to acquire the necessary content expertise in AD biology, ultrasound theranostics, imaging, and murine AD models. Through meetings with my mentors and conducting my experiments, I will acquire experiential lessons in rigorous experimental design, data analysis, and presentation. My comprehensive training plan will prepare me to achieve my career goal of becoming a physician-scientist pursuing bench to bedside translational research.

项目总结/文摘