Both authors contributed to the article and approved the submitted version. Conflict of Interest PF has received funding from Insightec which has funded some of the clinical studies cited. the delivery of newly developed molecular therapies. Keywords: FUS, blood-brain barrier, Alzheimer’s disease, Parkinson’s disease, focused ultrasound (MRgFUS) In spite of major gains in the understanding of the biology of neurodegenerative disease such as Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington’s disease, they remain progressively disabling and deadly conditions. Although many brokers have Mouse monoclonal to Calcyclin provided neuroprotection in cellular and animal models of these conditions, none has resulted in clinically meaningful modification of their progressively worsening natural course. The need for effective disease modifying therapy (DMT) is so dire that brokers with likely marginal benefit such as the recently FDA approved aducanumab for AD generate great public interest (1). Although the factors responsible for the widespread failures of promising agents to translate into clinically effective DMTs are complex, a role for poor brain bioavailability has been suggested (2). This is particularly true for the growing pharmacopeia of molecular therapies including growth factors, enzymes, monoclonal antibodies, and genetic material, all too large to cross the specialized endothelia that compose the blood-brain barrier (BBB). Unfortunately, the intensity of research progress in the development of molecular therapies has greatly outpaced the development of strategies for their delivery to brain. Contemporary clinical trials of gene therapy for neurodegenerative disease continue to rely on invasive methods such intracerebral infusion (3, 4). The most well-explored strategy to Ginsenoside Rh1 allow large molecules to cross the BBB has been the creation of hybrid molecules that contain a domain name the binds to brain endothelial membrane transport receptors such as the transferrin and insulin receptors (5). These trojan horse therapeutics have begun to enter clinical trials (6). There has been a resurgence in interest in intra-arterial infusion of hyperosmolar solutions of mannitol to open the BBB, a method initially developed in the 1980’s (7, 8). The newest strategy to enhance delivery of therapeutics from blood to brain is to use focused ultrasound (FUS). The specialized endothelia of the brain have continuous tight junctions that form the BBB, limiting the movement of large molecules from the bloodstream into brain. Studies by Hynynen, McDannold, and colleagues (9C12) initially exhibited that FUS applied during the circulation of microbubble suspensions (FDA-approved ultrasound contrast brokers) can create a transient and safe disruption of the BBB, which can be targeted to a specific brain region using MRI. This allows large therapeutics to enter the brain from the systemic circulation including antibodies, growth factors, nanoparticles, nucleic acids, viral vectors, and even cells (13C19). Ginsenoside Rh1 Using pulsed ultrasound at a much lower intensity than the continuous ultrasound used for brain tissue ablation, the microbubbles undergo oscillations of expansion and contraction that cause transient separation of endothelial tight junctionsthe basis for the BBB (20, 21). The procedure can create transient (hours) opening of the BBB, sufficient to allow extravasation of large therapeutics without pathology or entry of blood components (22, 23). Delivery of large therapeutics across the BBB with any strategy has been limited by the inefficiency of the transfer where accumulation of 1C2% of the total blood injectate in the brain is a true accomplishment (5). Within safe parameters, BBB opening may last only a few hours, and the amount of the therapeutic entering brain is usually much less. Studies of molecular therapies usually find Ginsenoside Rh1 that <0.1% of the injected agent can be detected in the sonicated region of brain after MRgFUS-mediated opening of the BBB (24). The first application of this strategy was in brain tumor therapy where in preclinical models of brain metastatic breast cancer, FUS-mediated BBB opening substantially improved the efficacy of the antihuman epidermal growth factor 2 monoclonal antibody trastuzumab (24). Clinical trials of FUS opening to enhance chemotherapy of brain tumors are currently in progress (25). For neurodegenerative diseases, studies using MRI guided FUS (MRgFUS) have enhanced delivery of several potential DMTs including genes in preclinical models of PD. The delivery of glial cell-derived neurotrophic factor (GDNF) and the related factor neurturin from the blood was improved in rodents with the use of this strategy (26, 27). Gene delivery of GDNF has been successful in restoring dopamine metabolism and reversing motor abnormalities in a toxin-induced rat model of PD (28). In an effort to improve the efficiency of delivery (a persistent problem with all blood to brain strategies), the plasmid was preloaded into the microbubbles to enhance its concentration in the Ginsenoside Rh1 region of FUS-mediated BBB opening. Gene delivery for GDNF has also been Ginsenoside Rh1 successful with enhanced brain distribution using brain penetrant nanoparticles with FUS mediated BBB.