Noninvasive, neuron-specific gene therapy can be facilitated by focused ultrasound and recombinant adeno-associated virus

Wang, Shutao; Olumolade, Oluyemi; Sun, Tao; Samiotaki, Gesthimani; Konofagou, Elisa E.

doi:10.1038/gt.2014.91

Cited by 122 publications

(106 citation statements)

References 32 publications

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“…Use of pressurized convection-enhanced delivery (CED) and magnetic resonance imaging (MRI)-guided infusion can lead to significantly better distribution compared to single injections of smaller volumes (Bankiewicz et al, 2000). Facilitated access across the BBB with AAV has also been achieved using focused ultrasound and microbubbles (Wang et al, 2015). …”

Section: Deliver the Vector The More The Better (Modes And Sites mentioning

confidence: 99%

Viral vectors for therapy of neurologic diseases

et al. 2017

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Neurological disorders – disorders of the brain, spine and associated nerves – are a leading contributor to global disease burden with a shockingly large associated economic cost. Various treatment approaches – pharmaceutical medication, device-based therapy, physiotherapy, surgical intervention, among others – have been explored to alleviate the resulting extent of human suffering. In recent years, gene therapy using viral vectors – encoding a therapeutic gene or inhibitory RNA into a “gutted” viral capsid and supplying it to the nervous system – has emerged as a clinically viable option for therapy of brain disorders. In this Review, we provide an overview of the current state and advances in the field of viral vector-mediated gene therapy for neurological disorders. Vector tools and delivery methods have evolved considerably over recent years, with the goal of providing greater and safer genetic access to the central nervous system. Better etiological understanding of brain disorders has concurrently led to identification of improved therapeutic targets. We focus on the vector technology, as well as preclinical and clinical progress made thus far for brain cancer and various neurodegenerative and neurometabolic disorders, and point out the challenges and limitations that accompany this new medical modality. Finally, we explore the directions that neurological gene therapy is likely to evolve towards in the future.

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Section: Deliver the Vector The More The Better (Modes And Sites mentioning

confidence: 99%

Viral vectors for therapy of neurologic diseases

et al. 2017

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“…Indeed, the delivery of chemotherapeutic drugs (Escoffre et al 2013; Kang et al 2010; Kotopoulis et al 2013; Tinkov et al 2010), DNA (Carson et al 2011; Christiansen et al 2003) and siRNA (Carson et al 2012; Kinoshita and Hynynen 2005) has been shown in both in vitro and in vivo contexts. In addition to these applications, studies have shown that ultrasound stimulated microbubbles can transiently and locally disrupt the blood brain barrier (BBB) in order to facilitate drug delivery for the treatment of brain disorders (Park et al 2012; Tung et al 2011; Wang et al 2015; Weber-Adrian et al 2015). …”

Section: Introductionmentioning

confidence: 99%

Fluid Viscosity Affects the Fragmentation and Inertial Cavitation Threshold of Lipid-Encapsulated Microbubbles

Helfield

Black

Qin

et al. 2016

Ultrasound in Medicine & Biology

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Ultrasound and microbubble optimization studies for therapeutic applications are often conducted in water/saline, with a fluid viscosity of 1 cP. In an in vivo context, microbubbles are situated in blood, a more viscous fluid (~4 cP). In this study, ultra-high speed microscopy and passive cavitation approaches were employed to investigate the effect of fluid viscosity on microbubble behavior at 1 MHz subject to high pressures (0.25 – 2 MPa). The propensity for individual microbubble (n=220) fragmentation was shown to significantly decrease in 4 cP fluid as compared to 1 cP fluid, despite achieving similar maximum radial excursions. Microbubble populations diluted in 4 cP fluid exhibited decreased wideband emissions (up to 10.2 times), and increasingly distinct harmonic emission peaks (e.g. ultraharmonic) with increasing pressure as compared to 1 cP fluid. These results suggest that in vitro studies should consider an evaluation using physiologic viscosity perfusate before transitioning to in vivo evaluations.

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“…BBBD, the subject of the current study, reversibly opens the blood-brain barrier (BBB) enabling the delivery of even large-molecule therapeutics to the central nervous system and offers great potential for treating multiple neurological disorders. This technology has been demonstrated in rodent (11)(12)(13)(14)(15)(16) and nonhuman primate (17,18) models, and clinical trials are underway (19,20).…”

mentioning

confidence: 99%

Closed-loop control of targeted ultrasound drug delivery across the blood–brain/tumor barriers in a rat glioma model

Sun

Zhang

Power

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

199

172

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Cavitation-facilitated microbubble-mediated focused ultrasound therapy is a promising method of drug delivery across the blood-brain barrier (BBB) for treating many neurological disorders. Unlike ultrasound thermal therapies, during which magnetic resonance thermometry can serve as a reliable treatment control modality, real-time control of modulated BBB disruption with undetectable vascular damage remains a challenge. Here a closedloop cavitation controlling paradigm that sustains stable cavitation while suppressing inertial cavitation behavior was designed and validated using a dual-transducer system operating at the clinically relevant ultrasound frequency of 274.3 kHz. Tests in the normal brain and in the F98 glioma model in vivo demonstrated that this controller enables reliable and damage-free delivery of a predetermined amount of the chemotherapeutic drug (liposomal doxorubicin) into the brain. The maximum concentration level of delivered doxorubicin exceeded levels previously shown (using uncontrolled sonication) to induce tumor regression and improve survival in rat glioma. These results confirmed the ability of the controller to modulate the drug delivery dosage within a therapeutically effective range, while improving safety control. It can be readily implemented clinically and potentially applied to other cavitation-enhanced ultrasound therapies.drug delivery | focused ultrasound | acoustic cavitation | treatment control | blood-brain barrier

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Noninvasive, neuron-specific gene therapy can be facilitated by focused ultrasound and recombinant adeno-associated virus

Cited by 122 publications

References 32 publications

Viral vectors for therapy of neurologic diseases

Viral vectors for therapy of neurologic diseases

Fluid Viscosity Affects the Fragmentation and Inertial Cavitation Threshold of Lipid-Encapsulated Microbubbles

Closed-loop control of targeted ultrasound drug delivery across the blood–brain/tumor barriers in a rat glioma model

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