Blood-brain barrier disruption for the delivery of non-infectious viral vectors and proteins, preliminary study

Josquin Foiret, Hua Zhang, Brett Z. Fite, Tali Ilovitsh, Lisa M. Mahakian, Sarah Tam, Ulrika Beitnere, Benjamin Pyles, David Segal, Katherine W. Ferrara

Research output: Chapter in Book/Report/Conference proceedingConference contribution

1 Citation (Scopus)

Abstract

Angelman syndrome (AS) is a rare neuro-genetic disorder caused by loss of expression of the maternal copy of UBE3A in the brain inducing severe mental and physical impairments. Due to brain-specific genetic imprinting, the paternal UBE3A is silenced by a long antisense transcript. Inhibition of the antisense transcript could lead to unsilencing of paternal UBE3A, thus providing a therapeutic approach for AS. Treatment requires widespread delivery of gene regulators to the brain. Safe blood-brain barrier (BBB) disruption using focused ultrasound (FUS) combined with microbubbles has shown promising results in cancer applications and several clinical studies are underway. In this study, our goal is to deliver therapeutic agents to treat AS using FUS. Deverman et al. demonstrated that peptide PHP.B, when displayed on the 20-nm AAV9 capsid surface (AAV-PHP.B), enhanced neuronal transfection throughout the brain by 40-fold following IV injection in healthy mouse models [1]. Here, we seek to determine whether delivery of a construct with wide brain distribution can be augmented by enhancing the BBB transport. In this work, a 128-element 1.5 MHz therapeutic array was interfaced to the Vantage platform (Verasonics). In a mouse model, the BBB was successfully disrupted over an expanded treatment area by rapidly translating the beam along a predetermined pattern (swept focus) or by generating multiple foci simultaneously (multifoci). Comparing BBB disruptions with 16 foci and with a swept focus, no significant differences were found, suggesting that a multifoci approach can increase the disrupted area while reducing the number of transmission. Preliminary data obtained through immunofluorescence microscopy showed increased intensity in the MB-FUS+AAV-PHP.B group compared to the AAV-PHP.B group.

Original languageEnglish (US)
Title of host publication2017 IEEE International Ultrasonics Symposium, IUS 2017
PublisherIEEE Computer Society
ISBN (Electronic)9781538633830
DOIs
StatePublished - Oct 31 2017
Event2017 IEEE International Ultrasonics Symposium, IUS 2017 - Washington, United States
Duration: Sep 6 2017Sep 9 2017

Other

Other2017 IEEE International Ultrasonics Symposium, IUS 2017
CountryUnited States
CityWashington
Period9/6/179/9/17

Fingerprint

blood-brain barrier
brain
delivery
proteins
mice
translating
regulators
impairment
genes
peptides
platforms
cancer
disorders
injection
microscopy

Keywords

  • Blood brain barrier
  • Drug delivery
  • Focused ultrasound
  • Microbubble
  • Multifoci
  • Ultrasound contrast agent

ASJC Scopus subject areas

  • Acoustics and Ultrasonics

Cite this

Foiret, J., Zhang, H., Fite, B. Z., Ilovitsh, T., Mahakian, L. M., Tam, S., ... Ferrara, K. W. (2017). Blood-brain barrier disruption for the delivery of non-infectious viral vectors and proteins, preliminary study. In 2017 IEEE International Ultrasonics Symposium, IUS 2017 [8092207] IEEE Computer Society. https://doi.org/10.1109/ULTSYM.2017.8092207

Blood-brain barrier disruption for the delivery of non-infectious viral vectors and proteins, preliminary study. / Foiret, Josquin; Zhang, Hua; Fite, Brett Z.; Ilovitsh, Tali; Mahakian, Lisa M.; Tam, Sarah; Beitnere, Ulrika; Pyles, Benjamin; Segal, David; Ferrara, Katherine W.

2017 IEEE International Ultrasonics Symposium, IUS 2017. IEEE Computer Society, 2017. 8092207.

Research output: Chapter in Book/Report/Conference proceedingConference contribution

Foiret, J, Zhang, H, Fite, BZ, Ilovitsh, T, Mahakian, LM, Tam, S, Beitnere, U, Pyles, B, Segal, D & Ferrara, KW 2017, Blood-brain barrier disruption for the delivery of non-infectious viral vectors and proteins, preliminary study. in 2017 IEEE International Ultrasonics Symposium, IUS 2017., 8092207, IEEE Computer Society, 2017 IEEE International Ultrasonics Symposium, IUS 2017, Washington, United States, 9/6/17. https://doi.org/10.1109/ULTSYM.2017.8092207
Foiret J, Zhang H, Fite BZ, Ilovitsh T, Mahakian LM, Tam S et al. Blood-brain barrier disruption for the delivery of non-infectious viral vectors and proteins, preliminary study. In 2017 IEEE International Ultrasonics Symposium, IUS 2017. IEEE Computer Society. 2017. 8092207 https://doi.org/10.1109/ULTSYM.2017.8092207
Foiret, Josquin ; Zhang, Hua ; Fite, Brett Z. ; Ilovitsh, Tali ; Mahakian, Lisa M. ; Tam, Sarah ; Beitnere, Ulrika ; Pyles, Benjamin ; Segal, David ; Ferrara, Katherine W. / Blood-brain barrier disruption for the delivery of non-infectious viral vectors and proteins, preliminary study. 2017 IEEE International Ultrasonics Symposium, IUS 2017. IEEE Computer Society, 2017.
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abstract = "Angelman syndrome (AS) is a rare neuro-genetic disorder caused by loss of expression of the maternal copy of UBE3A in the brain inducing severe mental and physical impairments. Due to brain-specific genetic imprinting, the paternal UBE3A is silenced by a long antisense transcript. Inhibition of the antisense transcript could lead to unsilencing of paternal UBE3A, thus providing a therapeutic approach for AS. Treatment requires widespread delivery of gene regulators to the brain. Safe blood-brain barrier (BBB) disruption using focused ultrasound (FUS) combined with microbubbles has shown promising results in cancer applications and several clinical studies are underway. In this study, our goal is to deliver therapeutic agents to treat AS using FUS. Deverman et al. demonstrated that peptide PHP.B, when displayed on the 20-nm AAV9 capsid surface (AAV-PHP.B), enhanced neuronal transfection throughout the brain by 40-fold following IV injection in healthy mouse models [1]. Here, we seek to determine whether delivery of a construct with wide brain distribution can be augmented by enhancing the BBB transport. In this work, a 128-element 1.5 MHz therapeutic array was interfaced to the Vantage platform (Verasonics). In a mouse model, the BBB was successfully disrupted over an expanded treatment area by rapidly translating the beam along a predetermined pattern (swept focus) or by generating multiple foci simultaneously (multifoci). Comparing BBB disruptions with 16 foci and with a swept focus, no significant differences were found, suggesting that a multifoci approach can increase the disrupted area while reducing the number of transmission. Preliminary data obtained through immunofluorescence microscopy showed increased intensity in the MB-FUS+AAV-PHP.B group compared to the AAV-PHP.B group.",
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