Transgene distribution and immune response after ultrasound delivery of rAAV9 and PHP.B to the brain in a mouse model of amyloidosis

TY - JOUR

T1 - Transgene distribution and immune response after ultrasound delivery of rAAV9 and PHP.B to the brain in a mouse model of amyloidosis

AU - Kofoed, Rikke Hahn

AU - Heinen, Stefan

AU - Silburt, Joseph

AU - Dubey, Sonam

AU - Dibia, Chinaza Lilian

AU - Maes, Miriam

AU - Simpson, Elizabeth M.

AU - Hynynen, Kullervo

AU - Aubert, Isabelle

N1 - Publisher Copyright: © 2021 The Authors

PY - 2021/12/10

Y1 - 2021/12/10

N2 - Efficient disease-modifying treatments for Alzheimer disease, the most common form of dementia, have yet to be established. Gene therapy has the potential to provide the long-term production of therapeutic in the brain following a single administration. However, the blood-brain barrier poses a challenge for gene delivery to the adult brain. We investigated the transduction efficiency and immunological response following non-invasive gene-delivery strategies to the brain of a mouse model of amyloidosis. Two emerging technologies enabling gene delivery across the blood-brain barrier were used to establish the minimal vector dosage required to reach the brain: (1) focused ultrasound combined with intravenous microbubbles, which increases the permeability of the blood-brain barrier at targeted sites and (2) the recombinant adeno-associated virus (rAAV)-based capsid named rAAV-PHP.B. We found that equal intravenous dosages of rAAV9 combined with focused ultrasound, or rAAV-PHP.B, were required for brain gene delivery. In contrast to rAAV9, focused ultrasound did not decrease the rAAV-PHP.B dosage required to transduce brain cells in a mouse model of amyloidosis. The non-invasive rAAV delivery to the brain using rAAV-PHP.B or rAAV9 with focused ultrasound triggered an immune reaction including major histocompatibility complex class II expression, complement system and microglial activation, and T cell infiltration.

AB - Efficient disease-modifying treatments for Alzheimer disease, the most common form of dementia, have yet to be established. Gene therapy has the potential to provide the long-term production of therapeutic in the brain following a single administration. However, the blood-brain barrier poses a challenge for gene delivery to the adult brain. We investigated the transduction efficiency and immunological response following non-invasive gene-delivery strategies to the brain of a mouse model of amyloidosis. Two emerging technologies enabling gene delivery across the blood-brain barrier were used to establish the minimal vector dosage required to reach the brain: (1) focused ultrasound combined with intravenous microbubbles, which increases the permeability of the blood-brain barrier at targeted sites and (2) the recombinant adeno-associated virus (rAAV)-based capsid named rAAV-PHP.B. We found that equal intravenous dosages of rAAV9 combined with focused ultrasound, or rAAV-PHP.B, were required for brain gene delivery. In contrast to rAAV9, focused ultrasound did not decrease the rAAV-PHP.B dosage required to transduce brain cells in a mouse model of amyloidosis. The non-invasive rAAV delivery to the brain using rAAV-PHP.B or rAAV9 with focused ultrasound triggered an immune reaction including major histocompatibility complex class II expression, complement system and microglial activation, and T cell infiltration.

KW - adeno-associated virus

KW - Alzheimer disease

KW - blood-brain barrier

KW - focused ultrasound

KW - immune response

KW - machine learning

KW - microbubbles

KW - rAAV-PHP.B

KW - TgCRND8

UR - http://www.scopus.com/inward/record.url?scp=85122660848&partnerID=8YFLogxK

U2 - 10.1016/j.omtm.2021.10.001

DO - 10.1016/j.omtm.2021.10.001

M3 - Journal article

AN - SCOPUS:85122660848

SN - 2329-0501

VL - 23

SP - 390

EP - 405

JO - Molecular Therapy Methods and Clinical Development

JF - Molecular Therapy Methods and Clinical Development

ER -