Transgene distribution and immune response after ultrasound delivery of rAAV9 and PHP.B to the brain in a mouse model of amyloidosis.
Alzheimer disease
TgCRND8
adeno-associated virus
blood-brain barrier
focused ultrasound
immune response
machine learning
microbubbles
rAAV-PHP.B
Journal
Molecular therapy. Methods & clinical development
ISSN: 2329-0501
Titre abrégé: Mol Ther Methods Clin Dev
Pays: United States
ID NLM: 101624857
Informations de publication
Date de publication:
10 Dec 2021
10 Dec 2021
Historique:
received:
01
04
2021
revised:
12
08
2021
accepted:
05
10
2021
entrez:
11
11
2021
pubmed:
12
11
2021
medline:
12
11
2021
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 34761053
doi: 10.1016/j.omtm.2021.10.001
pii: S2329-0501(21)00158-3
pmc: PMC8560718
doi:
Types de publication
Journal Article
Langues
eng
Pagination
390-405Informations de copyright
© 2021 The Author(s).
Déclaration de conflit d'intérêts
The authors declare no competing interests.
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