Variants of the Adeno-associated Virus Serotype 9 with Enhanced Penetration of the Blood-brain Barrier in Rodents and Primates

Overview

Journal Nat Biomed Eng

Publisher Springer Nature

Specialty Biomedical Engineering

Date 2022 Oct 10

PMID 36217021

Authors

Yizheng Yao

Jun Wang

Yi Liu

Yuan Qu

Kaikai Wang

Yang Zhang

Yuxin Chang

Zhi Yang

Jie Wan

Junfeng Liu

Hiroshi Nakashima

Sean E Lawler

E Antonio Chiocca

Choi-Fong Cho

Fengfeng Bei

Affiliations

Soon will be listed here.

Abstract

The development of gene therapies for the treatment of diseases of the central nervous system has been hindered by the limited availability of adeno-associated viruses (AAVs) that efficiently traverse the blood-brain barrier (BBB). Here, we report the rational design of AAV9 variants displaying cell-penetrating peptides on the viral capsid and the identification of two variants, AAV.CPP.16 and AAV.CPP.21, with improved transduction efficiencies of cells of the central nervous system on systemic delivery (6- to 249-fold across 4 mouse strains and 5-fold in cynomolgus macaques, with respect to the AAV9 parent vector). We also show that the neurotropism of AAV.CPP.16 is retained in young and adult macaques, that this variant displays enhanced transcytosis at the BBB as well as increased efficiency of cellular transduction relative to AAV9, and that it can be used to deliver antitumour payloads in a mouse model of glioblastoma. AAV capsids that can efficiently penetrate the BBB will facilitate the clinical translation of gene therapies aimed at the central nervous system.

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