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Targeted Transgene Activation in the Brain Tissue by Systemic Delivery of Engineered AAV1 Expressing CRISPRa.

Abstract：

:Targeted transcriptional modulation in the central nervous system (CNS) can be achieved by adeno-associated virus (AAV) delivery of CRISPR activation (CRISPRa) and interference (CRISPRi) transgenes. To enable AAV packaging, we constructed minimal CRISPRa and CRISPRi transgenes by fusing catalytically inactive Staphylococcus aureus Cas9 (dSaCas9) to the transcriptional activator (VP64 and VP160) and repressor (KRAB and SID4X) domains along with truncated regulatory elements. We then evaluated the performance of these constructs in two reporter assays (bioluminescent and fluorescent), five endogenous genes (Camk2a, Mycn, Nrf2, Keap1, and PDGFRA), and two cell lines (neuro-2a [N2a] and U87) by targeting the promoter and/or enhancer regions. To enable systemic delivery of AAVs to the CNS, we have also generated an AAV1-PHP.B by inserting a 7-mer PHP.B peptide on AAV1 capsid. We showed that AAV1-PHP.B can efficiently cross the blood-brain barrier (BBB) and be taken up by the brain tissue upon lateral tail vein injection in mice. Importantly, a single-dose intravenous administration of AAV1-PHP.B expressing CRISPRa was shown to achieve targeted transgene activation in the mouse brain. This proof-of-concept study will contribute to the development of a non-invasive, specific and potent AAV-CRISPR system for correcting transcriptional misregulation in broad brain areas and multiple neuroanatomical structures.

journal_name

Mol Ther Nucleic Acids

journal_title

Molecular therapy. Nucleic acids

authors

Lau CH,Ho JW,Lo PK,Tin C

doi

10.1016/j.omtn.2019.04.015

subject

Has Abstract

pub_date

2019-06-07 00:00:00

pages

637-649

issn

2162-2531

pii

S2162-2531(19)30088-5

journal_volume

16

pub_type

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