Anti-adenoviral Artificial MicroRNAs Expressed from AAV9 Vectors Inhibit Human Adenovirus Infection in Immunosuppressed Syrian Hamsters

被引：18

作者：

Schaar, Katrin ^{[1
]}

Geisler, Anja ^{[1
]}

Kraus, Milena ^{[1
]}

Pinkert, Sandra ^{[1
]}

Pryshliak, Markian ^{[1
]}

Spencer, Jacqueline F. ^{[2
]}

Tollefson, Ann E. ^{[2
]}

Ying, Baoling ^{[2
]}

Kurreck, Jens ^{[1
]}

Wold, William S. ^{[2
]}

Klopfleisch, Robert ^{[3
]}

Toth, Karoly ^{[2
]}

Fechner, Henry ^{[1
]}

机构：

[1] Tech Univ Berlin, Inst Biotechnol, Dept Appl Biochem, Gustav Meyer Allee 25, D-13355 Berlin, Germany

[2] St Louis Univ, Sch Med, Dept Mol Microbiol & Immunol, 1100 South Grand Blvd, St Louis, MO 63104 USA

[3] Free Univ Berlin, Inst Vet Pathol, Robert von Ostertag Str 15, D-14163 Berlin, Germany

来源：

MOLECULAR THERAPY-NUCLEIC ACIDS | 2017年 / 8卷

基金：

美国国家卫生研究院;

关键词：

CARDIAC GENE-TRANSFER; RNA-INTERFERENCE; TRANSGENE EXPRESSION; PACKAGING SEQUENCE; REPLICATION; TRANSDUCTION; CIDOFOVIR; CHILDREN; DELIVERY; PROTEIN;

D O I：

10.1016/j.omtn.2017.07.002

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

Infections of immunocompromised patients with human adenoviruses (hAd) can develop into life-threatening conditions, whereas drugs with anti-adenoviral efficiency are not clinically approved and have limited efficacy. Small double-stranded RNAs that induce RNAi represent a new class of promising anti-adenoviral therapeutics. However, as yet, their efficiency to treat hAd5 infections has only been investigated in vitro. In this study, we analyzed artificial microRNAs (amiRs) delivered by self-complementary adeno-associated virus (scAAV) vectors for treatment of hAd5 infections in immunosuppressed Syrian hamsters. In vitro evaluation of amiRs targeting the E1A, pTP, IVa2, and hexon genes of hAd5 revealed that two scAAV vectors containing three copies of amiR-pTP and three copies of amiR-E1A, or six copies of amiR-pTP, efficiently inhibited hAd5 replication and improved the viability of hAd5-infected cells. Prophylactic application of amiR-pTP/amiR-E1A- and amiR-pTP-expressing scAAV9 vectors, respectively, to immunosuppressed Syrian hamsters resulted in the reduction of hAd5 levels in the liver of up to two orders of magnitude and in reduction of liver damage. Concomitant application of the vectors also resulted in a decrease of hepatic hAd5 infection. No side effects were observed. These data demonstrate anti-adenoviral RNAi as a promising new approach to combat hAd5 infection.

引用

页码：300 / 316

页数：17

共 2 条

[1] Lipid nanoparticle-encapsulated, chemically modified anti-adenoviral siRNAs inhibit hepatic adenovirus infection in immunosuppressed Syrian hamsters
Geisler, Anja
Dieringer, Babette
Elsner, Leslie
Klingel, Karin
Klopfleisch, Robert
Vornlocher, Hans-Peter
Kurreck, Jens
Fechner, Henry
MOLECULAR THERAPY-NUCLEIC ACIDS, 2023, 32 : 923 - 936
[2] Inhibition of Ad Infection by use of AAV Vectors expressing Anti-Adenoviral Artificial microRNAs
Schaar, Katrin
Geisler, Anja
Kraus, Milena
Roeger, Carsten
Fechner, Henry
HUMAN GENE THERAPY, 2014, 25 (11) : A95 - A95

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