Efficacy and safety of a SOD1-targeting artificial miRNA delivered by AAV9 in mice are impacted by miRNA scaffold selection

被引：7

作者：

Chen, Shukkwan K. ^{[1
]}

Hawley, Zachary C. E. ^{[1
]}

Zavodszky, Maria I. ^{[1
]}

Hana, Sam ^{[1
]}

Ferretti, Daniel ^{[1
]}

Grubor, Branka ^{[1
]}

Hawes, Michael ^{[2
]}

Xu, Shanqin ^{[1
]}

Hamann, Stefan ^{[1
]}

Marsh, Galina ^{[1
]}

Cullen, Patrick ^{[1
]}

Challa, Ravi ^{[1
]}

Carlile, Thomas M. ^{[1
]}

Zhang, Hang ^{[1
]}

Lee, Wan-Hung ^{[1
]}

Peralta, Andrea ^{[1
]}

Clarner, Pete ^{[1
]}

Wei, Cong ^{[1
]}

Koszka, Kathryn ^{[1
]}

Gao, Feng ^{[1
]}

Lo, Shih-Ching ^{[1
]}

机构：

[1] Biogen, 225 Binney St, Cambridge, MA 02142 USA

[2] Charter Preclin Serv, Hudson, MA USA

来源：

MOLECULAR THERAPY NUCLEIC ACIDS | 2023年 / 34卷

关键词：

AMYOTROPHIC-LATERAL-SCLEROSIS; ADENOASSOCIATED VIRUS; INTRATHECAL INJECTION; SPINAL-CORD; MUTANT SOD1; MICRORNA; SURVIVAL; NEURONS; DESIGN; GENE;

D O I：

10.1016/j.omtn.2023.102057

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：

Toxic gain-of-function mutations in superoxide dismutase 1 (SOD1) contribute to approximately 2%-3% of all amyotrophic delivered by adeno-associated virus (AAV) have been proposed as a potential treatment option to silence SOD1 expression and mitigate disease progression. Primary microRNA (pri-miRNA) scaffolds are used in amiRs to shuttle a hairpin RNA into the endogenous miRNA pathway, but it is unclear whether different primary miRNA (pri-miRNA) scaffolds impact the potency and safety profile of the expressed amiR in vivo. In our process to develop an AAV amiR targeting SOD1, we performed a preclinical characterization of two pri-miRNA scaffolds, miR155 and miR30a, sharing the same guide strand sequence. We report that, while the miR155-based vector, compared with the miR30a-based vector, leads to a higher level of the amiR and more robust suppression of SOD1 in vitro and in vivo, it also presents significantly greater risks for CNSrelated toxicities in vivo. Despite miR30a-based vector showing relatively lower potency, it can significantly delay the development of ALS-like phenotypes in SOD1-G93A mice and increase survival in a dose-dependent manner. These data highlight the importance of scaffold selection in the pursuit of highly efficacious and safe amiRs for RNA interference gene therapy.

引用

页码：1 / 12

页数：12

共 56 条

[1]

Al-Modawi R.N, 2021, Osteoarthr. Cartil. Open, V3

[2] Structural Differences between Pri-miRNA Paralogs Promote Alternative Drosha Cleavage and Expand Target Repertoires [J].