Abstract:
:Gene knockdown using short hairpin RNAs (shRNAs) is a promising strategy for targeting dominant mutations; however, delivering too much shRNA can disrupt the processing of endogenous microRNAs (miRNAs) and lead to toxicity. Here, we sought to understand the effect that excessive shRNAs have on muscle miRNAs by treating mice with recombinant adeno-associated viral vectors (rAAVs) that produce shRNAs with 19-nt or 21-nt stem sequences. Small RNA sequencing of their muscle and liver tissues revealed that shRNA expression was highest in the heart, where mice experienced substantial cardiomyopathy when shRNAs accumulated to 51.2% ± 13.7% of total small RNAs. With the same treatment, shRNAs in other muscle tissues reached only 12.1% ± 5.0% of total small RNAs. Regardless of treatment, the predominant heart miRNAs remained relatively stable across samples. Instead, the lower-expressed miR-451, one of the few miRNAs processed independently of Dicer, changed in relation to shRNA level and toxicity. Our data suggest that a protective mechanism exists in cardiac tissue for maintaining the levels of most miRNAs in response to shRNA delivery, in contrast with what has been shown in the liver. Quantifying miRNA profiles after excessive shRNA delivery illuminates the host response to rAAV-shRNA, allowing for safer and more robust therapeutic gene knockdown.
journal_name
Mol Ther Nucleic Acidsjournal_title
Molecular therapy. Nucleic acidsauthors
Course MM,Gudsnuk K,Desai N,Chamberlain JR,Valdmanis PNdoi
10.1016/j.omtn.2019.12.007subject
Has Abstractpub_date
2020-03-06 00:00:00pages
572-580issn
2162-2531pii
S2162-2531(19)30402-0journal_volume
19pub_type
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