Evaluation of double heptamer-type sgRNA as a potential therapeutic agent against multiple myeloma

Emergence of drug-resistant mutations in the course of myeloma cell evolution and subsequent relapse of myeloma appears to be currently inevitable in most patients. To remedy this situation, we are trying to develop therapeutic small guide RNAs (sgRNAs) based on tRNase ZL-utilizing efficacious gene...

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Published in:Blood cells, molecules, & diseases molecules, & diseases, 2019-11, Vol.79, p.102341-102341, Article 102341
Main Authors: Ishikawa, Tatsuya, Haino, Arisa, Ichiyanagi, Takashi, Seki, Mineaki, Nashimoto, Masayuki
Format: Article
Language:English
Subjects:
Animals
Cell Line, Tumor
Cell Survival - drug effects
Cyclin D1 - antagonists & inhibitors
Cyclin D1 - genetics
Drug Design
Gene Silencing
Heterografts - drug effects
Humans
Mice
Multiple myeloma
Multiple Myeloma - drug therapy
Multiple Myeloma - pathology
Proto-Oncogene Proteins c-bcl-2 - antagonists & inhibitors
Proto-Oncogene Proteins c-bcl-2 - genetics
RNA therapy
RNA, Guide, CRISPR-Cas Systems
RNA, Messenger
sgRNA
Survival Analysis
tRNase ZL
TRUE gene silencing
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Summary:Emergence of drug-resistant mutations in the course of myeloma cell evolution and subsequent relapse of myeloma appears to be currently inevitable in most patients. To remedy this situation, we are trying to develop therapeutic small guide RNAs (sgRNAs) based on tRNase ZL-utilizing efficacious gene silencing (TRUE gene silencing), an RNA-mediated gene expression control technology. We designed two sets of double heptamer-type sgRNA, which target the human BCL2 mRNA. Both sets of double heptamer-type sgRNA reduced viability of human myeloma cell lines, RPMI-8226 and KMM-1. We also performed a mouse xenograft experiment to examine how the double heptamer-type sgRNA DHa1(BCL2)/DHa2(BCL2) can reduce the growth of KMM-1 cells in vivo. Median survival periods of the sgRNA cohorts were greater than that of the control cohort by 11–43 days. Furthermore, we designed two sets of double heptamer-type sgRNA, which target the human CCND1 mRNA, and both sets synergistically reduced RPMI-8226 cell viability.
ISSN:1079-9796
1096-0961
DOI:10.1016/j.bcmd.2019.102341