Heptamer-type small guide RNA that can shift macrophages toward the M1 state

Blood Cells Mol Dis. 2021 Feb:86:102503. doi: 10.1016/j.bcmd.2020.102503. Epub 2020 Sep 7.

Abstract

Multiple myeloma is a refractory cancer of plasma cells. Although treatment strategies for multiple myeloma are getting improved year by year, in most cases patients relapse due to the emergence of drug-resistant mutations in the myeloma cells. The interplay between myeloma cells and tumor-associated macrophages (TAM) is important for the pathology. We thought that some heptamer-type sgRNAs for TRUE gene silencing would be able to transform TAM toward the M1 state and might become therapeutic drugs for myeloma. Here, we searched for heptamer-type sgRNAs that can shift macrophages toward the M1 state. We screened a heptamer-type sgRNA library for the ability to up-regulate IL-12b gene expression in human macrophage-like cell lines, and found three such sgRNAs. One of the sgRNAs, H12960, which also showed such ability in human fresh macrophages and mouse macrophage-like cell lines, efficiently suppressed human myeloma cell growth in SCID/NOD mice.

Keywords: Macrophage; Multiple myeloma; RNA therapy; TRUE gene silencing; sgRNA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Cell Line, Tumor
  • Cells, Cultured
  • Gene Expression Regulation, Neoplastic
  • Gene Silencing
  • Genetic Therapy
  • Humans
  • Interleukin-12 / genetics
  • Interleukin-12 / immunology
  • Macrophage Activation
  • Macrophages* / immunology
  • Macrophages* / metabolism
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Multiple Myeloma / genetics
  • Multiple Myeloma / immunology
  • Multiple Myeloma / therapy*
  • RNA, Guide, CRISPR-Cas Systems
  • Tumor-Associated Macrophages* / immunology
  • Tumor-Associated Macrophages* / metabolism

Substances

  • Interleukin-12