CDX-301 prevents radiation-induced dysregulation of miRNA expression and biogenesis

• Published in: Molecular therapy. Nucleic acids 2022-12, Vol.30, p.569-584
• Main Authors: Soni, Dharmendra Kumar, Kumar, Vidya P., Biswas, Shukla, Holmes-Hampton, Gregory P., Bhattacharyya, Sharmistha, Thomas, Lawrence J., Biswas, Roopa, Ghosh, Sanchita P.
• Format: Article
• Language: English
• Subjects: acute radiation syndrome; CDX-301; irradiation; microRNA; MT: Non-coding RNAs; Original; radiation countermeasures
• ISSN: 2162-2531; 2162-2531
• DOI: 10.1016/j.omtn.2022.11.010

Risks of radiation exposure necessitate the development of radioprophylactic drugs. We have reported the efficacy of CDX-301, a recombinantly developed human protein form of Fms-related tyrosine kinase 3 ligand (Flt3L), as a radioprophylactic and radiomitigatory agent. Here, we performed global microRNA profiling to further understand the mechanism of action of CDX-301. We find that CDX-301 administration 24 h prior to total body irradiation prevents radiation-induced dysregulation of microRNA biogenesis and expression in murine serum and spleen samples in a time- and tissue-dependent manner. Further analysis shows that activation of the HOTAIR regulatory pathway has a prominent function in radiation-induced injury responses, which is inhibited by pre-treatment with CDX-301. Moreover, CDX-301 attenuates radiation-induced dysregulation of several cellular functions such as inflammatory and immune responses. In corroboration, we also find that pre-treatment with CDX-301 restores the expression of bone marrow aplasia markers and inflammatory cytokines and growth factors, as well as the expression of genes associated with MAP kinase and TGF-β pathways that are altered by radiation. Our findings provide new insights into CDX-301-mediated molecular and cellular mechanisms and point to a possible novel radioprotective drug for the prevention of irradiation-induced injury and hematopoietic acute radiation syndrome. [Display omitted] This study identifies that CDX-301 averts radiation-induced lethal responses through prevention of dysregulated microRNA biogenesis, inhibition of HOTAIR regulatory pathway and Flt3L, and attenuation of dysregulated cellular functions, thus providing new insights into CDX-301-mediated molecular and cellular mechanisms and pointing to a possible novel radioprotective drug for hematopoietic acute radiation syndrome.