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

Dharmendra Kumar Soni; Vidya P. Kumar; Shukla Biswas; Gregory P. Holmes-Hampton; Sharmistha Bhattacharyya; Lawrence J. Thomas; Roopa Biswas; Sanchita P. Ghosh

Molecular Therapy: Nucleic Acids (Dec 2022)

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

Dharmendra Kumar Soni,
Vidya P. Kumar,
Shukla Biswas,
Gregory P. Holmes-Hampton,
Sharmistha Bhattacharyya,
Lawrence J. Thomas,
Roopa Biswas,
Sanchita P. Ghosh

Affiliations

Dharmendra Kumar Soni: Department of Anatomy, Physiology and Genetics, School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD 21045, USA
Vidya P. Kumar: Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences, Bethesda, MD 20889, USA
Shukla Biswas: Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences, Bethesda, MD 20889, USA
Gregory P. Holmes-Hampton: Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences, Bethesda, MD 20889, USA
Sharmistha Bhattacharyya: Department of Anatomy, Physiology and Genetics, School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD 21045, USA
Lawrence J. Thomas: Celldex Therapeutics, Inc., Fall River, MA 02723, USA
Roopa Biswas: Department of Anatomy, Physiology and Genetics, School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD 21045, USA; Corresponding author Roopa Biswas, Department of Anatomy, Physiology and Genetics, School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD 21045, USA.
Sanchita P. Ghosh: Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences, Bethesda, MD 20889, USA; Corresponding author Sanchita P. Ghosh, Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences, Bethesda, MD 21045, USA.

Journal volume & issue: Vol. 30
pp. 569 – 584

Abstract

Read online

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.

Published in Molecular Therapy: Nucleic Acids

ISSN: 2162-2531 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Therapeutics. Pharmacology
Website: https://www.cell.com/molecular-therapy-family/nucleic-acids/latest-content

About the journal

Abstract

Keywords