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Cited by 16Effects of Radiation ExposureRNA Interference and Gene DeliveryImmunotoxicology and immune responses

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Reversing radiation-induced immunosuppression using a new therapeutic modality

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Courtney, Colleen M., Sharma, Sadhana, Fallgren, Christina, Weil, Michael M., Chatterjee, Anushree, Nagpal, Prashant·2022·Life Sciences in Space Research
DOI 10.1016/j.lssr.2022.05.002

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Abstract

Radiation-induced immune suppression poses significant health challenges for millions of patients undergoing cancer chemotherapy and radiotherapy treatment, and astronauts and space tourists travelling to outer space. While a limited number of recombinant protein therapies, such a Sargramostim, are approved for accelerating hematologic recovery, the pronounced role of granulocyte-macrophage colony-stimulating factor (GM-CSF or CSF2) as a proinflammatory cytokine poses additional challenges in creating immune dysfunction towards pathogenic autoimmune diseases. Here we present an approach to high-throughput drug-discovery, target validation, and lead molecule identification using nucleic acid-based molecules. These Nanoligomer™ molecules are rationally designed using a bioinformatics and an artificial intelligence (AI)-based ranking method and synthesized as a single-modality combining 6-different design elements to up- or downregulate gene expression of target gene, resulting in elevated or diminished protein expression of intended target. This method additionally alters related gene network targets ultimately resulting in pathway modulation. This approach was used to perturb and identify the most effective upstream regulators and canonical pathways for therapeutic intervention to reverse radiation-induced immunosuppression. The lead Nanoligomer™ identified in a screen of human donor derived peripheral blood mononuclear cells (PBMCs) upregulated Erythropoietin (EPO) and showed the greatest reversal of radiation induced cytokine changes. It was further tested in vivo in a mouse radiation-model with low-dose (3 mg/kg) intraperitoneal administration and was shown to regulate gene expression of epo in lung tissue as well as counter immune suppression. These results point to the broader applicability of our approach towards drug-discovery, and potential for further investigation of our lead molecule as reversible gene therapy to treat adverse health outcomes induced by radiation exposure.

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Metadata

Authors
Courtney, C. M., Sharma, S., Fallgren, C., Weil, M. M., Chatterjee, A., & Nagpal, P.
Affiliations
  • BioWorks (United States) (US)
  • Colorado State University (US)
Corresponding author
Nagpal, Prashant
ORCID
Venue
Life Sciences in Space Research
Publisher
Elsevier BV
Published
2022-11
Volume
35
Pages
127-139
ISSN
2214-5524 (ISSN-L)
DOI
10.1016/j.lssr.2022.05.002
OpenAlex
W4280521825
Cited by
16
References
3
Citations by year
2024: 10 · 2023: 1 · 2022: 5
FWCI
2.29
Type
journal article
Language
en
Open access
Licence
Locations
  • Life Sciences in Space Research (publishedVersion, cc-by-nc-nd)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed (publishedVersion)
Funders
National Aeronautics and Space Administration (80NSSC21C0242, NNX15AK13G)
Topics
  • Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Effects of Radiation Exposure
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotoxicology and immune responses
Keywords
radiation-induced immunosuppression, nucleic acid therapeutics, GM-CSF, erythropoietin, gene expression modulation, peripheral blood mononuclear cells, gene therapy, space radiation, astronaut health
MeSH terms
Animals, Artificial Intelligence, Humans, Immunosuppression Therapy, Leukocytes, Mononuclear, Recombinant Proteins, Granulocyte Colony-Stimulating Factor, Cytokines, Mice

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