Reversing Radiation-Induced Immunosuppression Using a New Therapeutic Modality

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 lead molecule as reversible gene therapy to treat adverse health outcomes induced by radiation exposure.

Targeting neuroinflammation by pharmacologic down-regulation of inflammatory pathways is neuroprotective in protein misfolding disorders

“…Nanoligomers™ were synthesized using previously published procedure ( 1-5 ). Briefly, the Sachi bioinformatics platform was used to identify the lead Nanoligomer™ sequence of the DNA/RNA binding domain.…”

Looking on the horizon; potential and unique approaches to developing radiation countermeasures for deep space travel

“…An analogous but distinct nucleotide-based therapeutic approach involves the Nanoligomer TM (Sachi Bioworks) platform developed by Drs. Anushree Chatterjee and Prashant Nagpal's team (35). A Nanoligomer is composed of six design elements, including a peptide nucleic acid (PNA), a synthetic DNA-analog where the phosphodiester bond is replaced with 2-N-aminoethylglycine units, as the nucleic acid binding domain, and an engineered nanoparticle for facile cellular and tissue delivery of the naked molecule (36,37).…”

“…Anushree Chatterjee and Prashant Nagpal's team (35). A Nanoligomer is composed of six design elements, including a peptide nucleic acid (PNA), a synthetic DNA-analog where the phosphodiester bond is replaced with 2-N-aminoethylglycine units, as the nucleic acid binding domain, and an engineered nanoparticle for facile cellular and tissue delivery of the naked molecule (36,37). Nanoligomers offer improved stability, facile delivery and internalization, high target specificity (on-target) and minimal off-target activity.…”

“…Nanoligomers offer improved stability, facile delivery and internalization, high target specificity (on-target) and minimal off-target activity. They can be designed to rapidly create a library of many therapeutic molecules that can be screened (36,37). This approach is a high-throughput method to customize peptide-nucleic acid-based gene-specific reversible therapeutics with high precision.…”