Reversing radiation-induced immunosuppression using a new therapeutic modality

Courtney, Colleen M.; Sharma, Sadhana; Fallgren, Christina M.; Weil, Michael M.; Chatterjee, Anushree; Nagpal, Prashant

doi:10.1016/j.lssr.2022.05.002

Cited by 16 publications

(90 citation statements)

References 72 publications

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“…Next, all the candidates in the bioinformatics generated in silico Nanoligomer library were scored and ranked as described in detail elsewhere. 60 Following this, top Nanoligomer designs (at least three per target- one per genomic location) incorporating all six different design elements were synthesized as a single modality using high throughput peptide synthesizer and purified (Fig 1). A Missense Nanoligomer (designed with no homology to any gene in the specific genome at the DNA/ mRNA level) was also designed and synthesized to rule out any possible non-specific effects.…”

Section: Resultsmentioning

confidence: 99%

“…Previously, we have demonstrated that Nanoligomer technology is very effective in identifying immunotherapy lead targets and molecules for countermeasure development. 60…”

Section: Introductionmentioning

confidence: 99%

“…Previously, we have demonstrated that Nanoligomer technology is very effective in identifying immunotherapy lead targets and molecules for countermeasure development. 60 To screen and rank these targets and identify the best-in-class and potential first-in-class therapeutic molecule, we applied Sachi's Nanoligomer discovery engine to regulate the abovementioned neuroinflammation relevant targets (pro-inflammatory cytokines, inflammasome, transcription factors, and combinations) to identify the most effective upstream regulator for developing countermeasures for chronic neuroinflammation.…”

Section: Introductionmentioning

confidence: 99%

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Identifying Optimal Neuroinflammation Treatment Using Nanoligomer™ Discovery Engine

Sharma¹,

Borski

Hanson

et al. 2022

Preprint

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Acute activation of innate immune response in the brain, or neuroinflammation, protects this vital organ from a range of external pathogens and promotes healing after traumatic brain injury. However, chronic neuroinflammation leads to the activation of immune cells like microglia and astrocytes causes damage to the nervous tissue, and is causally linked to a range of neurodegenerative diseases such as Alzheimers diseases (AD), Multiple Sclerosis (MS), Parkinsons diseases (PD), and many others. While neuroinflammation is a key target for a range of neuropathological diseases, there is a lack of effective countermeasures to tackle it, and existing experimental therapies require fairly invasive intracerebral and intrathecal delivery due to difficulty associated with the therapeutic crossover between the blood-brain barrier (BBB), making such treatments impractical to treat neuroinflammation long-term. Here, we present the development of an optimal neurotherapeutic using our NanoligomerTM discovery engine, by screening downregulation of several proinflammatory cytokines (e.g., Interleukin-1β or IL-1β, tumor necrosis factor-alpha or TNF-α, TNF receptor 1 or TNF-R1, Interleukin 6 or IL-6), inflammasomes (e.g., NLRP1), key transcription factors (e.g., nuclear factor kappa-B or NF-κβ) and their combinations, as upstream regulators and canonical pathway targets, to identify and validate the best-in-class treatment. Using our high-throughput drug discovery, target validation, and lead molecule identification using a bioinformatics and AI-based ranking method to design sequence-specific peptide molecules to up-or down-regulate gene expression of the targeted gene at will, we used our discovery engine to perturb and identify most effective upstream regulators and canonical pathways for therapeutic intervention to reverse neuroinflammation. The lead neurotherapeutic was a combination of NanoligomersTM targeted to NF-κβ (SB.201.17D.8_ NF-κβ1) and TNFR1 (SB.201.18D.6_TNFR1), which were identified using in vitro cell-based screening in donor-derived human astrocytes, and further validated in vivo using a mouse model of lipopolysaccharide (LPS)-induced neuroinflammation. The combination treatment SB_NI_111 was delivered without any special formulation using a simple intraperitoneal injection of low-dose (5mg/kg) and was found to significantly suppress the expression of LPS-induced neuroinflammation in mouse hippocampus. These results point to the broader applicability of this approach towards the development of therapies for chronic neuroinflammation-linked neurodegenerative diseases, sleep countermeasures, and others, and the potential for further investigation of the lead neurotherapeutic molecule as reversible gene therapy.

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Section: Resultsmentioning

confidence: 99%

“…Previously, we have demonstrated that Nanoligomer technology is very effective in identifying immunotherapy lead targets and molecules for countermeasure development. 60…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Identifying Optimal Neuroinflammation Treatment Using Nanoligomer™ Discovery Engine

Sharma¹,

Borski

Hanson

et al. 2022

Preprint

Self Cite

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“…Scoring and ranking of the bioinformatics generated in silico Nanoligomer library was achieved as described in detail previously. 30 Briefly, we ranked the immunotherapy targets and respective Nanoligomer molecules using a score based on potential off-targets, binding specificity, etc. The first weighing coefficient for target specificity ( ω iMM ) was the ratio of measured dissociation constant ( K D ) with respective mismatches .…”

Section: Resultsmentioning

confidence: 99%

“…Previously, we have demonstrated that Nanoligomer technology is very effective in identifying lead targets and molecules for reversing radiation-induced immune dysfunction. 30…”

Section: Introductionmentioning

confidence: 99%

Screening Immunotherapy Targets to Counter Radiation-Induced Neuroinflammation

Sharma¹,

Fallgreen

Weil

et al. 2022

Preprint

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Galactic cosmic rays (GCR) in space induce increase in cerebral amyloid-β levels and elevated levels of microgliosis and astrocytosis, causing accelerated neurodegeneration from this increased neuroinflammation. Even exposure to low-levels of high-Z high-energy (HZE) radiation (50 cGy) has been shown to induce biochemical and immunohistochemical changes in short-term leading to degradation in cognition, motor skills, and development of space-induced neuropathy. There is lack of effective neuroinflammation countermeasures, and current experimental therapies require invasive intracerebral and intrathecal delivery due to difficulty associated with therapeutic crossover between blood-brain barrier. Here, we present a new countermeasure development approach for neurotherapeutics using high-throughput drug-discovery, target validation, and lead molecule identification with nucleic acid-based molecules. These NanoligomerTM molecules are rationally designed using a bioinformatics and AI-based ranking method and synthesized as a single-modality combining 6-different design elements to up- or down-regulate gene expression of target gene at will, resulting in elevated or diminished protein expression of intended target. This platform approach was used to perturb and identify most effective upstream regulators and canonical pathways for therapeutic intervention to reverse radiation-induced neuroinflammation. The lead NanoligomerTM and corresponding target granulocyte-macrophage colony-stimulating factor (GM-CSF) were identified using in vitro cell-based screening in human astrocytes and donor derived peripheral blood mononuclear cells (PBMCs) and further validated in vivo using a mouse model of radiation-induced neuroinflammation. GM-CSF transcriptional downregulator Nanoligomer 30D.443_CSF2 downregulated proinflammatory cytokine GM-CSF (or CSF2) using simple intraperitoneal injection of low-dose (3mg/kg) and completely reversed expression of CSF2 in cortex tissue, as well as other neuroinflammation markers. These results point to the broader applicability of this approach towards space countermeasure development, and potential for further investigation of lead neurotherapeutic molecule as a reversible gene therapy.

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