The MCART Consortium Animal Model Series

MacVittie, Thomas J.

doi:10.1097/hp.0000000000000318

Cited by 16 publications

(3 citation statements)

References 35 publications

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“…In due course of time, survivors of ARS may experience the DEARE, which typically manifest as a chronic illnesses affecting multiple organ systems [43]. Development of DEARE take months and years and usually manifest in the lung as pneumonitis and fibrosis.…”

Section: Suitability Of Nhps As Animals Models For Studying Radiatmentioning

confidence: 99%

Nonhuman primates as models for the discovery and development of radiation countermeasures

Singh

Olabisi

2017

Expert Opinion on Drug Discovery

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Introduction Despite significant scientific advances over the past six decades toward the development of safe and effective radiation countermeasures for humans using animal models, only two pharmaceutical agents have been approved by United States Food and Drug Administration (US FDA) for hematopoietic acute radiation syndrome (H-ARS). Additional research efforts are needed to further develop large animal models for improving the prediction of clinical safety and effectiveness of radiation countermeasures for ARS and delayed effects of acute radiation exposure (DEARE) in humans. Area covered The authors review the suitability of animal models for the development of radiation countermeasures for ARS following the FDA Animal Rule with a special focus on nonhuman primate (NHP) models of ARS. There are seven centers in the United States currently conducting studies with irradiated NHPs, with the majority of studies being conducted with rhesus monkeys. Expert opinion The NHP model is considered the gold standard animal model for drug development and approval by the FDA. The lack of suitable substitutes to NHP models for predicting response in humans serves as a bottleneck for the development of radiation countermeasures. Additional large animal models need to be characterized to support the development and FDA-approval of new radiation countermeasures.

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Section: Suitability Of Nhps As Animals Models For Studying Radiatmentioning

confidence: 99%

Nonhuman primates as models for the discovery and development of radiation countermeasures

Singh

Olabisi

2017

Expert Opinion on Drug Discovery

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“…Dosimetry was calculated using standard clinical protocols based on baseline CT scans of the tissue area to include a 2 cm margin beyond the lungs. Dosimetry calculations and a retrospective dose-reconstruction study have been described in detail previously 50,51 . Medical management was provided on an individual basis based on a set of clinical triggers and included, hydration, antibiotics, analgesics, anti-diarrheals, antipyretics, anti-emetics, anti-ulceratives, nutritional support, and blood transfusions.…”

Section: Methodsmentioning

confidence: 99%

MALDI-MSI spatially maps N-glycan alterations to histologically distinct pulmonary pathologies following irradiation

Carter

Parker

Hankey

et al. 2020

Sci Rep

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Radiation-induced lung injury is a highly complex combination of pathological alterations that develop over time and severity of disease development is dose-dependent. following exposures to lethal doses of irradiation, morbidity and mortality can occur due to a combination of edema, pneumonitis and fibrosis. Protein glycosylation has essential roles in a plethora of biological and immunological processes. Alterations in glycosylation profiles have been detected in diseases ranging from infection, inflammation and cancer. We utilized mass spectrometry imaging to spatially map N-glycans to distinct pathological alterations during the clinically latent period and at 180 days post-exposure to irradiation. Results identified alterations in a number of high mannose, hybrid and complex N-glycans that were localized to regions of mucus and alveolar-bronchiolar hyperplasia, proliferations of type 2 epithelial cells, accumulations of macrophages, edema and fibrosis. The glycosylation profiles indicate most alterations occur prior to the onset of clinical symptoms as a result of pathological manifestations. Alterations in five N-glycans were identified as a function of time postexposure. Understanding the functional roles n-glycans play in the development of these pathologies, particularly in the accumulation of macrophages and their phenotype, may lead to new therapeutic avenues for the treatment of radiation-induced lung injury. Radiation-induced lung injury (RILI) is a complex combination of pathologies that include vascular damage, epithelial cell death followed by hyper-proliferation, edema, and mixed immune infiltrations resulting in pneumonitis and an aberrant wound-healing processes that ultimately lead to the development of pulmonary fibrosis 1-4. Accidental or intentional exposures to high doses of ionizing radiation results in RILI, which contributes to increased risk of mortality within months 3,4. RILI is also a common side effect of thoracic radiotherapy for treatment of malignancies; it often limits curative therapeutic strategies 1,5. Whereas RILI due to radiotherapy can be controlled to prevent mortality, accidental or intentional exposures to lethal doses of ionizing radiation result in significant lung disease development 3,6-8. To date there are no Food and Drug Administration (FDA) approved therapeutic options to treat or mitigate RILI and the molecular mechanisms leading to the development of pulmonary fibrosis remain incompletely understood. Protein glycosylation is a post-translational modification that plays essential biological roles in structural and modulatory processes, and cell-cell recognition 9. More specifically, glycoproteins are involved in protein folding, molecular trafficking and clearance, and secretion processes 10-12. On the cell surface, membrane-bound glycoproteins are binding ligands for host-host interactions that include cell adhesion, receptor activation and extracellular matrix molecules, and host-pathogen interactions that enable bacteria and viruses to attach and gain entry...

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“…Such long-term, ‘late-effects’ of radiation exposures have been studied extensively over many decades starting from the dawn of the nuclear age, but this complex of diseases has renewed interest (and has been in part relabeled/recharacterized as ‘delayed acute radiation effects’ or DEARE) of late due to the advent of potential preventive treatments ( Medhora et al, 2012 ; Singh and Seed, 2020b ). This disease complex, this syndrome, DEARE, expresses as chronic illnesses involving several important organ systems including, but not limited to the lung, kidney, heart, and GI tract ( MacVittie, 2015 ; MacVittie et al, 2019 ; Unthank et al, 2019 ). Expression of delayed effects takes several months to years, and ultimately results in multi-organ failure and mortality.…”

Section: Introductionmentioning

confidence: 99%

Repurposing Pharmaceuticals Previously Approved by Regulatory Agencies to Medically Counter Injuries Arising Either Early or Late Following Radiation Exposure

Singh

Seed²

2021

Front. Pharmacol.

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The increasing risks of radiological or nuclear attacks or associated accidents have served to renew interest in developing radiation medical countermeasures. The development of prospective countermeasures and the subsequent gain of Food and Drug Administration (FDA) approval are invariably time consuming and expensive processes, especially in terms of generating essential human data. Due to the limited resources for drug development and the need for expedited drug approval, drug developers have turned, in part, to the strategy of repurposing agents for which safety and clinical data are already available. Approval of drugs that are already in clinical use for one indication and are being repurposed for another indication is inherently faster and more cost effective than for new agents that lack regulatory approval of any sort. There are four known growth factors which have been repurposed in the recent past as radiomitigators following the FDA Animal Rule: Neupogen, Neulasta, Leukine, and Nplate. These four drugs were in clinic for several decades for other indications and were repurposed. A large number of additional agents approved by various regulatory authorities for given indications are currently under investigation for dual use for acute radiation syndrome or for delayed pathological effects of acute radiation exposure. The process of drug repurposing, however, is not without its own set of challenges and limitations.

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The MCART Consortium Animal Model Series

Cited by 16 publications

References 35 publications

Nonhuman primates as models for the discovery and development of radiation countermeasures

Nonhuman primates as models for the discovery and development of radiation countermeasures

MALDI-MSI spatially maps N-glycan alterations to histologically distinct pulmonary pathologies following irradiation

Repurposing Pharmaceuticals Previously Approved by Regulatory Agencies to Medically Counter Injuries Arising Either Early or Late Following Radiation Exposure

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