Biology subjects

West, N.

Publications and source records attributed to West, N..

3 recordsLinked to original sources

bioRxiv2021

A SARS-CoV-2 targeted siRNA-nanoparticle therapy for COVID-19

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in humans. Despite several emerging vaccines, there remains no verifiable therapeutic targeted specifically to the virus. Here we present a highly effective siRNA therapeutic against SARS-CoV-2 infection using a novel lipid nanoparticle delivery system. Multiple small-interfering RNAs (siRNAs) targeting highly conserved regions of the SARS-CoV-2 virus were screened and three candidate siRNAs emerged that effectively inhibit virus by greater than 90% either alone or in combination with one another. We simultaneously developed and screened two novel lipid nanoparticle formulations for the delivery of these candidate siRNA therapeutics to the lungs, an organ that incurs immense damage during SARS-CoV-2 infection. Encapsulation of siRNAs in these LNPs followed by in vivo injection demonstrated robust repression of virus in the lungs and a pronounced survival advantage to the treated mice. Our LNP-siRNA approaches are scalable and can be administered upon the first sign of SARS-CoV-2 infection in humans. We suggest that an siRNA-LNP therapeutic approach could prove highly useful in treating COVID-19 disease as an adjunctive therapy to current vaccine strategies.

synthetic biology↗

bioRxiv2021

An integrated comparative physiology and molecular approach pinpoints mediators of breath-hold capacity in dolphins

Ischemic events, such as ischemic heart disease and ischemic stroke, are the number one cause of death globally. Ischemia prevents blood, carrying essential nutrients and oxygen, from reaching tissues and organ systems, leading to cell and tissue death, and eventual organ failure. While humans are relatively intolerant to these ischemic events, other species, such as marine mammals, have evolved remarkable tolerance to chronic ischemia/reperfusion during diving. Here we capitalized on the unique adaptations of bottlenose dolphins (Tursiops truncatus) as a comparative model of ischemic stress and hypoxia tolerance to identify molecular features associated with breath-holding. Using RNA-Seq we observed time-dependent upregulation of the arachidonate 5-lipoxygenase (ALOX5) gene during breath-holding. Consistent with the RNA-Seq data, we also observed increased ALOX5 enzymatic activity in the serum of dolphins undergoing breath holds. ALOX5 has previously been shown to be activated during hypoxia in rodent models, and its metabolites, leukotrienes, induce vasoconstriction. The upregulation of ALOX5 occurred within the estimated aerobic dive limit of the species, suggesting that ALOX5 enzymatic activity may promote tolerance to ischemic stress through sustained vasoconstriction in dolphins during diving. These observations pinpoint a potential molecular mechanism by which dolphins, and perhaps other marine mammals, have adapted to the prolonged breath-holds associated with diving.

physiology↗

bioRxiv2020

NAT8L mRNA oxidation is linked to neurodegeneration in multiple sclerosis

RNA oxidation has been implicated in neurodegeneration, but the underlying mechanism for such effects is unclear. Recently, we demonstrated extensive RNA oxidation within the neurons in multiple sclerosis (MS) brain. In this report we identified selectively oxidized mRNAs in neuronal cells that pertained to neuropathological pathways. N-acetyl aspartate transferase 8 like (NAT8L) mRNA is one such transcript, whose translated product enzymatically synthesizes N-acetyl aspartic acid (NAA), a neuronal metabolite important for myelin synthesis. We reasoned that impediment of translation of an oxidized NAT8L mRNA will result in reduction in its cognate protein, thus lowering NAA level. This assertion is directly supported by our studies on a model cellular system, an MS animal model and postmortem human MS brain. Reduced NAA level in the brain hampers myelin integrity making neuronal axons more susceptible to damage, which contributes in MS neurodegeneration. Overall, this work provides a framework for mechanistic understanding of the link between RNA oxidation and neurodegenerative diseases.

molecular biology↗