Sepsis is the single most frequent cause of death in hospitalised patients, causing 8 million deaths each year. Supportive care is given, underlying infections treated, but there is no effective treatment.
Researchers sprinkled a plastic nanoparticle with sialic acid ligands that modulated macrophage immune cells. This produced a therapeutic response in mouse models of sepsis, in human lung cells and an ex vivo human lung model.
Sepsis occurs when chemicals released into the bloodstream to fight an infection trigger an inflammatory cascade that can damage organs.
“We saw increased survival in mice and in in vitro and human models we saw reduced pro-inflammatory cytokine production,” explained Chris Scott, researcher at Queens University Belfast, UK, and senior author of a new study in Science Translational Medicine.
“You need to get macrophages under control quickly in sepsis. We hope we’ll have something that can be administered in an ICU to prevent a cytokine storm or seen an effect within hours.”
The nanoparticles target Siglecs, proteins found on the surface of immune cells that recognise a type of sugar called sialic acid. “These receptors help the immune system distinguish between self and non-self and are important in regulation of immune responses in diseases like inflammation,” molecular biologist James Paulson at the Scripps Research Institute in the US told this publication.
“The authors exploit Siglec function by attaching sialic acids to nanoparticles that exploit the function of Siglecs and control inflammation,” he added.
The sialic acid ligands do not elicit the necessary response on their own, but do so only when conjugated to a nanoparticle.
“Macrophages try to gobble up the nanoparticles and remove them from circulation, so we are getting a targeting effect using the nanoparticle that you couldn’t get with a soluble antibody,” said Scott.
Translation is key
His team saw translation as key to their strategy. “Often macromolecular drugs are very hard to translate because they are so complicated. We tried to keep it as simple as possible so it could be converted into an industrial process,” Scott said.
Cutting off the cycle of inflammation could allow sepsis but also a frequent complication called ARDS to be treated. This is where the lungs cannot provide enough oxygen for the rest of the body. Up to 25% of patients with severe sepsis develop ARDS and up to half of these patients will die.
These findings are surprising “since it had not been previously reported that engaging this siglec receptor with nanoparticles displaying the glycan (sugar) ligand would have such profound effects on inflammation,” noted Paulson.
“The usual challenges are there [regards moving to the clinic], but the novel therapeutics like this present additional manufacturing challenges and might encounter an extended regulatory approval process,” he adds.
The new drug was developed by Queens University Belfast, UK, and its efficacy in sepsis models was shown in collaboration with Trinity College Dublin, Ireland.